Mediation by serotonin of the antiaversive effect of zimelidine and propranolol injected into the dorsal midbrain central grey

Abstract

Previously reported results indicate that serotonin (5-HT) inhibits the neural sub strate of aversion in the dorsal midbrain central grey (DCG) of the rat. In addition, the present results show that microinjection of the 5-HT uptake inhibitor zimelidine (100 nmol) into the DCG of rats with chronically implanted chemitrodes raised the threshold of aversive electrical stimulation. This antiaversive effect of zimelidine was antagonized by pretreatment with the 5-HT₂ receptor blocker ritanserin (10 nmol), also microinjected into the DCG. In contrast, the antiaversive effect of the benzodiazepine agonist midazolam (40 nmol) was unaffected by ritanserin. Propranolol (2.2, 4.4 and 8.8 nmol) raised the aversive threshold in a dose-depen dent way following its injection into the DCG. The antiaversive effect of 4.4 nmol of propranolol was antagonized by previous administration of ritanserin (10 nmol). Moreover, combined administration of zimelidine (100 nmol) followed by propranolol (4.4 nmol) caused an anti aversive effect which was equivalent to the sum of the effect of each drug alone. These results indicate that the antiaversive effect of intracerebrally injected zimelidine and propranolol is mediated by endogenous 5-HT, through activation of 5-HT₂ receptors.

Get full access to this article

View all access options for this article.

References

Audi E.A. , Graeff F.G. 1984

Benzodiazepine receptors in the periqueductal grey mediate anti-aversive drug action Eur

J Pharmacol 103: 279-285

Ceulemans D L S , Hoppenbrouwers M-L J A , Gelders Y.G. , Reyntjens A J M 1985 The influence of ritanserin a serotonin antagonist in anxiety disorders: a double-blind placebo controlled study versus lorazepam . Pharmacopsychiatry 18: 303-305

Cook L. , Sepinwall J. 1975

Reinforcement schedules and extrapolations to humans from animals in behavioral

pharmacology Fed Proc 34: 1889-1897

Durel L.A. , Krantz D.S. , Barrett J.E. 1986

The antianxiety effect of beta-blockers on punished responding

Pharmacol Biochem Behav 25: 371-374

Graeff F.G. 1984 The anti-aversive action of minor tranquillizers , Trends Pharmacol Sci 5 230-233

Graeff F.G. 1987 The antiaversive action of drugs. In Advances in behavioral pharmacology, vol. 6 (eds Thompson T, Dews P B, Barrett J) Lawrence Erlbaum, Hillsdale, New Jersey, pp. 129-155

Graeff F.G. 1988 Animal models of aversion. In Animal models of psychiatry, vol. 1 (eds Simon P, Soubrié P, Widlocher D), Karger, Basel, pp. 115-141

Graeff F.G. , Rawlins J N P 1980 Dorsal periaqueductal gray punishment, septal lesions and the mode of action of minor tranquillizers. Pharmacol Biochem Behav 12: 41-45

Hodges H. , Green S. , Glenn B. 1987 Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination . Psychopharmacology 92. 491-504

10.

Kiser JrR.S. , Lebovitz R.M. 1975 Monoaminergic mechanisms in aversive brain stimulation . Physiol Behav 15: 47-56

11.

Kiser Jr R.S. , German D.C. , Lebovitz R.M. 1978 Serotonergic reduction of dorsal central gray area stimulation-produced aversion. Pharmacol Biochem Behav 9: 27-31

12.

Konig J F R , Klippel R.A. 1963 The rat brain in stereotaxic coordinates. Williams and Wilkins, Baltimore

13.

Leysen J.E. , Gommeren W. , Van Gompel P. , Wynants J. , Janssen P F M , Laduron P.M. 1985 Receptor binding properties in vitro and in vivo of ritanserin, a very potent and long acting serotonin-S2 antagonist . Molec Pharmacol 27: 600-606

14.

Lister R.G. , File S.E. 1983 Changes in regional concentrations in rat brain of 5-hydroxytryptamine and 5-hydroxyindolacetic acid during the development of tolerance to the sedative action of chlordiazepoxide. J Pharmacol 35: 601-603

15.

Marseillan R.F. 1977

A solid state sine-wave stimulator

Physiol Behav 19: 339-340

16.

Middlemiss D.N. 1984

Stereoselective blockage at [3H] 5-HT binding sites and at the 5-HT autoreceptor by propranolol Eur

J Pharmacol 101: 289-293

17.

Morato de Carvalho S. , de Aguiar J.C. , Graeff F.G. 1981 Effect of minor tranquillizers, tryptamine antagonists and amphetamine on behavior punished by brain stimulation. Pharmacol Biochem Behav 15. 351-356

18.

Ross S.B. , Ogren S.O. , Renyi A. 1976 (Z)-Dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl) propene (H102/09), a new selective inhibitor of the neuronal 5-hydroxytryptamine uptake Acta Pharmac (Kbh) 39 152-166

19.

Schenberg L.C. , Graeff F.G. 1978

Role of the periaqueductal gray substance in the antianxiety action of benzodiazepines

Pharmacol Biochem Behav 9: 287-295

20.

Schutz M T B , de Aquiar J.C. , Graeff F.G. 1985 Antiaversive role of serotonin in the dorsal periaqueductal grey matter. Psychopharmacology 85: 340-345

21.

Soubrié P. , Blas C. , Ferron A. , Glowinski J. 1983 Chlordiazepoxide reduces in vivo serotonin release in the basal ganglia of 'encephale isolé' but not of anaesthetized cats: evidence for a dorsal raphe site of action. J Pharmacol Exp Therap 226: 526-532

22.

Stembush H W M 1981 Distribution of serontonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 6: 557-618

23.

Thiébot M.H. , Soubrié P. , Hamon M. , Simon P. 1984

Evidence against the involvement of serotonergic neurons in the anti-punishment activity of diazepam in the rat

Psychopharmacology 82. 335-359

24.

Tye N.C. , Everitt B.J. , Iversen S.D. 1977

5-Hydroxytryptamine and punishment

Nature 268: 741-742

25.

Tyrer P.J. , Lader M.H. 1974

Response to propranolol and diazepam in somatic and psychic anxiety

Brit Med J2: 14-16

26.

Weiner N. 1980 Drugs that inhibit adrenergic nerves and block adrenergic receptors. In The pharmacological basis of therapeutics (eds Goodman-Gilman A G, Goodman L S, Gilman A), 6th edition Macmillan, New York, pp 176-210

27.

Wise C.D. , Berger B.D. , Stein L. 1972

Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the

brain Science 177: 180-183