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1966 Some effects of lysergic acid diethylamide on visual discrimination in pigeons Daniel I. Becker Yale University
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Recommended Citation Becker, Daniel I., "Some effects of lysergic acid diethylamide on visual discrimination in pigeons" (1966). Yale Medicine Thesis Digital Library. 2386. http://elischolar.library.yale.edu/ymtdl/2386
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SOME EFFECTS OF LYSERGIC ACID DIETHYLAMIDE ON
VISUAL DISCRIMINATION IN PIGEONS
by
DANIEL 1. BECKER
A Thesis Presented to the Faculty and the Officers of the Yale University School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Medicine
September 1966 Department of Psychiatry Yale University School of Medicine
ACKNOWLEDGEMENTS
The author gratefully acknowledges his debt to Dr. James B. Appel and
Dr, Daniel X, Freedman. Dr. Appel's continual contributions of instruction, guidance and encouragement were invaluable. The experiments were conducted under his supervision In the Psychopharmacology Laboratory, Departments of
Psychiatry and Pharmacology. His influence is evident throughout this work.
Dr, Freedman provided a perspective and many helpful suggestions which greatly furthered these investigations.
Thanks also are due to Dr, Malcolm Bowers, whose generous aid and careful editing were most welcome.
This research was supported in part by USPHS Research Grants MH-03363,
MH-5942-14 and MH-5942-15 from the National Institute of Mental Health. ft’itJ*!^' a^p.9^vl,i94Kfe; -iidw ‘“lit '* ■ V.' ''.'A’ ,XCfi% ''^'^ ^“'^0 ^ '-'^''C,.; l,^»i^''f«ti^eid tabnu'' '^a . V: 'i^'v - ,/' ‘ .'iti'i'-’’*^^' * ''lifiMflMi' ^'" B*®’”' ' 1, , ' Ji ■ rT4-V^.i!f^ TABLE OF CONTENTS Page
List of Tables iv
List of Figures v
Introduction and Literature Review 1
Method
Subjects 6
Apparatus 7
Behavioral Procedure 10
Pharmacological Procedure 10
Results
Accuracy of Performance 11
Experiment I 11
Experiment II 14
Experiment III 18
The Experiments Combined 18
Dose-Response Data 18
Food Consumption 25
Discussion 30
Summary 36
References 37 diuW*.J btlio fiwsirto’uboitn'I IV
TABLES
Table 1. Average Per Cent Errors (Total Incorrect Responses Divided by Total
Responses) - Experiment I
Table 2. Average Per Cent Errors, NaCi and 20 pg LSD/kg, All Experiments
Table 3. Total Number of Pauses, All Experiments, by LSD Dose
Table A, Median Time of Pause Start and Median Pause Duration, All
Experiments, by LSD Dose 2tn^fT»h»qx3 llA ,g9l\<3ej qq CK bno iDoH v, .S «icloT ' Li Uf‘" ' ' x-i. .. .• V-*' ." ’,,• ...^L
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FIGURES
Figure 1. Flicker Control Apparatus
Figure 2. Experiment h Per Cent Errors by LSD Dose and Flicker Frequency,
Average of Six Birds
Figure 3. Experiment II: Per Cent Errors by Flicker Frequency, Average of
Three Saline Sessions for Each of the Six Birds
Figure 4. Experiment II: Per Cent Errors, Saline and Three LSD Doses, Shown
for Each Bird, Average of Six Different Flicker Frequencies
Figure 5. Experiment II: Per Cent Errors, Saline and Three LSD Doses, Shown
for Each Flicker Frequency, Average of Six Birds
Figure 6. Experiment III: Per Cent Errors by LSD Dose and Flicker Frequency,
Average of Six Birds
Figure 7. Dose-Response Measures: Rate of Response/LSD and Total Time/LSD ^ Rate of Response/NaCI Total Time/NaCi'
By LSD Dose for Each Experiment, Average of Six Birds
Figure 8. Median Pause Duration by LSD Dose, Shown for Each Experiment,
Average of Six Birds
Figure 9. Frequency of Pauses Occurring Per 2-Minute Time Interval After
Start of Experiment, Shown for Each Experiment and LSD Dose
Figure 10. Experiment II: Weight Gain Per Session by LSD Dose, Average of
Six Birds, Six Sessions Per Bird at Each Drug Dose and Eighteen
Sessions Per Bird with Saline Ifl'’"^;"v' '\, , ' .vNr^WVp»,i3,OZi yd fiior3;fn«'!).yT#^';il.tA ' > ,;;. eb'-M'S ,xf:-5. }p ,i»j80tav^.i,. ','^1 «9B^*^igkvA,.^yDn»upt»-i^ •»©>f3M'^ yd ^<>*^3.^ ,,0'f *" ' •. ^' '"■' ■ ' ^ " ’■ '* ■ 4)'': AffEra■;>'|-'■ »““ - — ■aftirIT-'V • bf»D-*’•- ©niloS-■■••'■r ^1 -8wii3,■- -J--^ ,/-T -- 'iU-".•'- -.T-w^.-- —••■^■ oi-. ■^,;,.,l\a '■VJ_.:i« - r ift.>}:>il3 tnsnsifHO x?? ?3 vgo^svA, tliJlfB H3P3 10^ ' ,„■'''' H.,,';, -4 ■ . '*"' 'I-:..C^^h. <'?^-^ . - uIy"^, nwcric ,e»epCl Q?J o^irif bno»ni|p2 v^'’oii3 Vrtt>»cnhbqx3 t/^C ©tuol^ft' f . , ,, ■• "1^- ''M . ,|1 '»■ * k’J #, V. „ ^ \ y till iiWiiKpa- '’.6_etuaii' ■i. ■'(f)' ^ i. ,'"* 'Hi ii- ibi!3 Mf2 }o 0^itn«vA , ’.,,,-^ =' Jbno q?-!\s;n°q^^ ,J'EiteM Mno<,»a-<.»Q A «U811 ^ f\r,.,)' f>r u,. 'i; «bil8 x»2 1o ©goievA ^tn©fini‘:9qx3 Hat)3 lo^ pcpO Q2J yfl jT^ tnejnl 19^x3 Hpd3 nwod2 ,9?o0 02J yd nmt4?'.uC}^»K<.o^‘oofb»M ,8'^'Migjn '< T ib>l8 xlZ W ©poi©vA ’ V I' .' mil A lo7is>lrtr,.9rrtf7 jatunfMrS g'^hiupii^O ii k:i>r’AA' 1. INTRODUCTION Experimental evidence, while often seemingly confused and contradictory, tends to confirm clinical reports that visual processes are uniquely sensitive to compounds of the general structure of lysergic acid diethylamide (LSD). Such agents have been called "hallucinogenic" or "psychotomimetic," perhaps because of bizarre visual sensations which sometimes occur in man following the ingestion of micro-quantities of drug. Neurological investigations generally report an increase in the electrical activity of visual systems with LSD, but neither the exact character nor the precise location of these effects is clear. Current knowledge of the neurophysiological effects of LSD relating to vision will be briefly outlined, beginning with the retina and progressing centrally. Jacobson and Gestring (1959) found that in 40% of cats given 50 micrograms per kilogram of d-LSD, spontaneous electrical potentials could be recorded from the eyeball which were abolished when the optic nerve was sectioned. Apter and Pfeiffer (1957) found that cats given 100 pg LSD/kg also demonstrated this effect. Schwartz and Cheney (1965a), also using cats, state that intra-peritoneal injec¬ tions of high doses of LSD produce a retinal state analogous to stimulation with light flickering at high frequencies. Apter and Pfeiffer conclude that LSD does not produce hallucinations in humans with section of the optic nerve. Jacobson and Gestring believe that the effects of LSD upon visual perception are central in origin, but Ostfeld (1961) feels that LSD in humans (75-100 pg) leads to hypoxic or toxic retinal changes. In a later paper. Krill, Alpert and Ostfeld (1963) found that LSD could indeed o1 ?{«vhu-ri?»-2 >(ji9upmu‘ s>id ?*5reie>jKnv:| iau'Siv of :''huc (Cil'J; .^fbtfntefxj^lo-fb h.iso Immisii^ «:nt }q j*bmKK:|mo;;;» ..f*', ''.V »«w«;ayi#d 2qDfbf»q 3jt^,jT,imofoHDV(2q’*' to rtsrOc'l avcx? «fn»QO fti>J'ti«5QrTi srit g''i-iwr.>!lvf+ nr O' nj luooo etniif ?T»ox»fl 'i , .^ihh !o 2'«-fittrtDtjp«'aiokm 3o >- .'Y lDohf:>r»^ i) aril n> *‘ao'>ioni no ■<''ioq:r»i yMuisn^^ 9fic®-j-q >ofl *»s*t:)oiorio foay& •tsrllte"’ 'tvd blw Iv-f^v yiivMoo srit Hflw qrttnrtlooc' ..bciilifiio xTlshu ad M;W '■••d/iv of -i •^■■: J lo yilor! no'. bno ooif»'’ imoiQO'tofnvor r'wio i;fro ofO' td ^'orn bnuol tyii'f Vv"» 0 Kna no«ionol moi^ hfirb‘,r^;n acf blun-a elolfnetoq IrnT-iilosir. .-t,';>t>nc-^fioq2 ,0?J-d motgolM laq (, onp intqA bbnoJlDaj 6vtt>n "dt nskHvv ha'tii’fJedo daid v ISwcisytjj orlt' ?tdf bftiDilmomeb osk* q/ O. i gif OOJ novio .'‘-o ■‘odt'':,nuot (K^t) itj^fb^ - -odjnt losnotiioq-oifnl ^odt alol? . qnl.iv.! o>‘ o ^ Iw.' ffiowHoc IHgi'l driw noi .tdotTiit? O'* ^u,0'J*.Hjnb a*oT2 loniJ ^i -ityubcto Gc'J kj j«job"*4pni k> .?>»»obi>pcrd dgtH r> f'.'. 1 .,„.;' tit' nJ t.'xo'tors'ouilr'ri •"’nt/boiri fon etWsb QEJ !t‘dj >V .ifd bno t*?tqA nrit forlt avai'Ud sjohtfsO brro noedoooL .csvi^o bifqo a'-if (lo. nollofc.v dtiw >nowi;H ( tc^l) b'le^fzO fud ^rdglto rt; Irytfnsci a-ro . loo*i '^.w^qu G?.J , .2oeor-dD lonil»i oixot to 5*xoqyrt at zboai (qq aonTK.id ni broabftl bluco C12J todf bnvo^ (c6i9() bla^1?0 bnc* ii'*q!A ,i9qDq ta ol c nl 2. induce hallucinations in humans without a functioning retina and decide that "LSD produces independent retinal and higher visual pathway effects. " In the visual pathways of the cat, LSD in doses of 100 to 250 pg/kg induced a general increase in tonic activity; the same effect could be produced by low frequency flickering light or changing light patterns (Schwartz and Cheney, 1965b)o One of the most consistent alterations in the visual system following LSD is depression or complete block of synaptic transmission through the lateral geniculate body, an intermediate station in the visual pathway (Bishop, Field, Hennessy and Smith, 1958; Evarts, Landau, Freygang and Marshall, 1955). This effect, however, occurs at fairly high doses; with less drug, increased cortical responsiveness to visual stimulation has been found (Brazier, 1964; Evarts, 1957). This is a significant point in that clinical and behavioral evidence also suggests that, while high doses of LSD may totally inhibit behavior, lower doses seem to produce observable perceptual changes. Even with lateral geniculate block, the cortical response to stimuli applied to the optic radiations proximal to the block is unimpaired (Evarts et al. , 1955). Whether LSD results in stimulation or depression of the visual cortex is not certain at this time. Purpura (1956), using the unanesthetized, paralyzed cat, found that LSD in doses of 2 to 30 pg/kg facilitated the primary cortical evoked potential to both visual and auditory stimuli. At doses of 40 to 60 pg/kg, depression of the auditory and continued facilitation of visual evoked potentials were found. However, in the unanesthetized rabbit, 25 to 100 pg/kg seems to produce a depression of the photic evoked response (Khazan and McCash, 1965). b'iw-O j ;v ■ I >i>; f g:; i p. i>*»:j.ubos(' b-=io SLjTOwvfyiT) V -,. . Vv' ■■ ,1.' c:n.aivs:'i«>iio JoaTiwioo t^Cirn'.jJ; ^'O s*nC . y(riSiON?f ■'i:.^ ■■ -.i ':-0 .M'iiaM' '<"'J;;2'i}Hf^ Qi2i ni ♦(ufU.