Evidences for the involvement of sigma receptors in antidepressant like effect of quetiapine in mice.

Although quetiapine is routinely used in the treatment of schizophrenia and bipolar disorders, the precise mechanism of its antidepressant activity is poorly understood. Since quetiapine binds with sigma receptor, the possibility exists that antidepressant action of quetiapine may be mediated through interaction with sigma receptors. In the present study, quetiapine [40-80 µg/mouse, intracerebroventricular (i.c.v.) and 40 mg/kg, intraperitoneal (i.p.)], sigma1 receptor agonist, (+)-pentazocine (120 µg/mouse, i.c.v.) and sigma2 receptor agonist, PB-28 [1-Cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)propyl]piperazine] (20 µg/mouse, i.c.v.) significantly decreased immobility time in forced swim test. In combination studies, the antiimmobility effect of quetiapine (20 µg/mouse, i.c.v.) was significantly potentiated by pretreatment with (+)-pentazocine (30 and 60 µg/mouse, i.c.v.) or PB-28 (5 and 10 µg/mouse, i.c.v.). Conversely, prior administration of sigma1 receptor antagonist, BD-1063 [1-[2-(3,4-Dichlorophenyl)ethyl]-4-methylpiperazine] and sigma2 receptor antagonists, SM-21 [(±)-Tropanyl 2-(4-chlorophenoxy)butanoate] antagonized the antiimmobility effect induced by quetiapine and its synergistic combination with sigma receptor agonists. These results demonstrated the involvement of sigma receptors in the antidepressant like effect of quetiapine and suggest that sigma receptors can be explored as a potential therapeutic target for the treatment of depressive disorders.

Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents.

The effect of agmatine in preclinical behavioral tests of schizophrenia has been examined in rodents. Agmatine at the doses of 40 and 80 mg/kg blocked conditioned avoidance responding, attenuated apomorphine induced climbing, diminished amphetamine and ketamine hyperlocomotor activity and augmented plasma prolactin levels. Pretreatment of animals with 20 mg/kg of agmatine potentiated the inhibitory effect of haloperidol (0.1 mg/kg, ip) and olanzepine (0.5 mg/kg, ip) in conditioned avoidance response test and apomorphine induced climbing. Agmatine alone at the doses tested here did not induce any cataleptic behavior in mice. However significant catalepsy was exhibited when agmatine (80 mg/kg, ip) was injected to mice pretreated with 5-HT1A receptor antagonist, WAY100, 635. These results indicate that agmatine via regulation of brain dopaminergic signaling modulates dopamine mediated behaviors. The alteration in the levels of endogenous agmatine may contribute to the genesis of psychosis and development of drugs that enhance endogenous agmatine content may be better therapeutic approach to treat schizophrenia with low incidences of extra pyramidal side effects.