d tion. Cold Spring Harbor Symp. Quant. Biol. (In cord was isolated from afferent input by a section of s press) the dorsal roots, indicating a direct spinal cord action e 2. Klainer, L. M., Chi, Y.-M., Friedberg, S. L. et al. (8). This facilitatory action was blocked by cyprohep- 5 Adenyl eyclase. IV. The effects of neurohormones tadine; whereas phenoxybenzamine blocked the facti- on the formation of adenosine 3', 5'-phosphate by itatory effects of methoxamine, showing that trypt- ) preparations from brain and other tissues. J. Biol. aminergic and noradrenergic processes are distin- Chem., 237:1239-1243, 1962. guishable in the cat and tile dog (1, 8). Tile C-fiber 3. Kebabian, J. W., Petzold, G. L., and Greengard, reflex in the acute decerebrate spinal cat, a nocicep- P. Dopamine-sensitive adenylate cyclase in cau- rive reflex related to the flexor reflex in the cbronic date nucleus of rat brain and its similarities to the spinal dog, is facilitated by LSD and tryptamine {9). • dopamine receptor. Proc. Natl. Acad. Sci., This effect was blocked by cyproheptadine and ' 69:2145-2149,1972. methysergide.Tryptamine administered close arteri- ally to the spinal cord in smaller doses also facili- tated the C-fiber reflex, indicating a direct action of Tryptamine in the Brain and tryptamine on the spinal cord. L-tryptophan also facilitates the C-fiber reflex, and this seems to be a Spinal Cord: Its Role in the LSD consequence of increased activity of tryptaminergic Response .... neurons rather than serotoninergic neurons in the C- fiber reflex pathway since its actions are antagonized W. R. Martin, M.D.,* J. W. Sloan, B.S.,* by a-methyl-DOPA and cyproheptadine but not by parachlorophenylalanhle (pCPA) (10). Additional sup- D. B. Vaupei, Ph.D.* et al. port for this hypothesis was obtained when it was found that 5-hydroxytryptophan (5-HTP) did not The administration of tryptamine to the chronic facilitate the C-fiber reflex (10). spinal dog produces a syndrome characterized by facilitation of the flexor reflex, evocation of the Tryptamine levels are slightly higher in white stepping reflex, body temperature increase, pulse matter than in gray matter, suggesting that tryptam- rate increase, respiratory rate increase, and dilation ine could be present in both long axons and of the pupils (1). The syndrome is similar to that interneurons. Furthermore, changes in regional trypt- produced by LSD and the LSD-like hallucinogens, amine concentrations were seen resulting from mescaline, psilocin, and DOM. Also, many of these transection of the spinal cord (4). Increases in effects are produced by LSD-like hallucinogens in tryptamine concentrations above the transection in man. Intravenously infused tryptamine produces the mesencephalon, cerebellum, pons medulla, and LSD-like effects in man i2). spinal cord resulted from a retrograde damming of Tryptamine is widely distributed throughout the tryptamine with proximal accunmlation in axons and _ central nervous system of several species including cell bodies. Thus, tryptamine from cells that project ] -'- man, steer, cat, dog, guinea pig. and rat (3,4). The from snpraspinal sites probably have stone modula- J cerebral cortex, caudate, hippocampus, hypothala- tory effect on spinal reflexes. In support of this mus, and thalamus of the dog release tryptamine hypothesis, it was fi)und that L-tryptophan, which (5,6). Pentobarbital anesthesia decreases and mono- facilitated the C-fiber reflex in the acute spinal cat amine oxidase inhibition increases tryptamine re- (10) and the flexor reflex in the acute spinal dog. has lease; whereas, intravenous infusion of tryptamine no effect in the chronic spinal dog (1). This was that increased blood levels from 9 ng/ml to 4000 believed to be due to a degeneration of descending ng/ml did not significantly increase tryptamine re- tryptaminergic pathways with a consequent atrophy covered in perfusates, of the mechanism tbr converting L-tryptophan to Tolerance to the effects of LSD in the chronic tryptamine presynaptically at tryptaminergic syn- spinal dog and cross tolerance to tryptamine could apses. Conversely, LSD was fimnd to have a greater be demonstrated (7). facilitatoryeffect in the chronic spinal rat than in the Spinal cord studies of tryptamine were extended tl, acute spinal rat (11). This could be exl, lained by the segmental and C-fiber reflexes of the acute increased sensitivity of tryptamine receptors due to decerebrate spinal cat. Tryplamine increased the denervation. These ohservations argue that there are mono- and pnlysynaptic retlcxes when tilt: Sl,iual spinal cord descending facilitatory tryptaminergic pathways, and I,SD-like hallucinogens vause reflex * Divisio(,fnR...... h, Add_,:,io,R....... hq:_,,,_,,NIDa.L_,_,o,, K_n,_ky facilitation by acting as tryptaminergic agonists. 