-b ©fp‘ban>if-v-?i np ^ .bxi .^ir*'f , ^/'-i'-?' .-, .v!i-'I ■-■>r:,'-n. '/riD DfTbi. v; '; ,^j-.-l'rtoJ , jC'Silio^' b,s:'..ciy'>:i.n ill/, vtiit'f ■(-• ^tw^r.c , ic . .r'S'--'i .jf MJv j ‘■l*6^.( ,lJ''5U'f : O'liyji: ,>C.‘i n;ylti3!ur^5i;.g tPi,«IV 0:| *'«■■■',»Vft'ooqio I ijzl,., 'fD:?';^bW'j f.-'-oivortiji L .; •i'.r'Ir,. t-■ (cf!^ aj. tM O'* ca^C'l. ■.•■■'.\‘K ' j •?civr')'!»j'J ■tk.i’iir,! s;!*' ■ '. 'vrv/fi Q^J vo ir-vu 5»^+1 !^3 -. • ■■ i.iXQi’/3) bi.,^iy\lO'U "swri K»^-^ h^-u; . ■ ■ i-:. i*. r;, -'-vitof../r,;,,, Cl2J^ ,1ao firi ,b^?:,,’M0-.b.:3,,o.iU oni.ja I, bo iovfjjk. ..vb uwiDi C: Aqy 0£ C? S A Qej frr ^ sii‘'‘^''',^i‘o,Qc -.* v/^ b t^/oc '(.A b'rjffkb' yto-.ii’Jito ‘otjii’v ot tw.tjiv'*-.’.,'’ si'Ofb&’'->!o‘''3 bu.'' I '.’ :'JCt*KaC‘i k*j»-.‘wi'/ro'i' i.Y‘H3!ib ;>.* *••■'? ■■■ 001-p’riCi , ti ■ H-’f'Jol^'/S ^fip^fjk.:,.on/j) ::■> ^ h'l t: In C i'',1 'UOli.'} --'vr ;V. 3. Khazan and McCash also found that 25-100 jjg LSD/kg produce a shift of the EEG to the alert pattern in rabbits, a finding which others have also reported in other animals, including man (Brazier, 1964; Bradley and Elkes, 1957), However, Purpura (1957) cautions that this may actually be the result of activation of inhibitory synapses; this activity may simulate the alerting response when viewed from the cortex. Evarts, in a 1957 review, notes that in 7 out of 10 humans tested, LSD administration resulted in increased photic driving of the EEG, and in 5 out of these 7, irradiation of the photic response to the frontal region was recorded. To summarize, then, LSD produces electrical changes in the visual system which seem to imply that some type or types (excitatory or inhibitory) of activity increases. The relationships between these changes and the behavioral effects of the drug are at present speculative, Behaviorally, LSD produces some consistent effects which can be noted. Transient interruption of responding ("pausing") has been observed in rats (Appel and Freedman, 1964; Liberson, Ellen, Schwartz, Wilson and Gagnon, 1962; Olds and Olds, 1964; Ray, 1965), guinea pigs (Liberson et al, , 1962), pigeons (Berryman, Jarvik and Nevin, 1962) and rabbits (McGaugh, de Baran and Longo, 1963). The tasks involved included responding for food on simple schedules of reinforcement, hypothalamic self-stimulation, approach behavior and complex discrimination learning (matching to sample). Similarly, depression or lowering of response rate has been seen in monkeys (Jarvik and Chorover, 1960), rats (Jarrard, 1963; Ray, 1965), humans (Ostfeld, 1961) and pigeons (Blough, 1957a). As would be expected, increase in reaction time is another common finding ®^ p\Qci:-'^»](? 64‘f j|ho yo'f i,/. '^'VL ■ ■ noinjvi^6p.:W. tii/^si is»fit Iwlt ; .,.;4^- 4r,!¥. ;; ,f „ ", r ■ •'iS ’■ ,._— ... 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"■I- ’W'^ md'hy2 touify artf nJ •Ri>iT»afi'f«» 293ufco-8q <35J vf^fW,> 83rh© loiDivorfsd ^f{t btiD eogooHj soarlt rteawHd icjlt’lwoi'tbbi *idT ^':wet«T>nJ nl^ ,■ »)(>{' . dy|?o}uD»c;^ ln©ti»iq to tns> Quib sHt ■f3 '^■ *b3>cwi od bo'j rt-JiWw amp? vS[i'l*iDi4l\/oitad < fc i xioi nii'bav jaacfo oaad gori ("^ijilcgpq'M Qrttb«oq»«r, k>i^<^;i1 ^(Sb9r ^ eglq 4?aoiu9 ,(e.A9f ^yofl yjblO bno ablQ | '^■>- ; > ' ''S‘^; ' U bo© ooiDfl ofo ^ligtroO^M) jtlddor bon (£p9f .otvaM bob'>l*Viiot ^ootTf^Ti^) l^ooc^{c^ <0 / &i H '•’alqffiia no booi ijrt’fenbq^si babolonf b«vlov/ir?,yiOf adt .lOo/vTi ■.:"■■ . * W ■ 'i .H,:: ' «aj ?*" '•oWofl jd rlobOTqqo ^ ooHotumfU'-'^fce olmoiodtoqy Oo»e«>iQt»b .{alqirvoa o1 enMptpm) gOM^Por ooitbolmi'iioefb'xolqfrtcso bno t ■ ■ .-ft' •' *“ ^ ^ , ■ ' ,J. ^ ® . ' ■ ,.4 ,{OA9f .i-’tavo^ofOfeOft' d jv'iot:} eyadncm nl'ogfp? nsi»d and aloiioanocNwi k> goheyvoi io ^ i^Sil ^ ^ ' ->^ S' .,- Hr' “SR(I , tvd^tfpi^j zdtomih bon (jt^ l ;td9t '\b‘ionibt).j^ctot .•:!» li • <■■ eo^boH nofWrto® wtoo^l '8mi4inoffj>r)8i''o; tfvv ' %■ ./'• ' ' ~'SM&. -V. ■ T.ir'u ^^-ir ‘ v'"' 4. with LSD (Berryman et aL , 1962; Edwards and Cohen, 1961; Faster, 1957,1959), Tolerance to the behavioral effects of LSD has also been investigated (Freedman, Appel, Hartman and Molliver, 1964). The fact that daily LSD administration leads to decreased food intake in rats (Hamilton and WiIpizeski, 1961), and that performance under LSD is increased with extra food deprivation (Mi Itzer, 1965) suggests that food may lose some of its reinforcement value under LSD; yet Jarrard (1963) found that 50 pg/kg in rats led to increased bar-pressing for food on certain schedules (VI). In experiments involving escape from shock, Hamilton (1960) reports that LSD increased the speed of running in the rat. He also found that LSD produced a higher percentage of avoidance in a conditioned avoidance situation; however, Appel (1965) found no such effect of LSD upon an unconditioned or conditioned escape wheel-turning response. Perceptual changes following LSD administration include increase in the visual threshold in humans (Carlson, 1958) and pigeons (Blough, 1957b) and changes in the dark adaptation curve in humans (Ostfeld, 1961). Peterson (1966) found that an increase in the apparent brightness of a visual stimulus occurred in monkeys given LSD. He also states that the shape of the visual discrimination curve was altered. Key (1961, 1964) also found that LSD produced an increase in auditory and visual stimulus genera I izatbn. The results regarding the effects of LSD upon accuracy as opposed to rate of performance are equivocal. The drug impaired monkeys' performance of a delayed alternation task (Jarvik and Chorover, 1960) and visual discriminations (Foster, 1957,1959), but no change in accuracy was noted in auditory boo ^b'lDswfcS ,S69? ^ Jo tg ^10!T>^^^^aQ) Q^J fJjUv . norr^is-a.Tj J) bsiogrh^avnl nsgd oglo £.oH Ic Io-.oiyoJ.ijJl o? j ^ Hrvdl-.'f'i boo rtoml'n':!-! Jg^soA n\ sdotn! foocJ b-'.ar'o'loab q-\ v'OdsI naHoiji::ni.:nbc OcJ vJ'itjb- forlt toiJ o-.’' beco;ii:.'rft ?.l C'?J j eD~orrno’':ooq -fojt brio . (J,W*, iJ?b'5::qi(W bob nbtjT".’i; • :< \f ■;»■•'• OO'.''' Oyi'. (c-J^ • . O-.V',. ■''*! .--, ■ i JjtJ’ OC'Ct ; ■■ Oc cnufJ iGc^f) *!. ’.’ < :.. go: r,l. ■ )'J b'j'''-^-y 1 .q nl ' !V) ' 'iu>'T5G opv ■* ly-b^'-•.•■ 1.': ■; ‘XA ' >vv>ri; ,,■ i-,.i ,ir.^ GitJ irdr^iK^j fiotiiGjcH J'vG -Gv ^'Oivi-C'/Of ..-y ■:■ baouboiq 02J 7001 bnucJ o^J:' 'iH , tO'! fG -r .,: ^ .,■' 'Q bfj'aqg 3m -■stfOi.Tij'. , ■!3V9WcH q-lGi v:;v.-Gi , ■. \ .-b'C /O b/:(OOib 'ba<’';' •"-/■ ' ■ GG; '. : v:: ig. .pov , , > -q . / ' y .1 bsoGitibRoq »o bonoJ br-'-'/Ow :\r. ncqu -J C .1 ’ ■ ^ -J ..{ ■ -'-'I g.g ■' Gi^qcA ■yii) i'viv li/c..'vv.- ■s;q”0(f? •:.*fi-i n: Si^ogiiDni abuior;' loi'o ffrDO Ud. . p/t IVt ■ ■ ■ ' ■ ''W^ • 1 • ,! ^ ■>i.C(io bou , ■ r^j': i5 ■; . br.b ■ ' b'-- ■ o bpuq-',- bnup^ (db9[) riOiTGtijb . J -■• .. . V'jli O i ij > 1 w-' J ^ s ‘w-G . 07 q OG • 1 b gH "i ' ’ •ni bivr'noo -o'b.o 'v G ’o : , ,)vr, ! r- 1 ^ t . . •:• ■ • ' v»aP:y3f(! or 7... ■' J. » 1* ':cjiK‘qiob7a.!"b i'. • .J; fc i-GPrb S i ,■.•ki•■^ Oic'o. f; j •;' ? C 3 10 0 ' O b a '.• 'J i>o < q ' J b j : n - ’ i f- ■ ?' - »- ^ , ^ . V f;. / b /, . b'o .V '.Gp : . • •iVijr-* *oct.'.iv hf: : bto-i boao.vqo ?.o yooildod r '■q^ CiiJ ?o ^^■ .b' ^ i ■ O ^'O eooC'iiTjo't I'lq ‘ • ,^.v sOG.'!' b^J'l^t.^£•.-li ^.o’fb ij>r f J Gv'Ovj;-v aio gDri:', ' .'’G^ini^.3-^lb v hoo 'bb9'! _ I' .;- - .:^..-X' rCf^c-'ii'S'* ..'bs/.>U.r’ \'»0'.fbu0 r:' G j'l ■ rT> •■•' (bZO\jZ-0X‘ .i'- fepncj ' fg 1 ^VrJ-'I j'rC*'. 5. discrimination in cats (Key, 1961) or in matching behavior in the pigeon (Berryman, et aL , 1962), Finally, Blough (1957a) found an increase in accuracy of complex brightness discrimination in pigeons, an effect which outlasted the depression of response rate which followed drug administration. Thus, LSD yields depression of response rate and transient interruption of responding as two general effects. The effects of LSD on running behavior (escape and avoidance) and accuracy of performance of a learned task are not nearly as clear. Following Blough, the experiments to be described investigate a visual discrimination using the pigeon as the experimental subject. Relationships between LSD dose and accuracy of performance, depression of response rate and inter¬ ruption of responding will be demonstrated. Since the period of experimentation was to last almost a year, the development of long-term tolerance to LSD might also be shown, and the effect of LSD on food consumption assessed. The task chosen was designed so that the difficulty involved was primarily "perceptual, " The pigeons were well-trained prior to drug administration and a minimum of "problem-solving" was needed for the bird to make the correct response. The discrimination was between flickering and steady light; the task difficulty could be altered by increasing the frequency of the flickering light. It is apparent that, as the flicker frequency is increased, a point will be reached at which the flickering light appears steady. This is the critical flicker frequency (CFF), a phenomenon which has been extensively investigated. It should be noted that in the present study CFF values were not specifically relevant; 6. CFF of the flickering light only means that the discrimination between flicker and steady has become impossible. Nevertheless, it is of interest that depressants of the CFF include barbiturates (Aiba, 1959), phenothiazines (Hoehn-Saric, Bacon and Gross, 1964; Karp and Pollack, 1963; Lloyd and Newbrough, 1964), nitrous oxide (Holland and Gooch, 1962), carbon monoxide (von Post-Lingen, 1964), electroconvulsive therapy (Mowbray, 1961) and brain damage (Taravella and Clark, 1963). Depression of the critical flicker frequency means, in these studies, that subjects discriminate between flicker and steady less well, while elevation of the CFF implies a better discrimination. Although the results of two recent experiments are contradictory (Holliday, Hall and Sharpley, 1965; Landis and Clausen, 1954) there is reason to believe that LSD should elevate the CFF. Two drugs related in some ways to LSD - d-amphetamine (Aiba, 1959) and psilocybin (Keeler, 1963) - both elevate this perceptual measure. Psilocybin is both chemically and clinically analogous to LSD, producing much of the same hallucinatory experiences and classed as a "psychotomimetic. " Amphetamine yields some behavioral changes similar to those of LSD (Hamilton, 1960) and clinically, large, prolonged doses of amphetamine may also be "psychotomimetic. " METHOD Subjects: Six male White Carneaux pigeons, three months old, obtained from Palmetto Pigeon Plant, Sumter, S.C. , were permitted to eat ad. lib. for five days in individual home cages, and a free-feeding weight was obtained for each bird. The pigeons were then reduced to 80% of this weight by feeding 5 grams daily of a mixture of 40% vetch, 50% Kaffir corn and 10% hemp seed. This was ™^,,. . ^3W-' ’''^.