Abstract
A quasi-morphine withdrawal syndrome (QMWS), produced in opiate-naive rats with an injection of isobutylmethylaxanthine (IBMX) and the opioid antagonist naloxone, allows one to study the expression of opiate withdrawal in the absence of the acute or chronic effects of opiates and the adaptive processes termed dependence. The allegedly selective and long-acting serotonin2 (5-HT2) antagonist ritanserin attenuated the QMWS-induced suppression of fixed ratio (FR) operant responding, which is a sensitive measure of the expression of a QMWS. When administered 30 min prior to precipitation of the QMWS, the lowest dose of ritanserin tested (0.158 mg/kg) was the most effective in blocking the expression of withdrawal; however, there was not complete reversal of the behavioral suppression. Acutely, the two higher doses of ritanserin tested (2.5 and 10 mg/kg) suppressed responding when given alone. This may have masked their ability to attenuate a QMWS. At a dose of 2.5 mg/kg, ritanserin completely blocked the QMWS-induced suppression of responding 24 h post-administration, at a time when its actions at other receptors (e.g., alpha2) have dissipated. At an equivalent dose, the shorter-acting 5-HT2 antagonist mianserin was unable to attenuate the QMWS-induced suppression of FR operant responding 24 h post-administration. The 5-HT2 antagonists reportedly produce a paradoxical down-regulation of 5-HT2 binding sites upon chronic treatment, rather than the expected supersensitivity. Chronic treatment with ritanserin (2.5 mg/kg/day for 7 days), but not mianserin (same regimen), attenuated a QMWS 24 h after the final injection, thus supporting with a functional measure, the down-regulation of such binding sites by ritanserin. These results suggest that ritanserin may prove useful in treating the symptoms of withdrawal during opiate (e.g., heroin and methadone) detoxification, without causing supersensitivity of 5-HT2 receptors upon chronic treatment.
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References
Baldessarini RJ, Cole JO, Davis JM, Gardos G, Simpson G, Tarsy D (1980) Tardive dyskinesia. Task Force Report No. 18, American Psychiatric Association, Washington, DC
Blackshear MA, Sander-Bush E (1982) Serotonin receptor sensitivity after acute and chronic treatment with mianserin. J Pharmacol Exp Ther 221:303–308
Blackshear MA, Martin LL, Sanders-Bush E (1986) Adaptive changes in the 5-HT2 binding site after chronic administration of agonists and antagonists. Neuropharmacology 25:1267–1271
Collier HOJ, Francis DL, Henderson G, Schneider C (1974) Quasi morphine-abstinence syndrome. Nature 249:471–473
Collier HOJ, Cuthbert NJ, Francis DL (1981) Character and meaning of quasi-morphine withdrawal phenomena elicited by methylxanthines. Fed Proc 40:1513–1518
Colpaert FC, Meert TF, Niemegeers CJE, Janssen PAJ (1985) Behavioral and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rat. Psychopharmacology 86:45–54
Dwoskin LP, Neal BS, Sparber SB (1983) Yohimbine exacerbates and clonidine attenuates acute morphine withdrawal in rats. Eur J Pharmacol 90:269–273
Ferster CB, Skinner BF (1957) Schedules of reinforcement. Appleton-Century-Crofts, New York
Francis DL, Roy AC, Collier HOJ (1975) Morphine abstinence and quasi-abstinence effects after phosphodiesterase inhibitors and naloxone. Life Sci 16:1901–1906
Gandolfi O, Barbaccia ML, Costa E (1985) Different effects of serotonin antagonists on3H-mianserin and3H-ketanserin recognition sites. Life Sci 36:713–721
Gudelsky GA, Koenig JI, Meltzer HY (1987) Selective desensitization of serotonin (5-HT) receptor-mediated hyperthermia by mianserin and other 5-HT antagonists. Neuropharmacology 7A:707–712
