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Nabtic Trammi I¢,Tt I T the Lateral G.Tnicvdate / ')Ldcus of the ( At

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Nabtic Trammi I¢,Tt I T the Lateral G.Tnicvdate / ')Ldcus of the ( At Psychopharmacology. Pharmacologic effects on behavior. Ed.by: Pennes, H.H. Hoeber-Harper, New York 1958, p. ]_73-2o2.. LSD 633/BOL CHAPTER Vlll Effect,s _f a Series tf lndolcs on ,S)'nabtic Trammi_i¢,tt i_t the Lateral G.tnicvdate /_')ldcus of the (_at EDWARD V. EVARTS SINCE tloffman's origillal observation (20) on the psychologic effects of d-lysergie acid diethylamide (LSD), its mechanism of action has been the subject of considerable investigation. The observations of Woolh_v a_d Shaw (21) and of Gaddum (11) on the antagonism of LSD to the effects of 5-hydroxytrypta- mine on smooth muscle have suggested the possibility that the psychologic effects of LSD in ma_ may be the result of an in- teraction between LSD and 5-hydroxytryptamine in the central nervous system. The observations by Pletscher et al. (16) on the effects of reserpine on 5-hydroxytryptamine levels in the brain have suggested that the neuropsyehologic effects of reser- pine may also be related to an interaction with the latter. Re- cently, Gaddum (]2) and Rothlin (19) have criticized the theory that mltagonism of LSD to an action of 5-hydroxytrypta- 173 I r! 174 PsYt'HOPtiAI_MACOLOGY mine is involved in the effects of LSD on the brain; both in- vestigators point out that a number of 5-hydroxytryptamine antagonists, the in vitro potency of which (as tested on a smooth muscle preparation) is equivalent to that of LSD, do not pro- duce psychologic effects of the type produced by LSD. It would appear, then, that the degree to which the effects of LSD on cerebral function are related to 5-hydroxytryptamine is still a matter of speculation. The experiments to be described were carried out to obtain further data concerning certain electro- physiologic effects of 5-hydroxytryptamine, LSD, and of a series of tryptamine and LSD derivatives. It seemed that such data might be relevant to the question of interaction between LSD and 5-hydroxytryptamine in the central nervous system. One of the eleetrophysiologic effects of LSD is depression of synaptie transmission in the lateral genieulate nucleus (9). The present study reports observations on the effects of a number of indole derivatives on lateral genieulate transmission. These in- doles mav be divided into the two general categories of trypta- mine derivatives and of LSD derivatives. The effects of these agents alone and the interaction between these agents and LSD were observed. There were several reasons for selecting the lat_.ral genieulate nucleus as a site at which to test the effects ,_f and interactions between the various indole deriva- tives First, the f¢mn of file genieulate response to optic nerve shock is separal_le into easily measured presynaptie and post- synaptie conq_<mt.nts (8). Secolld, genieulate transmission is depressed by LSD at a dose which does not depress transmis- sion at other _ynapses in the primary ascending visual system, i.e., the s,vnaps¢,s of the retina and of the geniculate radiation fibers with cortical cells (9). The high degree of resistance to LSD-induced depression at geniculocortical and retinal synapses suggests that block of geniculate transmission by LSD is not the result of a nonspeeific depression of central nervous system activity. LSD causes a marked reduction in the amplitude of the postsynaptie response to single optic nerve shock; however, following closely spaced '2-10 msec.) stimuli to the optic EFFECTS OF INDOLES ON SYNAFFIC TRANSNIISSION 175 nerve, recruitment occurs, and a postsynaptic response of almost normal amplitude may be recorded (9). With sufficiently large doses of LSD, geniculate transmission may be almost com-- pletely blocked, and recruitment does not occur. This type of change in the pattern of geniculate excitability is not produced by acute asphyxia, which, in the nembutalized preparation, causes a decrease in tile amplitude of the postsynaptic genicu- late response without recruitment. Bishop and McLeod (2), after extensive studies on the effects of asphyxia on geniculate transmission, concluded that asphyxia itself could not produce any steady degree of block of geniculate synapses, since that level of asphyxia which caused block of geniculate transmission also disrupted the animal's vital functions and led to changes in the excitability of presynaptic structures. Their studies indi- cate that any steady degree of block of geniculate transmission by a given drug is unlikely to be a secondary result of the drug's effects on cerebral oxygen tension. The characteristics of the lateral geniculate response, there- fore, are such as to make it a suitable object with which to study drug interactions. Unfortunately, a number of character- istics of the geniculostriate system decrease its utility as a site for studying the mechanism of LSD action. The dose of LSD required to depress geniculate transmission is considerably greater than that required to depress certain other central nervous system synapses, particularly those mediating tile trans- callosal response (15) and the suprasylvianstriate reaction (18). Furthermore, the drugs being investigated cannot be ap- plied directly to the area where they presumably act, but must be administered bv an indirect route. Such indirect administra- tion is unsatisfactory, in the case of certain indoles. 