¥^ ^MAjiif>.iA ■ ■ ■ 5v,.*'^, . :''w fihyihfi»'1» ""■'Jl'';, '■ '. ■ / ^\‘l . ,;j; ' , -.' ’'’5«1J /, *'■ ' «yfaJuv' i£L •"■'li a nf'b ^ ' '' ® y I bho ylU.'j'mojio titob i? .4ia^oem ioihq«ai<|tq ef/H atovolf rhod i?«pfiOiwq>;9 Y'^toAiabllofVfibi^^a^ to rioum gn^«hotlft ,024 jtyo^(i»io'\lfooift{b ■'iv ' ■" ^' ' ' " v^' ' • C ^lagficHp tmt>iyiortad <#wjoe ebUfy artlmoto*lqwA **. ofiAff4 'M fel/jV:'".'.' 'V: 1.''■(■■' ■' . ■!■ * •*' rnoit btfnlotiyo ,blo>btr>onr» 09tHf ;^!ty'»O!*i^f^ iwosrKoO oil .1? w low iiiifi k) ititrtxiw o to 7. the food mixture used throughout the entire period of study. Birds were maintained at 80% free-feeding weight by supplementary feeding in their home cages immediately following an experimental session. Water was always available in home cages which were housed in a room of constant temperature and humidity with a 12 hour light-dark cycle. Apparatus; The experimental box was a modified version of that described by Ferster and Skinner (1957). Two keys which could be transiIluminated were placed two inches apart and equidistant from the food magazine. When the magazine was opened to make food available to the birds a loud click occurred and the food was illuminated by a small light bulb placed high in the magazine structure. White noise was generated in the box to remove the distraction of external sound in the lab. The small house lights were gradually dimmed and finally extinguished before actual testing was begun, so that the only Illumination in the box was provided by lights behind the translucent keys. Two lights behind each key. General Electric Neon NE 51, were connected in parallel to the output of a tachistoscopic timer (R.C. Gunter Associates, Charlton, Mass.) which was driven by a square-wave stimulator (Bio-Electronic Laboratory, Div, of TALCO Engineering Co. , Inc. , Hamden, Conn.). The purpose of the above apparatus was to provide a controlled source of flickering light. The intensity and duration of the on phase were regulated by controls on the tachistoscopic timer. The frequency of the flicker, that is, the number of on pulses per second, was controlled by the square-wave stimulator. The intensity of the lights was maintained at a constant level throughout all experiments. In addition, for practical reasons, the duration of the on phase. 8. i.e. , the pulse width, was kept at 4 milliseconds. The flicker frequency was varied as will be described below. It is apparent then, that as the frequency of flicker was increased, the total on time of the lights was increased also. For example, at a flicker of 30 cycles per second, the lights are on for 30 x 4 msec, or 120 msec, per second. At a flicker of 50 cps the on time is 200 msec./sec. Thus a discrimination between two flicker frequencies may involve the number of on pulses per second, the duration of the on phase or both. The advantage of using this type of task is that its difficulty can be easily and continuously varied by adjusting the flicker frequencies of the stimuli which are to be discriminated. In practice, the pigeons were required to discriminate between a flickering and a "steady" light. (Actually, a flicker of 100 cps was used for the "steady" condition.) The lights behind both keys were operated together. When the lights were "steady," only pecks on the left key in the box were rewarded. At randomized, preset intervals, the condition was switched to "flicker." The lights then flickered at the desired frequency for the specific day's run, and only pecks on the right key were rewarded. (See Fig. 1.) The average length of each flicker or steady interval was 40 seconds. The various conditions were programmed automatically by relay and timing circuits located in an adjoining room. Counters recorded responses on each key for both flickering and steady intervals. Two cumulative recorders were also used, one for correct responses (left key pecks on "steady," right key pecks on "flicker") and one recorder for errors. ■' ■" ''^1 'if- ■ . lOTl ^ .« ■ ,5DVV ycjnoop*'!^ ^ 10. £t>w v.'^tfe'i'v/UsllK'} \ ‘fO-^, ,'0 .;:>!.aiM ^ x'p^^ lolf noy*o rfrloJ} 3«^'l ^h'.!o.:>'i£ t?>q ^3lp^(p Ot i>'^o ^alcrnoxtr* , ,09?'\,. po ^sW't eq.',* Oc Jo TJj^yfl’V » {.A .br^oDa/.'I'bcJ' ..sorm ft; • ^ ■ ^ ^ ' \ tj • k' ■ ' , ■ . ■ *o ‘f^dir^uff,sd^^tsvl jvi-rj, y!)^1 ft'ipAStuoft-tt ow'f 'n??i3iv4't'?ri ■. ■' 'nM.iiJiOitifa o auHT , , J ‘0 t#n'T' dic/d ny a^jiad.A no ^>ii^ ,no*^oojib v'sdl -bfi'" .:j.' no bs'r.fjv, '.liop !>i>o o*d no"/ yi|ijr>ff-i)r 2i( fcwf? ’>o aq'-;i aiif* jv.ii^u ■ befr'-r7tr •,'i‘''J'f D n.s,-d o)i.>''’»i/rft'»a.3!ii.’ biwiupwt-t&iovv s •,;? 5t , Qpll'joriq rJ "ybcat/f’' 5»di ba^u ^o•v .2(.p 0}( !.• I * M' .y a-ji/t:jA| "yboftid" c bau ofit r*s.i V b'3''tOioC' ir: ,' t'!i'kJ. brndtij »n’T ■ ■■ ■>■' tA } •‘b':'v/"j. aisA'xo'f t:iA'* ■■■, y&d ‘i'.>' •,>»'! ■ -■ '.dnc .Vbo*»)*“ rti'H’ ' , 1I»>1 ,>i!| ' 0-! bZC-.' /■’C'i'iitjrOO' .'dl , --il ■•^'•~ ,'.-^S'fTK'.bf'Cd sdoaq yd'* ' dnc ,ou> ? yj-lt -vb .»o'} v-^;'-■h■..;‘•,^: .^rfl ;o osdt ' dobe V ntpn^l iSoo-iavo on"^ • . ^ hP ->^2) .b-d. -aiet'.'. • '■;iu?-» Cidl no ^ ' ■*■ , " y ^onooi e 0.?’ -y , 'ip1ni''ybo-:'1a Tfl (.'.nifT.i !, !.rno yoiol yd ^ir. oitamcv-r'bnrr.mo'ipoiq ji*// /no!■<'.!■:■;■);>:*-' . ./oi'u; • ■’•b'f'' ■ ■ „ , ' ■.'/i' YaM n">0''3 '10 5»3noqi'«'» biferLOsi i'^pvnv.ioJ .rT"‘vo'’ r i’nl'i'l.-'O 'icl irv .■.>/,.; -.-i.fv^aiip',' '; ■i/'b '.^tr-' /•i*rbiooSi .--i {slo/nO'-' 0‘*'' .'•'\i ..-.f'. '’ '■o •^y.''\.', no' ’'^^'rr^q '{g.J ' .•/■febd'**'" ( ■'• V‘!-Vj'i!q 'd'‘-’1^ :o,'.’ii,*urt‘'! ■'o'. rA .■9nc- .bofew ■"'’■VyY'V^ ' ' '' ■ . ' , /■ :''V I'V ...lot'p'tp^ i‘.'b . i» iirf’ip |jno ('^'nAal,: f :V‘ • ' fi.K Figure 1. Flicker Control Apparatus Lights — Tachistoscopic Timer Stimulator constant variable flicker 100 cps adjustment Left ; J^ight f-switch "Randomizer," control ling switch When switch is at "Left," lights are "steady," left key is "correct," that is, pecks on the left key are rewarded. (See text.) Figure 1 t J , > L-y 10. Behavioral Procedure; Since the birds were experimentally naive, a period of approximately five weeks was necessary for training. After being taught to eat food from the magazine, the pigeons learned to peck at the keys to obtain food. At this time, each peck was reinforced (CRF); later larger numbers of responses were required to obtain a reinforcement (fixed-ratio or FR). Finally, the birds were required to discriminate so that only "correct" pecks brought reinforcement. Three experiments were run during the period July, 1965 to May, 1966. Throughout all experiments the number of correct responses necessary to obtain a reinforcement was 35 (FR35). The magazine was open and food was available for 3 seconds at each reinforcement. All experimental runs were terminated automatically as soon as 60 reinforcements were given. For the first experiment, the discriminations 30 cps vs steady, 50 cps vs steady and 70 cps vs steady were run. Experiment II was identical in all details except that flicker levels of 50, 55, 58, 62, 66 and 71 cps were employed; Experiment III investigated discrim¬ inations of 10, 20 and 30 cps vs steady. Pharmacological Procedure: LSD in ampules of 0. 1 mg/ml was obtained from Sandoz Pharmaceuticals, Hanover, N. j. The drug was administered in doses of 20 micrograms per kilogram, 40 pg/kg and 80 pg/kg to each bird at each flicker level. Each LSD day was preceded by a physiological saline control day run at the same flicker frequency and followed by a non-injection control day. Thus in the first experiment there were nine different 3-day runs for each of the six pigeons, one at each dose level for each flicker level. All saline and LSD doses were administered by intra-muscular (IM) injections approximately 1 cm lateral to the sternum, immediately before the start of the experimental session. ■'/ I I ■ ^ I 11. The order of presentation of flicker cycle frequencies and drug dose levels for all experiments was determined by a Latin square design. RESULTS The accuracy of each pigeon's visual discrimination was assessed by dividing the number of incorrect responses per session (x 100) by the total number of responses emitted during the session, thus obtaining a per cent errors score. The effects of LSD upon accuracy of the visual discrimination will be considered first; other dose-response data will follow. EXPERIMENT I: A major purpose of this experiment was to explore the range of flicker frequencies the pigeon can discriminate from "steady" under the experimental conditions. To accomplish this, flicker frequencies of 30, 50 and 70 cycles per second were used. Performance under LSD was always compared to the bird's performance on the identical task run the day before under NaCl. Reference to Fig. 2 shows that LSD at all three dose levels increased the accuracy of the discrimination 30 cps vs steady light. This increase in accuracy was not, however, statistically significant (t-test for differences, p<.20). Fig. 2 also reveals that the birds do worse on the 70 cps vs steady discrimination than they do on either the 30 or the 50 cps vs steady discrimination. Table 1 shows the average error data obtained. Each value represents the average per cent errors (total incorrect responses divided by total responses) for 18 experimental sessions (one session per bird at each of the three LSD dose levels times six birds). These data suggested that the range between 50 and 70 cycles per second flicker would be worth exploring. ■/ 12. Figure 2. Experiment I: Per Cent Errors by LSD Dose and Flicker Frequency, Average of Six Birds FLICKER FREQUENCY (cycles/sec) SdOdH3 lN33H3d 13. Table 1 AVERAGE PER CENT ERRORS - EXPERIMENT F Hcker Frequency Nad LSD 30 cps 5.9 3.5 50 cps 8.7 8.9 70 cps 49.4 51. 