Abstract
This study examined the effects of various drug treatments (IP injections) proposed to modify central 5-hydroxytryptamine (5-HT) activity on a conditioned suppression of drinking behavior in water-deprived rats. The subjects were trained to drink their daily water requirement during a 10-min session. Intermittent tone periods of 7 s were then introduced, the last 5 s of which the drinking tube was electrified. The animals gradually suppressed tube contacts during the tone to a low constant level within 2 weeks of training. Diazepam increased punished responding dramatically. The 5-HT antagonists methysergide (1–18 mg/kg), cyproheptadine (1–18 mg/kg), metergoline (0,25–2.0 mg/kg) and cinanserin (10–100 mg/kg) failed to induce large, reliable increases in punished responding. When a low dose of diazepam was combined with 5-HT antagonists, only one treatment, methysergide at 3 mg/kg, potentiated the anticonflict activity of diazepam. Acute or chronic treatment with PCPA increased behavior suppressed by punishment, but this effect was weak, brief, and poorly related to the depletion of brain 5-HT. LSD (0.3–100 μg/kg) administered 1,10, or 30 min before the test was ineffective in overcoming suppression by punishment. Mescaline (6–30 mg/kg) had no significant effect on punished responding. 5-HTP (18 mg/kg) decreased the number of shocks accepted, but not after pretreating with carbidopa. Pretreatment with carbidopa plus 5-HTP potentiated the anticonflict effect of diazepam. The 5-HT agonist mCPP (0.25–2.0 mg/kg) enhanced suppression due to punishment, but only in doses that interfered with unpunished responding. The 5-HT-releasing agent fenfluramine (0.25–1.0 mg/kg) did not affect this behavior. Amitriptyline pretreatment in a dose not affecting unpunished behavior (5.6 mg/kg) potentiated the diazepam-induced increase in punished responding. These results are difficult to reconcile with the proposal that suppression of behavior consequent to punishment is related to brain 5-HT activity.
Similar content being viewed by others
References
Aghjanian GK, Foote WE, Sheard ME (1970) Action of psychotogenic drugs on single midbrain raphe neurons. J Pharmacol Exp Ther 171:178–187
Andrews DW, Patrick RL, Barchas JD (1978) The effects of 5-hydroxytryptophan and 5-hydroxytryptamine on dopamine synthesis and release in rat brain striatal synaptosomes. J Neurochem 30:465–470
Babbini M, Gaiardi M, Bartoletti M (1976) Effects of combined treatment with nortriptyline and lorazepam on conflict behavior and motility of rats. Psychopharmacology 48:251–254
Beer B, Chasin M, Clody DE, Vogel JR, Horovitz ZP (1972) Cyclic adenosine monophosphate phosphodiesterase in brain: Effect on anxiety. Science 176:428–430
Blakely TA, Parker LF (1973) The effects of parachlorphenylalanine on experimentally induced conflict behavior. Pharmacol Biochem Behav 1:609–613
Byck R (1975) Drugs and the treatment of psychiatric disorders. In: Goodman LS, Gilman A (eds) The pharmacological basis of therapeutics, 5th ed. The MacMillan Co., New York, pp 152–200
Carlsson A, Corrodi H, Fuxe K, Hokfelt T (1969) Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-ethyl-metatyramine. Eur J Pharmacol 5:357–366
Carter RB, Dykstra LA, Leander JD, Appel JB (1978) Role of peripheral mechanisms in the behavioral effects of 5-hydroxytryptophan. Pharmacol Biochem Behav 9:249–253
Commissaris RL, Lyness WH, Moore KE, Rech RH (1981a) Differential antagonism by metergoline of the behavioral effects of indolealkylamine and phenethylamine hallucinogens in the rat. J Pharmacol Exp Ther 219:170–174
