Enhancement of serotonin-1A receptor dependent responses following withdrawal of haloperidol in rats.
Although haloperidol is widely prescribed for the treatment of schizophrenia, its beneficial effects are accompanied by extrapyramidal side effects (EPS). In view of a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the elicitation of EPS, the present study concerns pre- and postsynaptic responses to a selective 5-HT-1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) following acute and chronic administration of haloperidol in rats. In the acute administration study, effects of 8-OH-DPAT (0.5 mg/kg) were monitored 30 min after single injection of haloperidol (5 mg/kg). In the chronic administration study, effects of 8-OH-DPAT (0.5 mg/kg) were monitored 48 h after withdrawal from repeated (two times a day for 2 weeks) administration of haloperidol (5 mg/kg). The intensity of 5-HT syndrome elicited by 8-OH-DPAT was taken as measure of postsynaptic response. 8-OH-DPAT-induced decreases of 5-HT synthesis were taken as measure of presynaptic response. Results showed that 8-OH-DPAT-induced locomotion was smaller in acute haloperidol-treated rats. Conversely, these effects of 8-OH-DPAT were greater in chronic haloperidol-treated rats. Animals injected acutely or chronically with haloperidol exhibited greater 5-HT synthesis in the striatum. Administration of 8-OH-DPAT did not decrease 5-HT synthesis in the striatum of acute haloperidol-treated rats but decreased it in the striatum of chronic haloperidol-treated rats. The results show an increase in the effectiveness of pre- and postsynaptic 5-HT-1A receptor dependent responses following chronic administration of haloperidol. A causal role of 5-HT-1A receptor responsiveness in the greater incidences of EPS in patients treated with typical neuroleptics such as haloperidol is discussed.
Haleem
Darakhshan Jabeen
DJ
Department of Biochemistry, Neurochemistry and Biochemical Neuropharmacology Research Laboratory, University of Karachi, Karachi, 75270, Pakistan. haleemdj@hotmail.com
Khan
Nadia Hasan
NH
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001480:Basal Ganglia Diseases / Q000209:etiology / Q000503:physiopathology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome; D009435:Synaptic Transmission
D018492:Dopamine Antagonists; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006220:Haloperidol