1 ^Each figure represents the average for 18 experimental sessions. 14, EXPERIMENT Ih Six closely spaced levels of flicker frequency were used: 50, 55, 58, 62, 66 and 71 cps; drug doses, as before, were 20, 40 and 80 pg LSD/kg. In order to determine the degree of covariance of increasing drug dose and increasing task difficulty (increased flicker frequency) with respect to errors, a Wilcoxon^^. interaction test (Wilcoxon, 1949) was performed; the degree of interaction was not significant ^<. 12), The effect of increased flicker frequency upon errors is shown in Fig, 3. The regular increase in errors manifested by the S-shaped function is significant by the Wilcoxonrank test (p<,001). The effect of LSD upon accuracy of discrimination was examined from two approaches. Fig, 4 shows the average errors at all flicker levels combined, for each bird at each drug dose. Twenty pg LSD/kg reduced average errors for five of the six birds; eighty pg/kg increased errors for five of the six birds, T-tests for differences were performed in both the above cases but were not significant (p<,20). Figure 5 shows average errors combined for all birds, at each flicker frequency and each drug dose. It is evident that at each flicker level, 20 pg LSD/kg reduced the birds' average errors. The t-test for differences is significant here at p<.02. Eighty pg/kg raised errors at five out of six flicker levels but this effect was not significant (p<. 12). The major conclusions of this experiment regarding errors are: 1, As flicker frequency is increased, accuracy of visual discrimination between flickering and steady light decreases (p<.001). 2. 20 pg LSD/kg significantly improves visual discrimination in the flicker frequency range between 50 and 71 cps (p<.02). :|j TM3;>Ai5)3«!X3 ■ 66 ,£6 /StjL ^0£ rb,w»eu yo/isup^ii'^ isjIoIM )c AbvuI btor.'q.i ylsiola xiS o1 r-9b-jo nl -eACidJ ©H 08 b^D 0^ ,0$ 5i3W .O’iO^Oc! ?.V ^i©;;Ob ©Olb ;2qD bno ymeoaTa-ni bno a^ob gutb ©nleaaiont ‘;o a.'^fiDhuvoo "lo erft anjrmalob “ < noxoc?iiW D ^5iOT»si ot / (Dnsapai} la.jfil!) b-.,;:;? :>«!) ytluaRnb Ion iow nojlbrrjsir.i V.> gangab sr'if \b£tfninf-oa eow ,r,oxc?oIl;of noilODiatni . ^ (?vf . >rf tn£>Dnirt|:'i? .0 .^i'l n: . voib 41 £>0113 noqu ^rsnaupst^ b^isotf-om ^ *oa^>3 »dlT rnooi^tngli ?( nottpnul b'pqorl?-? pHi ;■ ,( > ■ n >40f-)ip.nl iriugav^HT I ' .(fOO.'q) ,'rfr7-. ^^.lOXOoliW ^fll QW' l ioil brjoimnx*. 4;>’.v noitonininoeib Vo yoDiuPoo .'io,n>j G?J Vo sr!T icV ^b^nidmoo ilpvol >diioiil lio tc fn'iia '*£0i9vd ^r>i lo] e^ovia 3^Di9vo beovbai g>i\0dJ gi^ y1ny.vT .o^ob r^uib ri:>Oi> I0 buld rloDo ■ ' ?biici xie “(Hi Ovii lO’ boSP-^tPiij DA/aq y}r'i;;;tO xt? sHt Vo <0^ . 'pi toDol^'.'i^ie 1(jo aioyi' toJ 9.>odr‘ rirll Hiod ni boi'm^-lioq oiaw ssoodialVfbi yoT'''irp-;^ laxoiil Hot>o 10 ^ebitd llo toi b&ni-rjfnoo rfjois*VD jr'vcvHi £ 1 r-\^dJ Dq 0\ Javol ta>j‘pir‘ (bo,-( n> ♦'•rit tr,-*LIvo 4i ii xeeb rooe bno JO j»-5oriT .47o»'3'oqoi.jvO 'ebad aHl baoubai ioslV; z'Hi ;ud iiovol isNoilV xh Vo I1.0 ovit to no-'o t'paioT p> pq yrHc‘3 .J0.>q .!!?f .'’^} tnc. fVirtj.H2 loo aow ^ :aiD 410116 QrtibiOQOi 106X1 laqx? eiHt Vo ?ni‘i;uio!'•■>'> lejofn 6r?T lou?iv Vo ^Doio'joo ^b6406'JDni. ci yo(i6up6jV lei-ioir; .:A .• .{f00.>q) eozPoiosb logfl yboota bno j-n»iQ>jDin ne^wled no.tc (irphoeib aHt ni nc}lort‘rnn:>i.fh |cu2lv ssvoiom' yllntJoiVifigii gV'yCidJ n.- CS S .(S!0.'>q) ?qp {'" bno Od .latj'viad sgopi yon« .paiV 15. gure 3. Experiment II; Per Cent Errors by Flicker Frequency, Average of Three Saline Sessions for Each of the Six Birds 40 35 if) 30 (T O on CC LJ 25 z: u o cr 20 LJ Q. 15 10 5 \I I_I_I_L. 50 55 58 62 66 71 FLICKER FREQUENCY (cycles/sec) 16. gure 4. Experiment Ih Per Cent Errors, Saline and Three LSD Doses, Shown for Each Bird, Average of Six Different Flicker Frequencies BIRD NUMBER AVG. 27YF 28YF 24YF 25YF 23YF 25YF 26YF AVG. 28YF 26YF 27YF AVG. 24YF 23YF 26YF 24YF 28YF 27YF 25YF 23YF 10 y77777777777777777777777)7777X \r77777777777777777777A XZZZZZZZZZZZZZZZZZZZZZZZZZZ2 V7777T77Z777Z7Z: 7ZZZZZZZ22ZZZI 7777777777277 27777277777777\ :77777777777-777777777?7777777777777777777777777777k T7777777777777777777y77777777772 7777777777777777777)7^ 7777777777777777777777777777777777777777777772 ZZ2ZZZZZ2ZZZI 777777777777/7777777777777777)7777777^ V77777777777777777777Z- 7277-7777777777777777777777771- 'ZZj^^////77777777777y/////77///7777777Z2!: V7777777777777777777777/7777A 77777777777777777777/7777/77777772' 77777777777777777777777777: 777777777^77777777777772 20 1 PERCENT ERRORS 20 /i.g/kg 80 /xg/kg 40 /xg/kg EZZZJ LSD 2 NgCI 40 ^YTS i. m BT '. Hrss HP" niurt uniAiRPu Or** .9VA ■■.. Jh.y- ^YCS ^‘7> 'i^f'- ^Y^S , * •■' f 4 .ff ' ^Yes '• f'‘ ... •i • • • w r'S-i*' ' ;■* T- ivas m ■•iJ* D" kC: 5SSS^ ‘..iiIE^‘ I —i'kii, »l t <11 ^ '=iY8s*:.'d I, e OS 0^^ os: V, .fy’.Af ■' '."A ^ k ■i,.!fi,iy "'?i»i-j ■■ 17. Figure 5. Experiment 11: Per Cent Errors, Saline and Three LSD Doses, Shown for Each Flicker Frequency, Average of Six Birds 20 fig/kg 40 ftg/kg 80 /x.g/kg o SdOddB lN30d3d o FLICKER FREQUENCY (cycles/sec) 18. 3o A disruptive effect of 80 pg LSD/kg upon visual discrimination is suggested by the above data (p<. 12). EXPERIMENT III: The increased accuracy of the birds on the 30 cycles per second discrimination found at all drug doses in Experiment 1 prompted a further investigation of the area of the "easy" discrimination. For this experiment, flicker levels of 10, 20 and 30 cps were used. Fig. 6 demonstrates no major effect of LSD on errors, although at both 20 and 30 cps, 20 pg/kg improved performance. The lack of a clear-cut effect can perhaps be ascribed to the fact that the task was too easy, i.e. , there was not much room for improvement, THE EXPERIMENTS COMBINED The most interesting result of the three experiments with regard to errors was the effect of 20 pg LSD/kg. These data are shown in Table 2, At nine of the eleven flicker level runs in the three experiments, LSD at this dose improved accuracy on the visual discrimination. The t-test for differences is significant (p<.05). DOSE-RESPONSE DATA The dose-response results were similar for all three experiments and will be considered together. Occasionally at the 20 pg/kg dose level, and often at the higher levels, the bird would stop responding altogether and remain immobile in the experimental box. This is the typical response to LSD shown by animals on FR schedules (Freedman et al. , 1964). The parameters of these "pauses" are discussed in the following section. Here, however, it is to be noted that two measures of time in the session can be obtained. One is total time in the experimental box ^ ■ ■' ■>'"^'V!^- ; .j, .„ :cu2iv‘r(9q. I gj)'' 0?i gu 03 1o O'/itqaT^ib ^ 0 / .(!^.; .,i^''q) ctob '/d <'( noiloniftin^aib ■ :>(i' ; ,y* *■ ' in TM3MIH3 bnoct.' viitq OL arlt no atnid *?;i> lo o 1, jtqr,«;»■;.q f tnDrni'i'iqx^ oi eoiob ^^U'lb h-o !;:• bnuc^ no'iionlmnDjib ^-ir.fafn'■oqv,;' i-'/-'. ?;0( iWii.T,nq?tb " obi ♦c oo’fO uni ^ • 'li'yvui •-ojofii cf! ;-■i'r.'r'.'ito:'-';*;?’..-V .gf'f .bocc -QO 0'^ bno 0£ ^0* <9 ' - ■.'■in Oti’- cocimi O'i , aqo Oi-' bo.~ OS. fifod ^ no Gc io 'Vt'.no «i»r{t oi b'3di>*?o sqo. qjq noo ■"> !o >.'11 oonoftno1“-oq ■ •■'‘■■n&vo'iq'n* T; tofi 2uw o'jorll , ..i o.'f .'rvA' .-I-' * orb iodl too' •j ■■ ■•TiM/Ali^3'lX3 3HT ..'•OV!- Ol biopo ib.v (‘obf -.il lo HT 'Ml lo cinin lA aldoT »■*'< owo - jio v'^h ;■,. •'''s h^ tofi^ir. ■^rit !’&voK3rfii oc.i'^ .'ifii !i'i 0 nroil’nDf' ?' Htb iwl (:«b7 -►oils-v'i i.-iin-ib :v.ii .ir*y^-,u'OC ‘ ^CL'.>q) AiAo 3eLi09?3P.-3e '^0 '».J !llvv brio ?1n;Mniionxft ■a^.-Mii |lo ^ :nliiv>*(; "'^v/ -Mi.':'?' -r•flT ■■•i ' to naitc bro ^laval 3.’t/’.j .■•.o O'". :• •' i'rKio.rocoO «. ^ 01 i. I ;domtT^j r.iciitji bou Tfori'rjrollo gnibi'vqeoT qon b^L/Ov.’b id sbi ^ibovol .sHqlri \ei nsvoHa C32J o1 «4f oq^^n lrj;q'< .>dt (ji jfViT ini-c si. t'^qA.'' a/t1 f)iD ' r'v^-joq" ajot’’ t -* ;-->'nDif*cj -.>b i , .io ViinjL.-v;i i rolobo/tdi T V ’ ' ' . ^ ' -• .^v* .t'H'.'OO;- ■>/! ior]-f b-’■'j r>' fi ?< ^-.ov-^wob .rr-i *.o** gni w 'I-., qdf ni s., . ■ ^^.!ii*jj^^||i.ocl 1 • ■lnomitaqxir oWf (N: oi'fli'f lOiOt ii anO .b^loid'’' •■;■': rt.^ nniistn otU ni cMlI !l 19. Figure 6. Experiment III: Per Cent Errors by LSD Dose and Flicker Frequency, Average of Six Birds 20 /i.g/kg 40 /tg/kg SUOUUl lN30d3d O Csi O ro o FLICKER FREQUENCY (cycles/sec) 20. Table 2 PER CENT ERRORS, NaCI vs 20 jjg LSD/kg, AVERAGED OVER 6 BIRDS Flicker frequency Nad 20 fjg LSD/kg (cps) EXP. I 30 5.9 3.2 50 11.9 8.5 70 46.1 50.8 EXP. II 50 7. 