Commissaris RL, Lyness WH, Rech RH (1981b) The effects old d-lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), pentobarbital and methaqualone on punished responding in control and 5,7-dihydroxytryptamine-treated rats. Pharmacol Biochem Behav 14:617–623
Commissaris RL, Rech RH (1982) Interactions of metergoline with diazepam, quipazine and hallucinogenic drugs on a conflict behavior in the rat. Psychopharmacology 76:282–285
Cook L, Davidson AB (1973) Effects of behaviorally active drugs in a conflict-punishment procedure in rats. In: Garattini S, Mussini E, Randall LO (eds) The benzodiazepines, Raven Press, New York, pp 327–345
Cook L, Sepinwall J (1975) Behavioral analysis of the effects and mechanism of action of benzodiazepines. In: Costa E, Greengard P (eds) Mechanism of action of benzodiazepines. Raven Press, New York, pp 1–28
Curzon G, Green AR (1970) Rapid method for the determination of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in small regions of rat brain. Br J Pharmacol 39:653–655
Dominic JA, Sinha AK, Barchas JD (1975) Effect of benzodiazepine compounds on brain amine metabolism. Eur J Pharmacol 32:124–127
Ford RD, Rech RH, Commissaris RL, Meyer LY (1979) Effects of acute and chronic interactions of diazepam and d-amphetamine on punished behavior of rats. Psychopharmacology 65:197–204
Geller I, Kulak JT, Seifter J (1962) The effects of chlordiazepoxide and chlorpromazine on a punished discrimination. Psychopharmacologia 3:374–385
Geller I, Blum K (1970) The effects of 5-HTP on parachlorophenylalanine (p-CPA) attenuation of “conflict” behavior. Eur J Pharmacol 9:319–324
Geller I, Hartmann RJ, Croy DJ (1974) Attenuation of conflict behavior with cinanserin, a serotonin antagonist: Reversal of the effect with 5-hydroxytryptophan and α-methyltryptamine. Res Commun Chem Pathol Pharmacol 7:165–174
Graeff FG (1974) Tryptamine antagonists and punished behavior. J Pharmacol Exp Ther 189:344–350
Greenblatt DJ, Shader RI (1978) Pharmacotherapy of anxiety with benzodiazepines and β-adrenergic blockers. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 1381–1390
Guidotti A (1978) Synaptic mechanisms in the action of benzodiazepines. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: a generation of progress, Raven Press, New York, pp 1349–1374
Gyermek L (1961) 5-Hydroxytryptamine antagonists. Pharmacol Rev 13:399–439
Haefely WE (1978) Behavioral and neuropharmacological aspects of drugs used in anxiety and related states. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 1359–1374
Haigler HJ, Aghajanian GK (1973) Mescaline and LSD: Direct and indirect effects on serotonin-containing neurons in brain. Eur J Pharmacol 21:53–60
Haigler HJ, Aghajanian GK (1974) Peripheral serotonin antagonists: Lack of antagonism to serotonin at identified serotonergic synapses in rat brain. J Neural Transm 35:257–273
Kilts CD, Commissaris RL, Rech RH (1981) Comparison of anti-conflict drug effects in several experimental animal models of anxiety. Psychopharmacology 74:290–296
Koe BK, Weissman A (1966) p-Chlorophenylalanine: A specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516
Lippmann W, Pugsley TA (1974) Effects of benzoctamine and chlordiazepoxide on turnover and uptake of 5-hydroxytryptamine in the brain. Br J Pharmacol 51:571–575
Miczek KA, Luttinger D (1978) Differential attenuation of two kinds of conditioned suppression by d-amphetamine and pentobarbital. J Pharmacol Exp Ther 205:282–290
Oppizzi G, Verde G, De Stefano L, Cozzi R, Botalla L, Liuzzi A, Chiodini PG (1977) Evidence for dopaminergic activity of methysergide in humans. Clin Endocrinol 7:267–272
Rech RH, Tilson HA, Marquis WJ (1975) Adaptive changes in behavior after chronic administration of various psychoactive drugs. In: Mandell AJ (ed) Neurobiological mechanisms of adaptation and behavior. Raven Press, New York, pp 263–286
