Noreen Samad

Reversal of haloperidol-induced tardive vacuous chewing movements and supersensitive somatodendritic serotonergic response by buspirone in rats

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the pathogenesis and treatment of TD because repeated administration of haloperidol resulted in an increase in the effectiveness of 5-HT-1A receptors while drugs with agonist activity at 5-HT-1A receptors could attenuate haloperidol-induced VCMs. The present study was designed to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-HT-1A receptors by the coadministration of buspirone could reverse the induction of VCMs and supersensitivity at 5-HT-1A receptors by haloperidol. Rats treated with haloperidol at a dose of 1 mg/kg twice a day for 2 weeks displayed VCMs with twitching of facial musculature that increased in a time dependent manner as the treatment continued to 5 weeks. Coadministration of buspirone attenuated haloperidol-induced VCMs after 2 weeks and completely prevented it after 5 weeks. The intensity of 8-hydroxy-2-di (n-propylamino) tetralin (8-OH-DPAT)-induced locomotion was greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. 8-OH-DPAT-induced decreases of 5-HT metabolism were greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. It is suggested that an impaired somatodendritic 5-HT-1A receptor dependent response is a major contributing factor in the pathophysiology of TD and a normalization of the somatodendritic response by drugs may help extending therapeutics in schizophrenia.

Reversal of haloperidol-induced extrapyramidal symptoms by buspirone: a time-related study.

Effects of coadministration of buspirone were investigated on the time course of haloperidol-induced extrapyramidal symptoms in rats. Rats treated with haloperidol at a dose of 1 mg/kg exhibited impaired motor coordination and a decrease in exploratory activity. Coadministration of buspirone at a dose of 1 mg/kg attenuated haloperidol-induced deficits of motor coordination but no effect was produced on the deficits of exploratory activity, possibly because of a ‘floor effect’. Long-term administration of haloperidol (1 mg/kg) twice a day for 5 weeks did not produce tolerance to haloperidol-induced deficits of exploratory activity. The deficits of motor coordination were attenuated after 4–5 weeks of drug administration. Coadministration of buspirone for 3–5 weeks attenuated and reversed haloperidol-induced deficits of exploratory activity. Deficits of motor coordination were smaller in rats cotreated with buspirone after 1 week but not after 2–5 weeks. Administration of haloperidol for 2 weeks elicited vacuous chewing movements with twitching of facial musculature that increased in a time-dependent manner as the treatment continued to 5 weeks. Animals cotreated with buspirone exhibited a gradual reversal of the response during 2–5 weeks of treatment. The mechanism involved in the attenuation/reversal of haloperidol-induced extrapyramidal symptoms by buspirone is discussed. Prior administration of buspirone for 2 weeks may be of help in the improvement of extrapyramidal symptoms induced by antipsychotic drugs.

Role of serotonin-1A receptors in restraint-induced behavioral deficits and adaptation to repeated restraint stress in rats.

8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-hydroxy-tryptamine (5-HT; serotonin)-1A agonist was used to evaluate the role 5-HT-1 A receptors in restraint-induced behavioral deficits and adaptation to repeated restraint stress in rats. Animals were injected with 8-OH-DPAT at a dose of 0.25 mg/kg 1 h before exposing to an episode of 2 h/day restraint stress daily for 5 days. Effects of drug administration and restraint stress on 24 h cumulative food intakes were monitored daily. Intensity of 8-OH-DPAT-induced serotonin syndrome was also monitored each day before submitting animals to the episode of stress. Exposure to the first episode of 2 h restraint stress resulted in a decrease in 24 h cumulative food intake and an attenuation of 8-OH-DPAT-induced serotonin syndrome monitored next day. The deficits attenuated following 2nd and 3rd 2 h/day restraint were not observed following the 4th and 5th 2 h/day restraint. The decreases of food intake following 1st and 2nd day restraint sessions were smaller in 8-OH-DPAT than saline-injected animals. Administration of 8-OH-DPAT on day 6 elicited comparable serotonin syndrome in unrestrained and repeatedly restrained groups. Brain 5-HT metabolism decreased in unrestrained but not repeatedly restrained animals. The results suggest that a decrease in serotonergic neurotransmission is involved in restraint-induced behavioral deficits while a normalization of serotonin neurotransmission due to desensitization of somatodendritic 5-HT-1A receptors may help cope with the stress demand to produce adaptation to stress.