1 5.1 55 16.9 8.6 58 23.1 16.2 62 34.6 28.9 66 39.1 39.0 71 43.7 39.2 EXP. Ill 10 7.3 8.0 20 3.1 3.0 30 8.3 4.4 21. required for the pigeon to complete the task of obtaining 60 reinforcements. This figure would take pause time into consideration. The other measure is running rate, computed by dividing total responses per session (including errors) by running time (total time minus pause time). The rate measure reflects the fact that a bird working at a difficult task might make more errors and therefore take longer to obtain 60 reinforcements than a bird working at an easy task. Also, if pause time were influenced by difficulty of the task (which, in fact, it is not) running rate would correct for that factor. The dose-response curves for the two measures are shown in Fig. 7. Total time per drug session is divided by total time in the NaCi session the day before. At all dose levels, as shown, the quotient is greater than one since total time under LSD is greater than total time for saline. Running rate per drug session was divided by running rate for the NaCi session of the previous day. At all dose levels, this quotient was less than one since the birds respond less rapidly during the drug sessions. These results are dose-related and hold up through all three experiments, although the effect seems to be less in the third experiment than in the previous two. Thus LSD both increases the amount of pausing and decreases running rate; the degree of both of these effects depends on dose. Interesting aspects of the pause data are shown in Tables 3 and 4. Table 3 illustrates the fact that there was no significant change in the number of pauses occurring in the three experiments, since Experiment II was twice as long as the others. The starting time data in Table 4 show no systematic change over the three experiments. There is a suggestion that increased drug dose leads to pauses beginning earlier in the session. ..j;nsoic-Jnl©i Od gninloldo >laot 'jrl> ‘if©ic|rt>09 oi (lOS'Qiq •?H'’ m} ,d ■''■ i lOfHo sflT .noslDi'grblv'nor; ofrti I'.rrtii bitit/ v ft-JugH airil \d (r50'.”'<^ gnlbylDnc) isq rioaruiq^qi !otoi' ’.j!v-bIv«b b'^tuqinoD ^aio'? hild'D idHi !~c1' ^» »i5»v, oi;.i! ..< V,, V| K > CelA . Jjof '(ioa qn U) gnlMiow 0 nofil Od > bl‘jO"/.’ gntnrjui (Ion A fi , VDOt ni ,(! iw) orH \’n hi>.-rnaqHni .icv^n-* fo:h lol ia>»';io3 iotoT .A* .gi^ ni ' A'one win i\MOic©fTi ow: otil ivi :ovu.o 0£r»»oq.-'^v.•.?■ ■’. vf)T .o.: I .'O • .-o yb I joU ■■)r!t n' &rn!i '.c;v;j i \rl b^i-bivib ?I noil<:n::c .'.‘vb laq »mH '■■mK 'c:^ol ’. -nu 9(K nubi ?i ®ffl ^nwrr!^ -a? ■©(-..!, tjo tA <•: S' f r'l’ ^tc onit-noJl .onilo-’ lo^ loioi nn«^4 Oc'.J "iiUnq .-c-i'i (»o b ''■Jc»V5‘''q of!t ?o tior, n. ,-jH t bsbJvib . m’ i. b nV.jtjni v‘'»' b'I't,ei.'uv. n.on'i} 300 n!3i'!( sDvv •."*>'^•'■Jp . '"Hf *ilav»S ■ ■; .|-?'io’* . .ti' vmoM '3nt-’ bo^ob't-'^aob y-io ctlo^j'i ?£S*f>'] .ftv.)t2?o» fS'Ht I nl rt.'fi’i Ir‘^’’•'h^vqA© bin'S wdl ni c.-??; jcJ oI *rnjs? IooHo ©tit - ^iinsn/liacixa .. I'V bffo gniyjr'-, • ! £• .a>*''T3'ni rllou - - uni ov-'t Ofil . j^r; -• .> 'I lo ctiO'i !o .jf'. -^oiCi ^;n!r*nui b ••t'-jt '■■ ,.f br*c Z n.-'..'!' -I? -jiL» i.fob azi^nq ydi 'o i^ailaoistnl ■( • n'arrii .*’ ?<’ll ni fmor'i fc’i.Jt''ir.qii on totoiliulf* 9 ■j. I ^0 ■i(i> -'.o opoedv O'-’.;, y . jii y/oH^ ^ t>ldDT nf oiob o,nH b^'t'-ot'. .,n*4'*o -,.'aooq ni rbo->! oeob goib bbispis.:' ‘ f'^'b -■orta^ggua d A ciadi .alfiominsq^o ijidl • ftoiuna aHi "•i 3?>ha» gi* ■♦n^d 22. r. n .. Rate of Response/LSD „ . gure 7 . Dose-Response Measures: —-—— -Sr■.-■7=1 Rate of Response/NaCI Total Time/LSD ^ g ljq Dose for Each Total Time/NaCi Experiment, Average of Six Birds Sessions Per Drug Dose Per Bird: Exp. Is 3 Exp. II: 6 Exp. Ill: 3 Hod3 lol aic ^v.B 'k\t^‘)o 69oi*v^\ t;i- iihnqx.^ m iblifl -^oS 920Q 1»3 20of«®1J ■jil £ ;I ,qx3 ' V fe-=a^v :I1 .q><3 ■ GilJl ,q>f3 " 't < * U*^ i/' t^'iJ . l.» m 23. Table 3 TOTAL NUMBER OF PAUSES LSD Dose: 20 pg/kg 40pg/kg 80pg/kg Exp. I 3 12 17 Exp. II 11 32 56 Exp. Ill 8 12 17 Experiments I and III: 18 experimental sessions per drug dose. Experiment II: 36 experimental sessions per drug dose. 1 esSUAM ^0J|33MUM JATOT ■'■ '‘v'vffv,,-;' ,C>S -V ' tr ■■■1 .“rtTr™ ' rti*‘ se f) \( A'"^','V';' ^'1 L y W 8 If V.. Jdk '.' • V . . ^■ ? ■ ’> -j./ ••. JfV • I ,. ■ I’i-t "' i. 'tf '?? ’■ ainotuot li--Tni»mJi£iq>!^si jBf " brrti F vtrvas-r’- ■ j, . 'Hi. v ;?i< '* ' ' ‘t. ; ’ . ;4 'fe' ■ . »’.. 5 ' (3 - gvsb lDlnamjisqH£> -iT :llt tiioosij-^qxB A' ' w; ^ y,*)iOh ’’ 1 V iT \iV 24. Table 4 MEDIAN TIME OF PAUSE START (MS, in minutes after start of experiment) AND MEDIAN DURATION OF PAUSE (MD, in minutes) Exp,. I Exp. II Exp. III LSD Dose (pg/kg) MS MD MS MD MS MD 20 20.8 4.9 13.0 3.6 9.5 1.0 40 10.8 13.0 13.0 8.6 6.0 1.4 80 6.8 38.7 7.0 18.9 9.0 2.6 W'.. M ^ 'ife ■' ' ’®‘'' ' (catuolm n\ ,QiA) BeUAS 30 MOItAiilUO HAi<13M OWA , ill f OM aM OM 2M CM 02J i i f. 1 ■III O.f 6,C \J.€f ' ■ . 0.6 >.8 o.ei Lv\~n 0 9 ,8< I OS \M 8^. ' ^ fl :■ -.r^T iHHMH ' , «,r» > .« A -4 ,■ ’ , ' pj^""' : ' ' .* . ^** ' ‘ i, f'A i|^ ^ ^ '»v. -,rar f '■■■’,v.P 25. The median pause duration data are shown in Fig. 8. It will be noted that pause duration increases with dose in each experiment. In addition, the data show that at each dose, pause duration decreased from one experiment to the next. As stated previously, the total period of experimentation lasted approximately one year. Thus, the pause duration results demonstrate a dose-response relation¬ ship and also the long-term development of tolerance to LSD. Another method of illustrating the pause results is demonstrated by Fig. 9. The frequency of occurrence of pauses per time interval after start is shown by LSD dose for each experiment. To count as a pause for a given time interval, a pause may begin during that time interval or it may have started previously and be continued into the time interval. For all experiments there is a peak of pause frequency at about 12 to 14 minutes after the start of the experiment. From one experiment to the next, however, the progressive decline in pause duration is illustrated by the decreasing frequency of pauses in the later time intervals. FOOD CONSUMPTION As noted in an earlier section of this paper, there have been suggestions both clinically and experimentally that LSD decreases food consumption. An attempt to verify these impressions was made. Each bird was weighed immediately before and directly after each experimental session. Since each session contained exactly 60 3-second reinforcement periods, comparisons between sessions regarding food consumption during the session can be made. The data from Experiment II were examined since,by the time that Experiment was run, defecation by the birds during the dis¬ crimination test (presumably due to the novelty of the experimental environment) iodi! »d Mt'kV' tl nJ nworiz q’io ofrl-) noilif^tub ncibfvtti forfT r-'*''b •sHt ^no'nibbc o( , tne(fn(ifcjqx^> o? c;£C’b r^TKv noUoiub s>auoq .ixttf’ '.«d' ot fodmlTsqxo sfto mc•^^ baEoai^&b rtbHo-jub saucvq »a2cb rl^oe to jodi woH? jqqo no!^o ■noitoiai s2no<;29-.-f)iob d M-faiJenOiTeb gtl'ice. noitoiub 97i.>oq eflt . ?u IT * ijwy «no .02J ct '5'>nDif'/Icl Iriftmqolavt^b ini»i-Qno} •?(* cjio boo qlH« .9 .p,;T \d bt^lO'''!'i./‘:''rngb '' eilii?T» SCMT-q ^dl .ni ft>-it2.:.jin Tc rtidlo^A QZa 7*! I'woH? lof^o loviS'Jn’ -inrilt oq .••f.iucq io ii>^ri.>nuu,'>o tc- yaqayj^T^ saut-q o Jovr^tiTi smit n^/iy o ■;oi o et- ’nuca oT .tri®fn{isqx5> loT eaob «i'J briw' ytOv " " !q bonnia 3VDd ^'t tn 11 io iovi^t-nl #fTtH 'oHi Qrliub nigi'd 'ijjOfn 3?ij07| ' :iooc; .-' aiftdt atn^'fin^qxo lll> •«.„T lov»»1rn »(/>»* b'>0'ii(nO3 cno .rto*^ ..li'jmlisqxa adi lo nc-a «»di lot^o jalunlrri Nf ot a( »o x^fieupanT af ncTiOM-b oauoq ni aniladb svi>oigoiq , Ix.-n aW-i ot 1 nsmiitiqx:# diiiii > ti ni ascuoq ^aoai.'P'iiil yniao-^iosb yd bctlDiltulll . -T .iOCT. • 1 jnc 1 ••r:'>gyi.ta natj-.i e- oH 9ii»d,f ^jeqoq «idi 'lo noHos? r n^ '.oitq-u'noi ;>'.o^ aoaooio'^b C'< ; yitoln -; liiorx*} bnO'yiIt’ainila '‘b./J !>btjff aov*' a:*. riqf'H 'Oiv ';; ytnev oi • ‘.ioS’ ■>'>tlD vlla'ii’u bnf; ^l©lDibftnini» ;x;vV btid dooT bnooa?-- v!fao,«73 b©n;i>ir-!0‘. noizasa doo© WDn)^ .i«oi:«8' tctnt> nci'anv^i’-.-' J '.or ? qoib'iOQSi inoiaasa ni’0^t©ri anoti loqirioa ^aboiioq i u*(iTt«aTio1rt«»i c’^v. JI insfr.ii3:j> V* fnot^ oloh ©f*' .®bom ©d Jioo noijana :>di ^^nliufc -ifb’et'i ;;rii'‘jb ?fc*ibi -c'; yd notloo&lob »riui aCr. t.i.w ©fnii w i yd^^Tifiic (Inai.if'oiiYt.fi lo-ii'v*.- ‘’-' q'.j eidi io yll©von o Figure 8. Median Pause Duration in Minutes by LSD Dose, Shown for each Experiment, Average of Six Birds Sessions Per Drug Dose Per Bird Exp. h 3 Exp. II: 6 Exp. Ill: 3 MEDIAN PAUSE DURATION (min) 80 27. Figure 9. Frequency of Pauses Occurring Per 2-Minute Time Interval After Start of Experiment, Shown for Each Experiment and LSD Dose (20 pg LSD/kg Results Too Small to be Shown for Experiments I and III) 11IT »in«T t>funiM-5 enhiu^sD 46sud id f!WoH2 ^■friomhsijxH }o tiolf i^stVA ij)VY»liij q;A[Q2J cm OS) e*oQ Q2J btio fK»inh«qx3 rtaoi; * ' & (Jfl but) j fln»ffir»»cfx3 id nworfS md gt Mom? ooT ' - i i ■iM V •/ * ,■'' ..’>1 CD O <* o o CD d CD lO OJ ifi L TIME AFTER INJECTION (min) JJ CD Jj C\J CO CO A0N3n03dd 3snvd 28. had ceased to occur. The results of the analysis are shown in Fig. 10. Average weight gain per session on saline days was 7. 7 grams; for 80 pg LSD/kg days it was 5.3 grams. The t-tests for differences comparing LSD days to the preceding NaCi days were not significant, although the tests for 40 and 80 pg/kg were suggestive (p<.07 and p<.08 respectively). ffpnaiflivA ,0'i ^:i'.m'’«t|w?«’» »4T'-' feas»^«'''b©d ' ,■■•. ' ®^''" '',fs ^ /'t 9.*i{bat'^'>q ol *^;t»b O^'J .^nliipqrco'^fi<3^^i'1;aB,^!b^'‘'%i''*«♦'«^^ €\.^ tow f' . "S jTP aiaw 9>!