5-Hydroxy- tryptamine, for example, undergoes rapid destruction in t:ivo, so that absence of effects even following its intracarotid adminis- tration may indicate only that the agent has not reached the site from which electric recordings are obtained. In the case of quaternary ammonium compounds, absence of effect after in- travascular administration may be the resldt of failure of the 176 PSYCHOPIIARMACOLOGY quaternary ammonium ion to cross the blood-brain barrier. These factors must necessarily limit the interpretations which may be based on the data to be presented. MATERIALS AND METHODS Cats weighing 2.5 to 4.5 Kg. were anesthetized with 30 mg./Kg, sodium pentobarbital (Nembutal), intraperitoneally. The optic nerve was.dissected free; stimulating electrodes were placed on the cut edge of the sclera (+) and on the optic nerve (-). Stimuli to the optic nerve were nearly square pulses of approximately 30 _tsee. duration. The intensity of optic nerve stimulus required to produce a near maximal geniculate re- sponse varied from preparation to preparation, over a range of 1,5 to approximately 5 volts. The geniculate response was re- corded with a stereotaxically placed steel needle insulated to the tip; the tip diameter was approximately 100 F" The cortical CH3 H H il HO CH2CH2NHz _---_FCH2CH2N_CH3 • I VI _N- _ /CH3CH3+ _ H H III HO CH?.CH2N,.cH3 HO CH2CHtN,,c41.19 H H IV {_---_-CH2CH2N_ CH3 CH_lO_"_---Tr- CH2CH2N_CH3 VIII _,_,,,N _ CH3 CH30_ CH3 H H Fzo. 16. Structures of tryptamine derivatives whose effects on genieulate trans- mission were studied. Compounds I, III, and IV caused depression of geniculate • transmission; the remainder were without effect on the lateral gerticaalate body or the cortical responses to optic nerve shock. EFFECTS OF INI)OLES ON SYNAPTIC TI_.NSNIISSION 177 response to stinmlation of the optic nerve was recorded from the lateral gyrus with a pore electrode filled with Tyrode's solu- tion. The brain was covered with a pool of continuously flowing Tyrode's solution which was maintained between 36 and 38 °. The cat's body temperature was also maintained at 36 to 38 °. - Drugs were injected intravenously or via the carotid artery on the side from which geniculate recordings were obtained. Eight tryptamine derivatives (Fig. 16) and four LSD deriva- tives (Fig. 17) were used. Dimethyltryptamine, _ bufotenine, b and 5-hydroxytryptamine _ were obtained as the free base and dis- solved as the creatinine sulfate complex. Tryptamine, c 5-hy- droxy- .3-(fl- dibutylaminoethyl )indole, d 5,6- dimethoxy- 3- (fl- dim ethylaminoethyl )indole, _ and g- ( fl- (2-methylpiperidyl ) ethyl)indole h were obtained in the form of the hydroehloride. Bufotenidine" was obtained as the iodide. LSD t and 2-bromo LSI) t were obtained as the tartrate. 2-Oxy LSD, _ a metabolic product of LSD, was formed from LSD by in vitro incubation of LSD ill a microsomal enzyme preparation (1). Gramine" was obtained as the free base, and dissolved as the hydrochlo- ride. 2,2'-Bis LSD disulfide _ was obtain6d as the free base. All of these drugs were obtained in solid form and dissolved in Tyrode's solution shortly before administration. In the case of the last two, a small amount of dilute HC1 was required to pro- mote solubility. The volume injected over approximately l0 sec. was 0.5 to 1.0 ml. regardless of the amount of drug administered. The drags were injected through a polyethylene canula placed in a small muscular branch of the common carotid artery, and ad- vanced to a point at which the tip of the canula was within the a Supplied by Upiohn Comp, ny. bSupplied by Dr. Evan Homing, National Heart Institute, National Institutes of tlealth, Bethesda, Md. c Supplied by the Eastman Kodak Company. a Supplied by Dr. Gordon Walker, National Heart Institute, National Institutes of Health. e Supplied by Dr. Melvin Fish, National Heart Institute, National Institutes of Ilealth. t Supplied by Sandoz Company. a Supplied by Dr. Julius Axelrod, Naional Institute of Mental Ilealth, National Institutes of Ileahh. h Supplied by Eli Lilly Company. i Supplied by Dr. Bernard Witkop, National Institute of Arthritis and Metabolic Diseases, National Insti- tutes of Health. 17_ PSYCHOPHARMACOLOCY /C2H5 IC2H5 H H H L SD 2-OXY LSD 2-BROMO L.,qD c4N_CZH5 C2H5",.u I_C C2H5 C2 H5"o_pC H H 2,2'-BIS LSD DISULFIDE GRAMINE Flc. 17. Structures of four LSD derivatives and granfine. Of the former, only LSD caused depression of geniculate transmission; the other three were with- out effect on the geniculate or cortical responses to optic nerve shock.
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