31 Because of the marked effect of LSD on feeling l l. Nozaki, M., and Bell, J. A. Responses of flexor states, perception, and thought processes and its reflex to LSD, tryptamine, 5-HTP, methoxamine, relationship to tryptaminergic processes, it has been and d-amphetamine in acute and chronic spinal concluded that the function of tryptaminergic neu- rats. Fed. Proc. (In press) rons could have psychiatric importance. Excessively 12. Martin, W. R., and Hewett, B. L. (Unpublished low activity of tryptaminergic neurons could c,mtrib- observations) ute to hypophoria which is common among narcotic addicts and alcoholics (12), while overly active tryptaminergic neurons could contribute to thought Session II disorders and perceptual distortions. Octopamine: Normal Occurrence References in Centraland Peripheral Nerves of Rats* 1. Martin, W. R., and Eades, C. G. The action of tryptamine on tile dog spinal cord and its relationship to tile agonistic actions of LSD-like Perry B. Molinoff, M.D.** psychotogens. Psychopharmacologia ( Berl ) , 17:242-257, 1970. In 1948, Erspamer (1) showed that extracts of the 2. Martin, W. R., and Sloan, J. W. Effects of posterior salivary gland of Octopus vulgaris had infused tryptamine in man. Psychopharmacolo- hypertensive effects on blood pressure after the gia(BerO, 18:231-237, 1970. extracts were irradiated with ultraviolet light in the 3. Martin, W. R., Sloan, J. W., Christian, S.T., presence of air. He named the parent substance and Clements, T. It. Brain levels of tryptamine, octopamine and identified it as 1-p-hydroxyphenyl- Psychopharmacologia (BerO, 24:331-346, 1972. ethanolamine. Kakimoto and Armstrong carried out 4. Sloan, J. W., Martin, W. R., Clements, T. It., et extensive studies of the phenolic acids in mammalian al. Factors influencing brain and tissue levels of urine (2,3). They found large amounts of an acid lryptamine: Species, drugs, and lesions. J. Neu_ which they tentatively identified as _p-hydroxyman- rochem., 24:523-532, 1975. delic acid, and they reasoned that it could be derived 5. Martin, W. R., Sloan, J. W., Buchwald, W.F., from octopamine. Chromatographic techniques were and Bridges, S. R. The demonstration of trypt- used to identify octopamine in the urine of rabbits amine in regional perfusates of the dog brain, that has been pretreated with iproniazid, an Psychopharmacologia (Berl), 37:189-198, 1974. inhibitor of monoamine oxidase. Using similar tech- 6. Sloan, J. W., Martin, W. R., and Buchwald, W. niques, Kakimoto and Armstrong (2,3) detected octop- F., Tryptamine in perfilsates of acutely decere- amine in the urine of humans and rabbits. Although brated dog. Fed. Proc., 34:307, 1975. octopamine was fimnd in various organs of rabbits 7. Martin, W. R., and Eades, C. G. Cross toler- treated with monoamine oxidase inhibitors, it was ance to tryptamine in the LSD-tolerant dog. not detected in tissue extracts of untreated animals. Psychopharmacologia (Bed), 27:93-98, 1972. The discovery that octopamine is a normal constit- 8. Vaupel, D. B., and Martin, W. R. Interaction of uent of mammalian tissues under some conditions oxotremorine with atropine, chlorpromazine, cy- led to several investigations of its biosynthesis (4-6). proheptadine, imipramine, and phenoxybenz- The administration of labeled tyramine led to the amine on the flexor reflex of the chronic spinal fi_rmation of octopamine which accumulated in adren- dog. Psychopharmacologia (Berl), 30:13-26, ergically innervated tissues. The ability of rat 1973. salivary glands to retain aH-octopaminewas de- 9. Bell, J. A., and Martin, W. R. Studies of creased by about 90 percent following denervation, tryptamine and lysergic acid diethylamide (LSD) suggesting that the conversion and retention of on cutaneous C-fiber and polysynaptic reflexes octopamine takes place in adrenergic nerve terminals in the cat. J. Pharmacol. Exp. Ther., 190:492- (7). Following the administration of :;H-tyramine, 3[-1- 500, 1974. octopamine accumulated in sympathetic storage 10. Bell, J. A., Martin, W. R., Sloan, J. W., and granules (8). It was released by stimulation of the Buchwald, W. F. The effect of L-tryptophan on spinal cord C-fiber reflexes. J. Pharmacol. Exp. *Supported by theUSPttSiNS102_)6}. Ther. (In press) **_p_,m_,toreh..... Io_y.U,_,_,_ ,,fC,,Io_,,.I_..... CoUo,._o 32 , _.................. ..... r l_ _ ............ IlL_ I _..........1 Ill.