Federation Proceedings 3/7, No. 3, (1978) 273

LSD-LIME HALLUCINOGENS IN THE DOG: VALIDATION STUDIES WITH ACUT_ AND CNSONXC I_rr_P.ACTIONS S_.EN A_-TZTP-AHYnROCANNA - MESCALINE (MES), PSILOCIN (PSI} AND DIMETHYLTRYPTAHIN£ (DMT). BINOL (_9-THC) _O PE_roBARBIT^B IN _ PIGEON. D._. McMillan, DR Vs..m]* and W.R, Marttn. NIDA Addiction Research Center. _eparunent of Pharmacology, School of Medicine, Univer$it-y_ Lexington. Ky. 40583, -- North Carollnar C_lapel Hill, N.C. 27S14. Single dose (t.v.) effects of MES(4 mg/kg), PSI (0.05 mg/ Pigeon= were trained to peck a response key to obtain kg) a,d DMT (0,3 mg/kg) were evaluated tn nontolerant and LSD food under a multiple fixed-ratio 30 response, fixed-interval tolerantchronicspinaldogs, AppetitesupgresSa.teffectsof 5-mln (mull FR 30 FI 5) schedule of relnforcement, Intra- MES and PSI were assessedIn intactdogs. Inn0ntolerantdog_ muscularIn_ectlonsof pentobarbltalproduceddose-dependent MES, PSI and DMT speclflcally resembled LSD (15 uglkg) and not decreases in the rate of reapondlng under both schedule eom- d-amphetamine (A) (2 _/k 9) with respect to thelr physiologic ponents. A dQila of Ag-TNC (l.O mg/kg) that produced no oon- and behaviora_ effects. LSD tolerant dogs (30 P9 LSD/kg/day) slstent effect when given alone, greatly potentiated the were cross tolerant to PSI and MES but not A. Partial cross cete-deereaalng effects of pentoherbital. Subsequently, the toleranceto DMT developedas itsmydrlaslsand facil_atlve pigeons w_re made tolerant to the effects of _9-TBC by plying effect on the flexor reflex were not slgnlflcantly reduced, lO mg/kg injentionB after the test sessions onM ondaye and These results are In agreement wlth clinical pharmacologlc Wednesdays and 20 mg/k9 injections after the test session on studies (Psychopharmac010gia2;147, 1961; 3:1, 1962; 3:219, Fridays for 4 weeks. Birds tolerant to Am-TaG were cross 1962; 5:217, 1964). LSD, MES and PSI administered s.c. sup- tolerant to penbobarbital, as demonstrated by a shift in the pressed food intake _n dog and produced parallel dose-response dose-affect curve that was approximately two-fold. Further- curves. However. their slopes were significantly less than more, in birds tolerant to 6_-THC the 1,0 mg/kg dose of A9. that of A. LSD, MES and PSI did not completely abolish food TBC no longer potentiated the rate-decreasing effect ofpento- intake as did A. In conclusion MES, PSI and DMT are pharma- barbital. Is fact_ these birds also showed an approximately cologlcally equivalent to LSD in the do9 as they are i, man htwlgho-foldec dosshes,ift Tofhus,the thpentobe acutarbitale combinationdose-effeofct a scmuarllve dtowarose do_ su_gesttn 9 that the dog can be used to assess c(xnpounds for _9-_c shifts the pentobarbital dose-affect Curve downward and tSD-llke activity, to the left, but in birds tolerant to 69-THC the pentobarbitai dose-effect Curve shifts to the right, regardless of whether or not the small dose of _9-THC is present. (Supported by NIDA Grant #DA-00570.)

_8 _HARMACOLOGY _29 PH_SMACOLOGY

THE BIPHA_IC EFFECT OF _9-TETRAHYDROCANNABINOL (Ag-THC) ON EFt:Eel'S OF MET}I/_IPHETAMINE ANP HALOPERIPOI. ON FINE M_I'OR CON- THE UPTAKE OF CATECHOLAMINES INTO SYNAPTO_OMES FROM RAT TROL BEFORE AND AFTEII REPEATED I_IECTfONS OF HETIbgWIIET_HNE, HYPOTHALAMUS AND CORPUS STRIATUM..M K. Pode_...... dsr t ....W.L. Deweez_- C.E. Joh_C_..Schustor, T. Ai_ner* and L.S. Seiden, a.d L.S. Harris. Dept. of Pharmacol., Mad. Col. of Vs., _f Chicago, Chicago, Ill. 6(_37 VS. Cotmm. Univ., Richmond, VA 23298. Three rhesus monkeys were trained fo extend tbeir arm and Concentrations of Ag-THC ranging from O.Ol to 100 uM were hold a lever with between 25 and 40 g of force for 3 or 5 con- tested for their effect on the uptake of 3H-dopamlne iDA) tinuous sac. Following each response of correct _brce and and 3R-noreplnephrlne (NE) Into synaptosomal preparatlons duration_ 1,5 ml of water was delivered. Sessions were con- _ao]ated from rat corpus stristum and hypothalamus. Concen- tinued uetil 50 water deliveries or 30 min had occurred. When tratlons of 0,05. 0.1 and 0.2 _M &9-THC caused a elgttlficaet rate and _atter_ of responding became _table, single i.m. in- increase in the _ptake of OK in the corpus strlatum (2&,34 and jections of either methamphetamine (HA) (O.O6-0.5 mR/kR) or 33% respectively_ and at O.I and 0.2 UM to the hypothalemua ha loperidol (HI (0.O1-0.08 m_/kg) were give_% 20 m_n before the (28 and 25Z respectively). At higher eoa%centrst_ona (IO _H session. Daily sessions were then terminated. Animals were and I00 BM) &9-THe caused a sl_Ifieant reduction in the given 2 dally i.m. injections of )_A for a period of 4 months. uptake of DA into corpus strlatum (35 and 80_ respectively) The dose was gradually increased from 0.5 to 16 mR/kg/in) as a_d hypothalamus (25 and 4BY respectIvely_. Similarly, con- tolerance developed to MAts anorcxigenic effects. Two weeks centrelines of 0.I end 0.2 uM 69-THC caused a aignlflcant following the cos_letion of this regimen, sessions were re- increase in the uptake of NE into the hypothalamus (33 and 2&_ armed. When responding became stable (2 months later), single respectively) and O.I _M hut not 0.2 pM 69-THC increased the injections Of MA and H were given as before, For 2 of the uptake of NE into the corpus strletum (38Z). ConcentratJoas animals, higher doses of MA were required to disrupt respond- of 10 and I00 UH &9-THC signlflcantly decreased the uptake of ing, indicating tolerance. For the third an/mal, there was NE into both hypothalamus and corpus strlatum. Concentrations no change. For both animals given 1|, lower doses d/erupted of O.OI and I uH were Insetlve on the uptake of both DA and NE. responding, indicating increased sensitivity. These c_anges _eee biphas_c effects of 69-q_HC on brain eatecholamines may in responsivity to _ and H are consistent with our prior explain the dual stimulatory-depreseant effects of thls drug findings that the repeated administration of HA produces in mice. (Supported by USPHS grant no. DA-004901. marked irreversible depletion of dopamine in the ni_ro_str}a- tel tract. (Supported by USPI_ NIDA Grants DA-OO2S0, -OO085 and -O00241

