clozapine and mosapramine

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects.

Topics: Animals; Antipsychotic Agents; Benzazepines; Brain; Clozapine; Corpus Striatum; Gene Expression Regulation; Genes, fos; Haloperidol; Immunohistochemistry; Male; Neurons; Nucleus Accumbens; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Risperidone

The affinities of mosapramine hydrochloride, an iminodibenzyl antipsychotic drug, for dopamine receptor subtypes were determined by human dopamine D2, D3 and D4 receptors expressed in several cell lines and compared with those of other neuroleptics. Tritiated spiperone bound to the membrane of transfected cells in a saturable manner, and the Kd values for dopamine D2, D3 and D4 receptors were 0.021, 0.12 and 0.10 nM, respectively. Mosapramine showed the highest affinities for these receptor subtypes among the antipsychotics tested. The ratio of Ki values between D2 and D3 (D2 Ki/D3 Ki ratio) in mosapramine was higher than that of haloperidol, indicating that the effects of mosapramine on D3 receptors were more potent than those of haloperidol. On the other hand, clozapine, risperidone and raclopride had higher affinity to D4, D2 and D3 subtypes, respectively. The affinities of mosapramine for D4 receptors was 8 times higher than that of clozapine, and the affinity for D3 receptors was 40 times higher than that of raclopride. These results suggest that the effect on D3 receptors may underlie at least a portion of mosapramine's atypical clinical profile.

Topics: Antipsychotic Agents; Benzazepines; Cell Line; Clozapine; Haloperidol; Humans; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D4; Receptors, Dopamine D5; Risperidone; Salicylamides; Spiperone

The affinity of mosapramine, an iminodibenzyl antipsychotic, to dopamine D3-receptors in rat brain was investigated by quantitative autoradiography of [3H]-7-OH-DPAT, a selective D3-ligand. Autoradiograms showed restricted distribution of [3H]7-OH-DPAT binding sites, with very high levels on the islands of Calleja (ICj), olfactory tubercle (Tu) and nucleus accumbens, while low but distinct labeling was observed in the molecular layer of lobule 10 of the cerebellum and caudate putamen (CPu). Binding of [3H]7-OH-DPAT completely disappeared when 1 microM dopamine was added, and it was reduced by the addition of mosapramine in a concentration-dependent manner. The displacing effect of mosapramine was more potent than that of haloperidol or clozapine in the brain regions examined. Mosapramine showed more potent affinity to receptors in Tu and ICj than those in CPu. On the other hand, haloperidol and clozapine did not show such regional differences. These results suggest that the high affinity of mosapramine to D3-receptors participates in, at least in part, the development of the clinical effects of mosapramine.

Topics: Animals; Antipsychotic Agents; Autoradiography; Benzazepines; Brain; Clozapine; Haloperidol; In Vitro Techniques; Ligands; Male; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3