Kleber HD (1983) Concommittant use of methadone with other psychoactive drugs in the treatment of opiate addicts with other DSM III diagnoses. In: Cooper JR, Altman F, Brown BS, Czechowicz D (eds) Research on the treatment of narcotic addiction-state of the art. US Department of Health and Human Services, Rockville, MD, pp 119–148
Kleven MS, Sparber SB (1987) Attenuation of isobutylmethylxanthine-induced suppression of operant behavior by pretreatment of rats with clonidine. Pharmacol Biochem Behav 28:235–241
Kleven MS, Sparber SB (1989a) Modification of the behavioral effects of 3-isobutyl-1-methylxanthine by serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal. Psychopharmacology 98:231–235
Kleven MS, Sparber SB (1989b) Morphine blocks and naloxone enhances the suppression of operant behavior by low doses of 3-isobutyl-1-methylxanthine. J Pharmacol Exp Ther 248:373–377
Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PFM, Laduron PM (1985) Receptor-binding in vitro and in vivo of ritanserin: a very potent and long acting serotonin-S2 antagonist. Mol Pharmacol 27:600–611
Leysen JE, Van Gompel P, Gommeren W, Woestenborghs R, Janssen PAJ (1986) Down regulation of serotonin-S2 receptor sites in rat brain by chronic treatment with the serotonin-S2 antagonists: ritanserin and setoperone. Psychopharmacology 88:434–444
Leysen JE, Van Gompel P, Gommeren W, Laduron PM (1987) Differential regulation of dopamine-D2 and serotonin-S2 receptors by chronic treatment with the serotonin-S2 antagonists, ritanserin and setoperone. In: Gram D, Potter P (eds) Clinical pharmacology in psychiatry. Springer, Berlin Heidelberg New York, pp 215–224
Neal BS, Sparber SB (1986a) Mianserin attenuates naloxone-precipitated withdrawal in rats acutely or chronically dependent upon morphine. J Pharmacol Exp Ther 236:157–165
Neal BS, Sparber SB (1986b) Ketanserin and pirenperone attenuate acute morphine withdrawal in rats. Eur J Pharmacol 132:299–304
Nielsen JA, Fossom LH, Sparber SB (1980) Metabolism of3H-dopamine continuously perfused through push-pull cannulas in rats' brains: modification by amphetamine or prostaglandin F2alpha. Biochem Pharmacol Behav 13:235–242
Niemegeers CJE, Colpaert FC, Leysen JE, Awouters F, Janssen PAJ (1983) Mescaline-induced head-twitches in the rat. An in vivo method to evaluate serotonin S2 antagonists. Drug Dev Res 3:123–135
Peroutka SJ, Snyder SH (1981) [3H]Mianserin: differential labeling of serotonin2 and histamine1 receptors in rat brain. J Pharmacol Exp Ther 216:142–148
Sanders-Bush E, Breeding M, Rosznoski M (1987) 5-HT2 binding sites after mianserin: comparison of loss of sites and brain levels of drug. Eur J Pharmacol 133:199–204
Sparber SB, Meyer D (1978) Clonidine antagonizes naloxone-induced suppression of conditioned behavior and body weight loss in morphine-dependent rats. Pharmacol Biochem Behav 9:319–325
Sparber SB, Gellert VF, Lichtblau L, Eisenberg R (1978) The use of operant behavior methods to study aggression and effects of acute and chronic morphine administration in rats. In: Adler MW, Manara L, Samanin R (eds) Factors affecting the action of narcotics. Raven Press, New York, pp 63–91
Sparber SB, Gellert VF, Fossom L (1979) On the use of operant behavior to study neuropsychopharmacology of opiates with special reference to dopamine in the central nervous system. Adv Biochem Psychopharmacol 20:453–491
Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New York
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Neal, B.S., Sparber, S.B. The serotonin2 antagonist ritanserin blocks quasi-morphine withdrawal at a time when mianserin is no longer effective. Psychopharmacology 100, 258–266 (1990). https://doi.org/10.1007/BF02244416
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DOI: https://doi.org/10.1007/BF02244416