\gu 08b '■^.1 29. Figure 10. Experiment II: Weight Gain Per Session in Grams by LSD Dose, Average of Six Birds, Six Sessions Per Bird at each Drug Dose and Eighteen Sessions Per Bird with Saline a> ttPilsw^ ftioO :I1-fnijmhoKqxJi ,0< •mfiH vrl^ ^abiifl Kf2 ®5i©-*9vA ,ttioO 0?J ^fd ? bno 'PIcCI ^ui<3 r®*l '% anfio^ •ItJw r, $)|( 0; * ( ■ MEAN WEIGHT 2 4 3 NaCI 20 40 80 DRUG DOSE (/ig/kg) 30. DISCUSSION The significant increase in accuracy following 20 |jg LSD/kg is perhaps the most important finding of the experiments. While previous research on critical flicker frequency suggested that an improvement in discrimination might be seen with LSD (see introduction), interpretation of the data is difficult. One suggestion might be that the drug, since it decreases the rate of responding, leads to a more deliberate choice by the bird. However, this notion is hard to support; while slowing of responding is an effect which is seen more and more strongly as dose is increased, accuracy, which is raised by low doses, declines with increasing dosage. It will be recalled that the duration of the total on period for the lights increased as flicker frequency was increased. Perhaps a light which is on for 400 milliseconds per second appears brighter to a pigeon than a light which is on for 200 msec/sec, even though the absolute intensity of the light when it is on is the same in both cases. Peterson (1966), as mentioned earlier, did find that 20-35 pg LSD/kg increased apparent brightness of a visual stimulus. If, for example, the apparent brightness of the lights were doubled, then LSD might have the effect of making the 400 msec/sec stimulus appear as bright to the pigeon as a flickering light whose on period was 800 msec/sec. The 200 msec/sec light might appear as bright as a 400 msec/sec light. Thus, the absolute difference in brightness between the two stimuli might appear to be equivalent to an on period of 400 msec/sec rather than 200 msec/sec, increasing the ease of discrimination between them. But this hypothesis is in conflict with the increases in generalization for m ;; -ifii v-i/iSL 'Wn" to^IHns no ^iK)f'/mq t^llnW^ Ik) gmbnlV tnottoqwl leow nm&z od iHojff. fit) lw .flusWfb £> oiob sHf It ($Zi Ml lo siloi i>H+ ^ggo^iDdb tr saof^ tDrt^ ■ " A. '%■ ■' - -v ^ X . W'-f V rtoifon ?fW» ,is»vt»woH ♦bild ©rtf \d esiorto affln^Sil'Sib' «iom » of «bo»t ilewIbrMSqm ^ boo oiom n!»isi it rtairty/no «i en5br*oqi'©i 16 QnJ*>(M»h aMrtw ^lKX|qii» o1 biW1 et ^1S -ttf ../I* , "W. ^eftibb wol \dl «i rlolrtw ^yooiusao «J ©lOb a&'^(V0noif8 ©tciHit " ^ “ .. " ,9ist>«ob Htiw jiKJiliwb . SB .a .,«. i ©rtt io) boHaq mo lof^ artt lo nol Joiyb artf tn# bbH^OOl tdl tl < — O ' ■ , 001- to> fws ■1^" lol f«o «» rttsFHw frtpiF D nortl no©9?q o o1 latrtgind'no»<^6 brfootNt tqq ©f'l e* rto tl <1 nadw irtotl ©rtllo yifwtdtni ©lubfib arti rtewortl nth'O , »««\ooe«i OOS I ^ ^ ' '•► ■ A; ,• r DU tZ'-^ tDr*1 bni> b?b ^laiboa boooFfi'iew so nioaial©^' _ ^$tsPo nf omot . IT -vT« '• ■*& ,. ■■ (T ' w. : .‘IT 4\1' .£5 / 'L % ftrti ,otdmt»-a icd «>! .«utomtte Isow^v n io I^o0frt^^hd l6a>bcK?o bawwionl! Q)<\d2lJ - (. ^ n/; « ... f 'tialb 9fii avort ♦rlgln 02J n&rii ^balrttyob, »\9w «tr%U arti lo ^tanfrtQndifnrtDqqo gnivaiiain o to no^glq arti offrtglio to tt>9(|qc dululiniHt 00b artt Q'ltjlaim lo •"''' rit loaqqo trtpti t!9s\:>9ffft OOS ©HT .,30»\3*<>ityn- 008 ^ awjrtw n (jjanirtgl id nl aanaia^^ib atulocdo artt ^M/dT «frtQ»t o^s\>Bifn 00b o io irtgiid 40 ‘i- ■ . • 00^ bohab no rro brightness found with LSD (Key, 1964), where stimuli of various intensities appeared less different from one another than they did normally, and therefore seems of dubious value. It is possible that the results are specific to a flicker discrimination and therefore are of little general interest. The neurophysiological evidence indicates that LSD treatment yielded electrical responses not unlike those found when the retinas were stimulated with flickering light (Schwartz and Cheney, 1965a, 1965b). Perhaps there is an additive effect operating, where a high frequency flicker, e.g. , 71 cps, which may appear steady to a bird given saline, is imparted with an extra "flicker" due to LSD. The 100 cps flicker presumably is at a high enough frequency so that it continues to appear steady after LSD administration. Yet this interpretation does not seem plausible. For one thing, LSD decreased errors at flicker frequencies where the birds were making only 7% errors when given saline. It is hard to imagine that this discrimination is so "borderline" for the pigeon that an additive mechanism could operate. In fact, if the action of the drug were to raise the flicker fusion "threshold," one would expect to see increased accuracy of discrimination only for the frequencies which, under saline, are above "threshold" and which the drug has shifted to below "threshold." The fact that LSD, at 20 pg/kg, increased accuracy generally over the whole range of flicker frequencies examined, suggests that the effect is some type of perceptual facilitation broader than just elevation of the CFF. Blough (1957a) tested pigeons on a task which required responding on one or the other of two keys. .f'"'i.-'nyilr‘'JO ov "fe 'lu'nil? O^J H+kv *’2 - ^ ‘ ■■ •sfj't bno ■ Ufr -?>’io rj'^ost I fosfiDaqqo !■ ;>cy V* bno n-j< ionim’tfO'ifh -"iMr-i'1 oo SiO^liiWfk; r'’!t-JoHi ei 1l eonobi-;' :'. •>!(:r*lo;.-'v ..bl^ ic otD aioHiorii o MivK)^ •s^o'■!•^ ^'-■' )j *■■ ■ ■■ ' jq?'?') («.'j; !t:>o'Q?J -loHt f^ttooibft* br;o i'•-'rsvvtI?rif.Ml p.ni’S>lDi.R b&iobirnJJf #‘t* ■> '/■:■:'< ■‘f’') noovy z' '.ri u - ••. 1; u'V-.‘ivi ♦'bbo f c r ,facA9f I ^cnMr.-e -lox. to i’. ' t i-i . r'vci*, \t>r. ''Mi!', , .p t'v ^ -/tinaupoi) v'drim I ■•.o': •’'.'' '^r\ j Svib '■ hO b ".■ i':,- i’l 02-i '’''il ■’’'•1'"’.' "''b ' ■ '■'’ “-i .!>■■■'' ® ** ' ■•! .-'. ■ lo^ .sljleuol] . V: !■• -t i ' ■'- . 05'*o' '>‘‘«Mi eult leY ^.w .,, , jbbj •■ b <* ‘ •■ -.•lit•^Dvj^•,^.' 1 ‘.’'•.i' 1..- rio'no b^oaiDob ■rs ?.'. i;c>i:r o>;U. iirif u-'-'i* . ; u. L-i h*':.' -i o**'-', uiidw .i'.«r{ ic.',c • .ii’joo n - . > * ■ ■tTobo y‘‘ ^di lo^ "n^wl ■■••iO ■'-'■idt" o. -i«/s -j-r',', 03 V'.'W :.> ^ril ©4t ^|- . d.'5ir:w iL’i :>.naup*»>^ V ; ■ ' •■ ' ’ ' - s -.oiWPl)!' bs^wor,' *-j? of l3»qH& vYolcd ct DM:'!;-*? if'ji u. ■* ‘. 'i bnn ’ 'Tin.- <#vodo «io •--< tsbov ” ,b*o4#»THl‘' Jilt , ; .•'; ■.'■■-■> ‘ . •CCM>I ■-'il \ O'-. *t< ^0^,1 'D'll 3 * :. ^ , ,,( f' 9'’x\'^ ■^1^1 zl ija' ■-' i>»!l ■»or:i ?'}?«r>oi <■*. '^r'ti 'oxo ‘sio-n'ilr» .?vKifn i.*lfiHw r :..'i ow< K> ftf}'* TO » depending upon whether a light in the box was on or off. The accuracy of performance under these conditions was improved by LSD. It is unlikely that the drug made it easier for the pigeon to tell whether the light was on or not. What is possible is that the drug somehow increased the "importance" of the light; that is, responses to distracting stimuli were less likely to be emitted under the drug. Thus in the present series of experiments, LSD may have given flicker a "sensory impact" which it did not possess or possessed to a lesser degree under saline, making it impossible for the change from steady to flicker to go unnoticed. This correlates well with clinical observations that humans taking LSD report great increases in perceived intensity of visual stimuli (Cohen, 1964). The data suggest that two effects may be operating after the pigeon has been given LSD. First, perception of sensory input is intensified (above). With relatively low doses of drug, e.g. , 20 pg/kg, this increase in perceived intensity has the effect of improving accuracy of performance on visual discrimination tasks which are already well-learned. It is apparent that this same effect of the drug, if of sufficient magnitude, might result in a behavioral change quite opposite to that of low doses. Thus 80 pg LSD/kg may intensify all stimuli to such a degree that perceptual disorientation is the result. The bird is unable to distinguish between the flickering and steady light stimuli since all sensory input is of literally staggering impact. High doses may therefore result in a decrease in accuracy. Blough used oral doses of 200 and 500 pg LSD/kg (1957a). Since drugs taken orally are absorbed more slowly and less completely than the same drug injected intramuscularly, Blough's doses may be more comparable to those used '"•:ji;>n.ojiO :>riiT .'i)o to f:c nl r63><3«> •. !. foril ■'■'■■’ .t Of'it ^trigM oril ’ vo.iCTxxfnfij'' ini s^c;<^ia-wcH'..9'w'^ «rs1 iqdt vi ftldi-Hjq .qinb *j'H i9bn\j bfttiirtM v / 51 .U’.ii ■i»«s»y«' ,i?i \'TO« eiHT .booilc' n*. ot ot ybr)->b pToii annoHo -vit loi oHiToqo'i n p<‘;t.''!om ‘ ?ioqo) C;^J qni^o! Iiytl .>it.-,i'r ' ioi"i t ;> !l-\v\ .■ihil-i'j^op . t^b?{ ,<19,^0'.'! ■i ^" lc‘0 '•■jr..-' V- ! .- :'jr; q e'it • yoftr ow' 'O-i't ; ...■,:, - ’' .qlV '■. . -a:-) i.'55}I?.i&TrTi «» .'To./r-? 10 >KiitqvOi>>q , v'i ri.'^ ■■■•.'•'(>.' r^i > i ■..‘■sri; •' :b!i lo ''i:y OC * .g.-v lo .fNCt' n',oI yl .^vl 10! vt ’ . . / > .•^•'m!T^^^? tv'vlfiv r o : * ri'Oilr-H ) ; ^TmuOOC Qfi.- r.iqmi Cf ^00^19 *Oll N b*: 'to^.' -'... v yboaiip dqo HoyWw i 1 ^ttbu'ioQon* *(»•■ .p'rto! .f».. .: - ii io <-yim sifit Lm! fn^itwr.^qo i\ yq Ok irarlT .- to 10(^f c>i vt 'o iqr .^.lup ■ . '.rnlo b- .cr; -o o ni . ' r : ■ .■•t.'r-r, ,ilb iouTv 'K 'r- \ ^.•:^! ■•■»',*!: ■-" o Ol HufT'.'. K- v (••lOf'lai \'C.r. q'i\0 br>o QrriiojjolH ©til nt-. > r '.; > 1^.■.»(:;,fihdt • ‘ ct» budoflT . llu <“u'rh flpIH . 1.i‘'M.'il Qpi'> . .-(/.r ., /I^..•K . ’.. >\ y’.owis.-. Ilo ilucn't* ^ '.pi' .'{qo!»i»>o» ri tfii.»T>io*b o ol tluewi -yom >SUib oonii! .(0^2.91) gi'yQ^J /OL b .^' . Uj i^ech bd«w i^Quof^ Qij^i.. .•i'-'.: Ii ^*o.;'f ic'-'l l?f!»> y)woj< 5 ..ii?*.-*'. 33. here than would at first appear. His testing sessions ran as long as 5 hours. The sessions in the present study lasted about 20 minutes if the bird were given saline or 20 pg LSD/kg, about 40 minutes if given 40 pg/kg and about 80 minutes if given 80 pg/kg. Perhaps if the sessions had been of greater length, an increase in accuracy would have become evident in the latter portion of the high-dose sessions, as "disorientation" subsided. Another possibility is that the stage of perceptual disorientation may be initiated by the rapid delivery to the brain of a large amount of the drug, with oral administration tending to decrease this sudden effect. In the present study, depression of response rate after LSD administration continued uniformly (except for the "pause" periods of no responding) throughout the experimental session. Blough found that this phase lasted about 2^ hours. The explanation for these results may lie with a second effect of the drug. One suggestion dealing with decreased rate would be that LSD results in general motor incoordination; however, the behavioral data on wheel-turning (Appel, 1965) and running responses (Hamilton, 1960) do not support this hypothesis. Decreased response rate may more probably be due to a decreased "interest" of the animal in the task, and specifically to a decrease in the reinforcing value of food. The evidence that the pigeons in this study eat less in LSD sessions, despite the fact that 60 reinforcements were presented in all sessions, might be construed as indicating a decrease in actual motor ability to get to the magazine during the 3-second periods in which food is available. However, Hamilton and Wilpizeski (1961) indicate that food consumption is decreased in a dose-related fashion by LSD .?rlT r'i'jori 00 co '■ .1Ci«qcjn Ictil 10 feJuow ’ '\l • i!n? fie‘/J{) s'^-^'v ' i ■:> '' O'i ybul? ^rf’)e«-»q ofil ril ifiolis??