Robichaud RC, Sledge KL (1969) The effects of p-chlorophenylalanine on experimentally induced conflict in the rat. Life Sci 8:965–969
Rubin B, Piala JJ, Burke JC, Craver BN (1964) A new potent and specific serotonin inhibitor (SQ10,643) 2′-(3-dimethylaminopropylthio)-cinnamanilide hydrochloride: Antiserotonin activity on uterus and on gastrointestinal, vascular, and respiratory systems of animals. Arch Int Pharmacodyn Ther 152:132–143
Samanin R, Bendotti C, Candelarssi G, Garattini S (1977) Specificity of serotonergic involvement in the decrease of food intake induced by quipazine in the rat. Life Sci 21:1259–1266
Samanin R, Mennini T, Ferraris A, Bendotti C, Borsini F, Garattini S (1979) m-Chlorophenylpiperazine: A central serotonin agonist causing powerful anorexia in rats. Naunyn-Schmiedeberg's Arch Pharmacol 308:159–163
Schoenfeld RI (1976) Lysergic acid diethylamide- and mescaline-induced attenuation of the effect of punishment in the rat. Science 192:801–803
Sepinwall J, Cook L (1978) Behavioral pharmacology of antianxiety drugs. In: Iversen LL, Iversen SD, Snyder SH (eds) Biology of mood and antianxiety drugs, Handbook of Psychopharmacology. Plenum, New York, pp 345–393
Sharma JN (1977) Microiontophoretic application of some monoamines and their antagonists to cortical neurons of the rat. Neuropharmacology 16:83–88
Skolnick P, Paul SM (1981) The mechanism(s) of action of the benzodiazepines. Med Res Rev 1:3–22
Sloviter RS, Drust EG, Connor JD (1978) Serotonin agonist actions of p-chlorophenylalanine. Neuropharmacology 17:1029–1033
Smith JE, Lane JD, Shea PA, McBride WJ (1977) Neurochemical changes following the administration of precursors of biogenic amines. Life Sci 21:302–306
Sokal RR, Rohlf RJ (1969) Biometry. W. H. Freeman and Co., San Francisco
Stein L, Wise CD, Berger BD (1973) Antianxiety action of benzodiazepines: Decrease in activity of serotonin neurons in the punishment system. In: Garratini S, Mussini E, Randall LO (eds) The benzodiazepines. Raven Press, New York, pp 299–326
Stein L, Wise CD, Belluzzi JD (1975) Effect of benzodiazepines on central serotonergic mechanisms: In: Costa E, Greengarc P (eds) Mechanisms of action of benzodiazepines. Raven Press, New York, pp 29–44
Stone CA, Wenger HC, Ludden CT, Stavorski JC, Ross CA (1961) Antiserotonin-anti-histaminic properties of cyproheptadine. J Pharmacol Exp Ther 131:73–84
Sullivan IW, Sepinwall J, Cook L (1978) Anticonflict evaluation of muscimol a GABA receptor agonist, alone and in combination with diazepam. Fed Proc 37:619
Swonger AK, Rech RH (1972) Serotonergic and cholinergic involvement in habituation of activity and spontaneous alternation of rats in a Y maze. J Comp Physiol Psychol 81:509–522
Trulson ME, Jacobs BL (1976) Behavioral evidence for the rapid release of CNS serotonin by PCA and fenfluramine. Eur J Pharmacol 36:149–154
Tye NC, Everitt BJ, Iversen SD (1977) 5-Hydroxytryptamine and punishment. Nature (Lond) 268:741–743
Van Riezen H (1972) Differential central effects of the 5-HT antagonists mianserin and cyproheptadine. Arch Int Pharmacodyn Ther 198:256–269
Winter JC (1972) Comparison of chlordiazepoxide and cinanserin as modifiers of punished behavior and as antagonists of N,N-dimethyltryptamine. Arch Int Pharmacodyn Ther 197:147–159
Wise CD, Berger BD, Stein L (1972) Benzodiazepines: Anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177:180–183
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kilts, C.D., Commissaris, R.L., Cordon, J.J. et al. Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam. Psychopharmacology 78, 156–164 (1982). https://doi.org/10.1007/BF00432255
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00432255