390 PHABMACOLOOY _3| PHARMACOLOGY

DEIr_LOPHE_IT OF Ct_8 TOLERANCE TO E_RBITAJ_ AND P_NTOBARBIT/L5 DIFEERENTIAL FUNCTIONAL IOLER.aiICE DEVELOPMENT AFTER ADHINIS- IN PATS. Judith A. Richter. In4t*.na U. Med, _h,_ TRA'ItON OF PHENOBaRBItAL [I'B) OR N,N-DIHETIIOXYHETHYL-PB (DB_W) In¢lanaPollm, IN h_202 IN TIIE RAT, L.S. Freer* J.A. Nuite* and B.B. (;allaj_[_, In order to develo_ _n in vltr_mo_el of br&in tolermnce Dept. of Pharmacol,, Georgetown Uni_,, Washington, I_ 20007 to _arblt_rates, we are teetlnK various me%ho_ of a_nls- There is some evidence that despite the sequential metabo- %ration of bsrblgsl (B) a_d Dentob_rbltal (PB) %o r_ts %0 de- lism of the snticonvulsant DMblP (eterobarb) to N-methoxy- velop _n vi-*o CBE to%e_oe. When Inereaslng concentre%ions methyl-PB (N_iP) and PB, less sedation accompanles the use of of B were supplied to rats In thel_ drlnki.K w&tem (Morgan DMMP than equiequivalent doses of PB alone. To _nvestigate e.__t_l,, Life Bet. 20: %93, 19771, br_dn eald pl_sma levels of the possible role of differential tolerance development to PB B gradueO.ly rose over the one month period to 800 nmoles/g following D_P administration, rats were acutely administered and 1_OO nmolee/m.l, respectively. After a test doee of _aB pharmacologically equivslent oral doses of PB or DMMP and l,p. toler_mt rags had at least twice the amo*mt of E u con- sacrificed at the time of loss of fhe righting reflex (LRR). trols in their brains at aw_kenlng. A smaller @tree of in PB _ _@4P were analyzed simultaneously by GLC. Mean brain w_vo. tolerance to PB ha_ been achieved by daily s.c. In- barbiturate levels, determined after acute PB or D_P, of Jecttons of Increasing 8mo_mte of PB In an oil suspension for 41.2 ± 2.6 (PB=IO0%) or 75,8 t 2.4 (PB=80%, MMP=20%} 0g/gm of h-5 days. Peak brain levels of _O nmolee PB/g were found wet weight tissue, respectively, were significantly different. ai'_er the lut injection. After a test doee of H_/_B l,p., To compare tolerance development, a "chronically equivalent" tolerant rata had 1.3-i.5 times ae mush PB ae control eats in dos_nK method (8oisse _ Okamoto, JPET, in press) was adapted their brains at awakening, ffowever _here was no decrease In for rats. After progressively increaslog doses of PB or O_IP the inhibition by PB in vitro of K+-stlmulate_ aeetyleholine were chronica11y (6 days) administered, mean brain barbiturate release from mldbraln ellces from PB-toler_nt rttte scampered levels at LRR of 80,S ± 6,3 (PB=lO0%) or li0.2 t 4.5 (PB=99%, to controls. These results s_ggee% either %ha% • greater _e- _MP=I%) Dg/gm, respectively, showed a sig1%ificant increase tree of CBS tolerance in vlvo manet be achlev_d in nrder to oh- after chronic D_P when compared to chronic PB. The differ- serve %clefs.nee %o this i_vi_l'9," effect, or that the toler- ences between acute _ chronic PB or D_FFiPwere else signifl- anee m_ not be cauae_ by a ehmage in release meeh_ati_ms, cant. These results indicate that the change in tolerated Further work ie In proKress to develop a hlgher degree of in CNS concentration o_ harb_turates foIIowlng DRgP administra- vivo CNS tolerance to PB in order to tes_ %hess poasibilltles, tics may he due to an h,crease in functional to]erauce devel- S_S_'pported by NIDA grant No, DA 00796). opment, ISupported by NINCDS (;rant NS Ii12b)