/ . 'l.jc.b!; *"’>:■ iuodo br-ii.' ■■ Vj- -j; 1 }, .,:ui■5»^T^ ;/'f' ,d:I'\'3?J uu OS 'fo •.tc'>5ia;il tir> ^ri-tpa*-:*! --cf Ij auCjVbvO .9>l''^5q i-'-rvip yrb io m ,, /i ’>> • ' ■ .' ' ;-’olv? ^'9 U^y.6i 'ivi.W fe!uCV' yjr, ■ al 'r •■, < -i . b .'• i-jb r' iftT.T-c'. ■ • ! r<)' 1 ■/ .1 ■ ' :b bfqo"’ ■ “b . b'*‘'.'••ij-frt» CO' \uni ■'■^'.bq’SrD'Joq /• • (ji qn'’:= :•' ' . . "';•■■ il:'/,. .o!nb c'!' ^0 . \ *!<>( tr.'i •:T>^l' .,i •■ I<1. 1- ', ■<';•■ . / " ■ jfyiqot j **i‘i< nl . _1* ^ I. 1 . luorl'jL'C"'"*" I 'i.i ■ . ;i iQ ibc-f !.•'■-■; ’.• i* ' v:'": iqo.D.-' ,■ b." -ni1no:i ' : '•! ')T>Hq :i 0 'f-r’i ... I-'-' ■' ' »jcjxo , ‘ ■ .' ■ ’: t-t; ■'-, r r' . /, 'fr -.t ‘■■V-.;li v) rt, 1i.'< «lHT . ••' ■ i Ot'.' ■ • b' .'-." •;■■' !. r'^'Ol^tV. . ol U'.r. tO.^'X i^qoA) Oibrnu-• bi . > ■■ n.!.. i'- i ;'1oi 'fVub’WO.VM 5 ■•»)•■'tc. y -1 .. . ^;jr' ; ^jb rr.!'',' i p;’^''unn lii>mim> ‘ ■*' ■ " .’■ h ,■ -■ I O’! f-.;' ■ ■ ,;1- ''‘•i:-’ ■, • v... ■ i «- ..HlJOi • bvi'-' '^1 1 ‘ .■'■''' ■ "’ ■ ' ''■i'-'-' ’ •■ '.'I - • ‘ ‘ 01 ;»t(f r?: ’.tr ■'.'>■ - •■! c;*^p r ' • ' , 0 , •. ( t r b’;/a;ttn ’ ' •y "t* Hr’ III 1, j-’fjvy nrro’.i'f' : m b n.-(< r b iLib ; ■ • . ■> b.^i.n ' ru v< 0 ijrt-i : '.'tyt: ?D •• , •*>V'.'J.'/CH . ■•! b itt'S.r 1 b '"'' ni ;. ■ ' ^ ' *>!. U : . V-.' - ■ u>(*f • h tt oi 0 ■ .-,’ r>M, , b'J V* ' It .■.'Ob- b.W) 34. in circumstances where rapid motor ability is not a factor. It is this decrease in motivation which may largely account for the slowing and interruption of responding seen in this study. Finally, the progressive decline in pause duration over the year during which the experiments were run must be explained. The median starting time and the time of maximum pause frequency (12-14 minutes after start) did not change appreciably. These may be related to physiological "constants" such as length of time necessary for the drug to reach its "active site" in the brain. The decrease in pause duration, however, may reliably reflect the development of long-term tolerance to the effect of LSD on food as a reinforcer. The mechanism of this development of tolerance is unknown at present. It is possible to speculate that perhaps continued administration of LSD leads to alteration in the molecular configuration at the "active sites" of the receptors for the drug, or that repeated LSD treatments deplete some vital intermediate necessary for the drugs continued action. One might suggest that LSD acts by releasing physiologically active compounds which then actually cause the changes which can be observed behaviorally. If, say, at the start of the experiments, 80 pg LSD/kg released enough of these compounds to cause the bird to "pause" for 40 minutes, one might imagine that at the time of the third experiment, only enough of these active intermediates were available to result in a pause duration of 3 minutes. A simpler hypothesis might be that the decreases in rate and the periods of pausing were responses by the pigeons to the novelty of the drug state, and that as this novelty was diminished by repeated drug administration, so the responses to it ■ '' . w tu mo-.iu"' ii 'I . ' .illy/ .;■" •:. to;.., »!-■ , ..-it.'-F' .,-Jt tfvl.’■:,. ij. y.l'.,’nVi • I.' J»mf O!.; b^y-H'I.'■!!>.;> &d tifjA! •: -.•.'t-ifW, erfi -- . ■ : • i-'. . i 4 V *^rif V/-;;::-.' ', vi.-'ucy.?-iTU'f'/ti ACJf.': v: _ t .>ir>n^' :.p - " .* ■ ... -r- ,-: bolpi-;;! •?■ ' •>•,;■■ ,. 'J'-lofo^iqqc' . ■,;,i ,fv - '•' -i; -■■- ■« '■■ .-■ '•?r>v< 07 3ijtl,vp^rtj v<*nr'h' • ■>! •<'' tii >'.'< !>v!'‘ ' \).T ': •. . ', -ii>v , ,n ’i*r?''./b ■ ;.;eyq n» ■ ; “ 1 ‘1 ' >v n.' .-. :ii,>1 no- G'^-l '• ' ui't '■’t •* "O'-l'.l ■ . '. e.i “.' •' '.7*ii '; - • ■ . q 1 •>>'■'■- . il )o aHi /■r ■H'.w: '' ■• ■ - ’ i- -' fi ■OJ ..- .■ ■ •?•'../■Ji ' i ' £^0 j\ ' :.< :^■■ ■ . , 1’■■ic.■• -e*Ui7>-‘-1 *i nt F ' Oliy j>in. , _ r -'■ , . ■ -J h J • • ;ir:,) '.: ■ J . ' '.’Vf'-' ■ '• * -•;ji ab iS'.'’ ' ru OUtDB n .'• T ! -q* 1 '! CFV, ,UD:;Mjol ' >|‘ ■■■ ■'■i'^f *0 ''ii‘' ’ll! O. c. -/{I- 7 Ov 1v : 1 ftl'Cv 1 ■ .cl 'V*j j: ' iw fl^UKStr I M.r .' -. gq 01^ ...... ^ ’ 'i'-i • -j; ! 1 ir. 1 ■ 1 ^ ii' •'* V’*' .Fo* “. 7.j'■ -J ■ . ' ;■’ ‘■■-.''V.i ( 11 V'’F * ■ • -fyiy^n io Si-.’ ■*0 sr'.l ,:.(;. ««n>< r>t i\>-f rbi •‘" ',' id A "o • - .• . ' •"•+ ■. . tooL-glp fTrl" ^(imj .'-yaieuix; 35. declined. Perhaps being in the experimental environment after LSD treatment was aversive to the birds and the decline in pause duration over the experiments reflects the pigeons' learning that the experimental session could be terminated more quickly by more rapid responding. It is not possible to choose among the above mechanisms with the data available. In conclusion^ then, the behavior shown by the birds after LSD is consonant with postulating two drug effects. One is an increase in perceptual "receptivity. " At low doses of the drug, the behavioral manifestation is an increase in accuracy of performance on a task where relatively simple responses to perceptual stimuli are required. At high doses the unchecked flood of perceptual input may lead to total disorientation and a resultant decrease in the apparent discrimination ability. The other major result of LSD administration seems to be a decrease in the value of food as a reinforcer and a decreasing rate of responding to obtain food in a dose-related fashion. This explanation does not preclude some degree of motor inhibition or incoordination as an additional effect of the drug. ' in ■■ ir-'-.;'Jl-mi; .'Jil.* tr.s/r.rJO'!»'/.•>•• I«:('-.■ cissi C'^jon '• -‘■r■■^':^or■•^^ n< *•'•'>(1 t il. bt'tC* iVrlf o') SviBlovo .- "!.•( c-iijc'j noig";?’ if.»i.^G‘fr't ,'';'.i7x-L> ->rH /-. ift '."il •; ' ^ r^': yfi' VHii, iTiD ':v^- •' ' *' ^id^^^vi:5 ^i,} 'Os.|irsi t i qo'. d >(l4^rup ^iorrs ... ^ ^ . ,*td'd >1;'•■■-'.tJiot^ ‘>Hi d-i;*y ?frwfr»JviO'Sf.' .> "vi.? ii,i^,'roo ii (.Ir. ' 9»it xd ■ ' *■ '**0^0 j- 5'''.'’q » ' 'I ni Miowtjfu .v^ • •p ;• ntl ^i aOi • ^Ui'.' f O .oJ#( i I .PvlT^i ' t'.' Wol lA .»• V .u iuixtili 'coir: . . >f'alcjmU li.'* . • Iv- *ir j>i o fK> £''inCii'V>'>na<| lo < r> •‘- •• ‘ ictni idijf )iq )'.> bo"'' c.' j ' pfA iA .'^iciii". ►O' c.itjifljiatllfe ' ’:-d/ i » p . • !.■• i I'•«!:>' ol?MO riuiioJn^l'Toalb • ,• • .'i^v’.i c! ... ' ■ -I i iv” ■, '..'^o r ■"jq' M Tc< -■ ;i-• i- i. :»v' ♦ -300 vaiDT©V f'>i V f • d io'auioy, :. ‘ ;? '■' '. iioi''-'*"'. Iti* ! ^ ■ '.■' T—itnoki, 0 • ;'o oatls: I'w;-, ♦ '.'be-no r.'' •■iL.P H^TH>0:.>nj TO ."lOtttdfdoJ 36, SUMMARY Six pigeons were tested on a visual discrimination between light flickering at various frequencies and a steady light, under saline and LSD. The birds were required to respond for food reward by pecking on the left key in the experimental box at FR35 if the light was steady, and at FR35 on the right key if the light flickered. Incorrect responses were never rewarded. Each experimental session continued until the bird obtained 60 reinforcements. The doses of LSD were 20, 40 and 80 pg/kg, administered by IM injection. Twenty pg/kg produced a significant increase in accuracy of performance and the results with 80 pg/kg suggest a decrement in accuracy. Consumption of the food reinforcer was decreased in LSD sessions, despite the fact that all sessions contained 60 reinforcements. Depression of the rate of responding and periods of complete cessation of responding were found to occur in dose-related fashion. Tolerance to the rate and pause effects apparently developed over the testing period of about one year. o V5^AMMU2 V'V.:4"' 4 . . o no »r«nw *Ao*^lq sbnic 'j(fl brio ^ r>igU *' br'iv/f',*io') >upn‘»^ stKjh-jA' 1e> loinaoi 'jqx-^ M-Ji n} y.it.>f /.-" I ®rff rtq gni'■!',.■•■•' v/i b*iow6T.hoo^/id?^brK>qi‘3\ oJ b^iiFcpei ' A ' ^ ^ ■• '.^^>1) >>Ht >i tHgi} *»nt rci io bon ,\by?t2 eow Mji'. s-rU £€;Vl to xod noilii''.'. -* f<“..L2 .bttbio.v-^! v-3.' 'V^'-asA/ wjancxqi'v; '.b9io;4oiB .eif-em* Oc- hao^td* bi'-j ^-tou beooitnoa ,fiollo«jni Ml vd .> Oil .iii '-'r >'> Od v.no Of* .Oi ©laiv.' ’.S. J i :■ £*.> r.I; ©rl ^ ‘*rlt c.-tr i.-/ *- 'tliOQ Iv \ow»o3;-o nt Mdawni inCDinn^-!?* f>.J ftne^-vT .'oo' 'i'f'i ?.-) 1-/:qntj?/ .y5r><-OJ«n ;'i rriMv '■ 'i ■ »ivi-qvo.’ 08 d^iw =^•<0 To tjol art oOqaeb ^ r-ji.'.tftt C^‘ ^ '' '.> Kr;^^^j^b ioW L caoi -3 ■ ■ , "ifc.'i,JO•:►*■» •'♦tCM ?.•'> Vj .irr;Vv ■ J.'. Ob b<»nfOlno3 • r . . ‘ fi* ii ..'O ot ‘‘Vow f-;;-ono^zsi lo nortOfceoD &fdlq»«>-'v f t'••. > btjq-!.,v!»b yFlO®tuq^,. ' v i.. .-•:: • wit ot ■-3iT01«1oT •tt-> • bolvqq 37. 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R. , "Action of D- Lysergic Acid Diethylamide on Lateral Geniculate Synapses," J. Neurophysiol. 21:529-549, 1958 Blough, D.S. , "Some Effects of Drugs on Visual Discrimination in the Pigeon," Ann. N.Y. Acad. Sci. 66:733-739, 1957a Blough, D.S. , "Effects of Drugs on Visually Controlled Behavior in Pigeons," in Gavattini, S. and Ghetti, V. (eds.). Psychotropic Drugs, pp. 110-118, Elsevier, Amsterdam, 1957b Blough, D.S., "Spectral Sensitivity in the Pigeon," J. Opt, Soc. Amer. 47:827- 833, 1957c Blough, D.S. , "A Method for Obtaining Psychophysical Thresholds from the Pigeon," J. Exp. Anal. Behav. 1:31-43, 1958 Carlson, V.R. , "Effect of Lysergic Acid Diethylamide (LSD-25) on the Absolute Visual Threshold," J. Comp. Physiol. 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J . •> '^r’ob*' ^,2-Vj '0^ . .^ :'5:A .^ .k ^nA .j'sn ■( ';'/■. ‘*,'8 bolloTtnoO/ ■ ' o lo ‘ , ,2.0 ^Hiy‘jcl3 • qq yCQurJ '0,v?9 ,(. ..-ifiA . joc ..Q'.' , i. " •-■ .. '1 - •1 iO ytivii. n:iJ lojt6-eq;" .2.0 ,Hpu3iJ „ ,rCy' sHt ro'l ei lrxiw ri | I;^:. i: rn., jr:t -.inioidO''50) A*' , .2.0 ■:'.vi .O,**-';. ' .vDikS .fnrA .L s-T'jI ->.*dA 'jdl no > ■■;i ' , Iyfltsi*-" biaA .. .?>. v .no.’jhoD ., I ■'i-' I c q .’.o. '' .I ”, rdorOw'' out-v'' .“’bVf ,>lioY w»M , r? .■•■'’v'jtA , ' ' ■’D\'a3 e K , ,2 38. Edwards, A.E. and Cohen, S., "Visual Illusion, Tactile Sensibility and Reaction Time under LSD-25," Psychopharmacologia 2:297-303, 1961 Evarts, E. V. , Landau, W, , Freygang, W. , Jr. and Marshall, W. H. , "Some Effects of Lysergic Acid Diethylamide and Bufotenine on Electrical Activity in the Cat's Visual System," Am. j. Physiol. 182:594-598, 1955 Evarts, E.V, , "A Review of the Neurophysiological Effects of Lysergic Acid Diethylamide (LSD) and other Psychotomimetic Agents," Ann, N.Y. 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W', Ib-'KtjM'■ -if , '»V ,','«iuQ\-.j>;i'^ .‘.W ^ .V^5 'r.;; .‘,;5,',ll no ' b'U- \ hf.lA ' lf.:-n?V j ;'. . !o;-.-,;'ti'i ,1. ,r\X ^ v^'--'v./:!- -r.vf r**' K- '. ■ ' • bv,?',....‘V ft‘b. ''■’ • ;'..^ vf’^'JOVj •:A ' ,ebi*»^’'''' .' " ' ' tK iiu-t-‘D (; ’1iK;-, ' I,-'.-. ■ tC' T.' ^ pfiU .8,'?' :. V i -.v ' ■ ■ , . , ■• ■>','\ i.-ri; , '; . • ..;,• (.1. '. , . . d . f 'Jinhffeml d , ' '■ • . i .1.1 " ^iW/i f I ' ' >' t • . ' I 1 i'Vv^iC) l,r .it-T':,' ..*'^ >’c{05-':'-^’JH,-'dT" , ,W . i. 1 •' ■-' '•■ 'M'(i.> , .<■ •'■/iij-- -,•■ i-* '■' :/1 'V}‘* . ' .1. irj*>w3 ‘ . ^ . .* < ' . * . - ’ . V -Vi’ .1. . “• ■ ••) \'l.,-' . ' •• . ! '-j •'.-Jj-v' , .n -"lo .v.j ,i\‘’ ^.bt'odsbl&O ■I '..■n<' . '• "K ^ - ' ' ■'■■ .<• '■' •' .• i* I : ■„ . ■ />it-, ' , . i ,D- ^oi.. - ..•'‘H •,,..., .0' . ' . lA A"/,/"' ft)! •■ I VJ . ' ’ , ■•■-■'it ’ . (qj) i bar . J . »/ . no 11 i ?n-H ■<’’A :,' ‘'''' .K'.'- ,f»oraiciH Qn .or.c. ;-■ i^oi ' v.V: n. ' '-.'n.. ■ ri ^ ' i, ' i j •• .-.tA}” ^ > K -■ i . 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Ophtha 1.62;599-603^ 1959 Jarrard, L.E. , "Effects of D-Lysergic Acid Diethylamide on Operant Behavior in the Rat^" Psychopharmacologia 5;39-46^ 1963 Jarvik, M.E, and Chorover^ S. , "Impairment by Lysergic Acid Diethylamide of Accuracy in Performance of a Delayed Alternation Task in Monkeys/' Psychopharmacologia^ 1:229-230, 1960 Karp, E. and Pollack, M. , "Comparative Studies on Chlorpromazine and Imipramine IIL Critical Flicker Fusion Thresholds in Psychiatric Patients," Psychopharmacologia 4:452-458, 1963 Keeler, M.H. , "Inter-Relations of the Effects of Psilocybin on Subjective Sensation, Photopic Critical Frequency of Fusion and Circulating Non-Esterified Fatty Acids," Experientia 19:37-38, 1963 Key, B.J. , "The Effect of Drugs on Discrimination and Sensory Generalization of Auditory Stimuli in Cats," Psychopharmacologia 2:352-363, 1961 Key, B.J. , "Alterations in the Generalization of Visual Stimuli Induced by Lysergic Acid Diethylamide in Cats," Psychopharmacologia 6:327- 337, 1964 ~ Khazan, N, and McCash, D. , "Effects of LSD-25, N, N-Dimethyltryptamine (DMT) and N, N-Diethyltryptamine (DET) on the Photic Evoked Responses in the Unanesthetized Rabbit," Arch. Int. Pharmacodyn. 2^:474-483, 1965 KrilI, A. E, , Alpert H. J. and Ostfeld, A. M. , "Effects of a Hallucinogenic Agent in Totally Blind Subjects," Arch. Ophthalmol. 69:180-185, 1963 Landis, C. , "An Annotated Bibliography of Flicker Fusion Phenomena," Ann Arbor, Mich. , Armed Forces National Research Council, 1953 Landis, C. and Clausen, J. , "Certain Effects of Mescaline and Lysergic Acid on Psychological Functions," J. Psychol. 38:211-221, 1954 Liberson, W.T. , Ellen, P. , Schwartz, E. , Wilson, A. and Gagnon, V. P. , "Further Studies of the Effects of Psychotropic Drugs on the Behavior of Guinea Pigs and Rats," J. Neuropsychiat. 3:298-303, 1962 Lloyd, D.N. and Newbrough, J.R. , "Sensory Changes with Phenothiazine Medication in Schizophrenic Patients," J. Nerv. Ment. Dis. 139:169-175, 1964 ^tJnrli'sO Br-J? .H A ^;o«>ecioi5iol rtJ lolVoHf:^) Ino'JoqO nr. eth<’m'‘4ydfiio*»iot k> '>h?fripl V' 'Ji-G b:-U'A biglO ■; J , ,'c ^ ■.;?v-.iev:'!~5 l-r^.o .B.M ,j4lviol '', ..\.'i>lno/'A f . ! 3' ■"'O'‘iv "fcf'Vv ctaryoisG d'>0 *•■■*> l;’;o ‘*ru.t'rr'io^q)'.''f»D 00 avjVt^oqiSW'j’D'' , .M L-^f' .3 ,C|io)l :;n no ri.dyaolij^l ^■•r/'•^id ''-’ V.. , .M,M ,, fj 11 In!u:;..tD ov’?o3 io \ort9'.p'S»3 J ’ Cd»'1 .SC-^Cr^? oHoiPnaqxj At^A yi '>:ji3't io no) I Li» lu I-'no C) y io;!<-u'C-bov r.citpn*^'’^e'C) n.o ^]uiC} V. T'j^m arfl>' , L.fi •'. Dig:.‘o.prr^oriqoHjy/n ytoi Vu'*, yd bojubn; Jlon OkwiV -o te0 4t<''3 fit ; no Hens*! A"' I,.6 '■'^^Z'6 oI^lojK"!'.-i-dqofi^vfG " , j'.-v^ li a-L^rujiy bvvA »ij.ne«\'J .■ ,;?cc ao'.mpic;y ;^l ,.0 ywo.>oM .bno! .M ,no3:ori>( b'^slovi ?i ' il^ oiii no (T3n) •*" " ;l y •■ I i on'-l i'oH n lo rfo33t5 ‘ , .iVt. A ,b-j -'C nflt> A^H naqlA ,llii^ ,S3i-OG '■'') ■ . ‘ HqO .doiA '\8!'.'otdu(" bri"^ /l!r'»-iT •-.; .f/-r)oA -- \ ii^l nnA ' ..r jr^onar^'^ •rli:i3 TaJoJR 'c ybqoi^O’MdJS Uui'r «•.. '"A" ^ .^ ^aibftoJ dO' ' .IL-.m-:!/ .•< .:,-5‘onoitoM »<'*;'-.■!■; '•.sr.vA . .,.0 .'/ , •■ ri'tA . b'*' ' Hr«' tT . '(•:o;9M llo ?f*.'yT':‘’ . .b uolD b'^n . j .,.*JbnDJ fC.9f J 9^- ((S:Sv .ion:/y.f3 A , ^n*- * nu 4 'i>:.i^. , ,n V .nonon'^ bn*- .-A , 1 ,i'*.cwili.£ » A.'v' ,r»o?‘tddlJ nz '^'ji'U a'''joifodox«f! 3o et;'>V43 o.'b t:> <.7*bot.? ’ »£0t Af^;C .U)iHoy»v7CA '\|lc;A.nc. c»nloO !■ Ivr PO'*o:*b^M c ivoiHlofiad^ Hl?\v r.*5oriDflD x'iO'»“'?i2" ^ v'-v* boo .M.G Ao?! ,cTf*961 i9€f uiG , .v*«5it'* ,1.oinbtilq:-'::ir^?2 r.l ...4 40, McGaugh, J,L. , de Baran^, L. and Longo, V.G,, "Electroencephalographic and Behavioral Analysis of Drug Effects on an Instrumental Reward Discrimination in Rabbits," Psychopharmacologia 4;126-138, 1963 Meltzer, D. , "Effects of Drugs on Approach Discrimination Under Two Deprivation Conditions," J. Comp. Physiol, Psychol. 59;289-292, 1965 ” “ Mendelson, J. and Bindra, D, , "Combination of Drive and Drug Effects," J. Exp, Psychol. 63:505-509, 1962 ~ Mishkin, M. and Weiskrantz, L. , "Effects of Cortical Lesions in Monkeys on Critical Flicker Frequency," J. Comp. Physiol, Psychol. 52; 660-666, 1959 “ Mowbray, R.M. , "The Effect of ECT on Perception of Flicker," Acta Psychiat. Scand, 36:149-156, 1961 ~ Olds, M.E. and Olds, J. , "Pharmacological Patterns in Subcortical Reinforcement Behavior," Int. J. Neuropharmacol. 2:309-325, 1964 Ostfeld, A.M. , "Effects of LSD 25 and JB 318 on Tests of Visual and Perceptual Functions in Man," Fed, Proc. 20:876-884, 1961 Von Post-Lingen, M-L. , "The Significance of Exposure to Small Concentrations of Carbon Monoxide," Proc, Roy. Soc. Med. 57:Suppl: 1021-1029, 1964 Purpura, D. P. , "Electrophysiological Analysis of Psychotogenic Drug Action," AMA Arch. Neurol. Psychiat. 75:122-131, 1956 Purpura, D. P. , "Experimental Analysis of the Inhibitory Action of Lysergic Acid Diethylamide on Cortical Dendritic Activity," Ann. N.Y. Acad, Sci. , ^:515-536, 1957 Ray, O.S. , "The Effect of Psychotogens on Approach and Avoidance Behavior," Int. J. Neuropsychiat. 1:98-103, 1965 Schwartz, A.S, and Cheney, C. , "Retinal Effects of High Doses of LSD in the Cat," Exp. Neurol. 13:273-282, 1965a Schwartz, A.S. and Cheney, C. , "Effect of LSD on the Tonic Activity of the Visual Pathways of the Cat," Life Sci. 4:771-778, 1965b Simonson, E, and Brozek, J. , "Flicker Fusion Frequency: Background and Applications," Physiol. Rev. 32:349-378, 1952 ^qo'';'5C'';'''v. -•eytoi} «>b J.i ■,di^judO ' oirrr^'.jr^.'M/ na noelKpr ' ;;:• / »'Y!fy>A b»^i' ' ' v ’ '; r biV-'! ”bx^:^ o.ieola'X^tTr)fo.'<:4CA'l.?v?1 ' ^yUdiioU (ii{ ' ' '. "/* . ■•/tU rjo(to;ilrf‘ri:><;tG d:.' ji^A Tjeo'^-iv-’iC!; '(;, . .. ilA*’ , ,o , . i ,.q,TK.D .{, q iO'b'v ^ ■»- •• CXi'^' .1 ", ?■ :jjfiH ' 'I.-.'-Av.i .'. ooi'wiiciitKil'i* ^ i.l a-'ibaiii .-■•o .s , '.. par^noM ri^^r,9^-ec^;£A no ..-s-:J 'Cj^itiop ^ . .J , i '• ■■'■ M ,'■ir-*r'.-'»M :Se AoV .. . '■• iS' ..;n,o") .'. •', , .>,tSDf.-‘‘'-'^’1 iV ■j ' '' .TO'-'a. ')•■^ I TO r.oi : •■■S /' 1: 9fiT- , M .v-.niiwoM ;'v'-*6?* 5-,' :' ii>Dinc:>Jv'c nl ^-TfStti.S |Dj’{:oioiJn'Ti«rH' , ^ v.3.M ^ io\^Uyj„ ’ fr,'..- V tc rj.-; ^/, '■.’•(n.r’ 01.: ;•;,-jifS ~ , .A/ .A ! A ''•'.roi'’! ' •’uM i! M'I >- * ■ ino ti • '.e-,^r I ^ ■ K Mneld :*HT'' . fJoV -KCf AqqocAd . ,5oJ - A ^ . » '"ii '■• > ‘. ’C^V lO ",nt*. -^A -. :r-spo*cd.. f. ■' 'o : , AnnA .oui^!.?* :y;-i'i ti.'-o' ubJCfTO*! , ibi-A;;[;e': /vM^ b'.''A ,Aq , . jx.! I;. -ivItoA/f-i; ■ ;c; x.-A ''-,tr>tt.pri**-:(,-,l-i'' ^ .O-^ou/qiu*? .ox:>A 'll (it vJf^A aA. ,v/iT ■ ■ ■ , , \i9f -•• A* .A;^ ,■ ‘ A’ -‘^Aov A br»c rlacoi',:- 'i.:t :-'-*<■1. ' ,. : ' Cl.) ir' V r»»o(3 •„> A_ A C’ xtx'. .i'.A ,\f>cwH^2 \C:>y. '-t .t^3 ".toD I ©fif Vo ;A'/.’. A .>»r»o.’' 'J. ■ nc- 0?J Vo 15<.0j3" .» !■ , yfsr.snO bno ,~.A r.? .'rwr^oc • j’Av : -,S^'.\-' 1 \■-^ .fot yVlJ " , fcD ©'ll I-- .\oy.'"^fi:''i loutiV br : .': r 7 ^ noboi ^.C ,.>J3\ci8 bot.i 3 ^noenomlS ,8\t--^ACr£C .vo/'^ Jo fey " ,-^notiodti<^qV* 41. 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' ■»•* ’ ■iWBt'-a . •V. :"’■ 1 ? < rii* W,.*l YALE MEDICAL UBRARY Manuscript Theses Unpublished theses submitted for the Master's and Doctor's degrees and deposited in the Yale Medical Library are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but passages must not be copied without permission of the authors, and without proper credit being given in subsequent written or published work. This thesis by has been used by the following persons, whose signatures attest their acceptance of the above restrictions. NAME AND ADDRESS DATE