Long‐term effects of JL 13, a potential atypical antipsychotic, on rat dopamine and serotonin receptor subtypes

Abstract

Changes in dopamine (DA) D(1), D(2), D(3), and D(4) receptors and serotonin 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate] for 28 days with osmotic minipumps and compared with the effects of other typical (fluphenazine) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other typical and atypical antipsychotics, JL 13 increased labeling of D(2) receptors in medial prefrontal cortex (MPC) and hippocampus (HIP) and D(4) receptors in nucleus accumbens (NAc), caudate-putamen (CPu), and HIP. In addition, JL 13 increased 5-HT(1A) and decreased 5-HT(2A) receptors in MPC and dorsolateral frontal cortex (DFC), an effect shared by atypical antipsychotics, and may contribute to their psychopharmacological properties. Clozapine and JL 13, but not other antipsychotics, spared D(2) receptors in CPu, which may reflect their ability to induce minimal extrapyramidal side effects. In addition, JL 13 but not other typical and atypical antipsychotic drugs increased abundance of D(1) receptors in CPu and NAc. JL 13 as well as other antipsychotic agents did not alter levels of forebrain D(3) receptors. An atypical-like profile of JL 13 on DA and 5-HT receptor subtypes should encourage further development of this compound as a novel atypical antipsychotic drug.

Long-term Effects of JL 13, a Potential Atypical Antipsychotic, on Ionotropic Glutamate Receptors

“…Reductions in NMDA receptor binding induced by JL 13 and other atypical antipsychotics in the CPu may arise from neurochemical changes initiated by well-documented interactions of these drugs with dopamine or serotonin systems, both of which may modulate glutamatergic neurotransmission (Aghajanian and Marek 2000;Carlsson et al 2001). In support of this hypothesis, we recently found that repeated treatment with JL 13 increased abundance of 5-HT 1A receptors and decreased 5-HT 2A receptor levels in rat frontal cortex (Moran-Gates et al 2006). JL 13-induced changes in concentrations of these 5-HT receptors in cerebral cortex may suppress Glu neurotransmission in corticostriatal …”

“…These findings support the hypothesis that AMPA receptors in these brain regions constitute common targets that mediate the actions of JL 13 and newer antipsychotic agents. Atypical-like profile of JL 13 on ionotropic Glu receptors, as well as dopamine and serotonin receptor subtypes (Moran-Gates et al 2006), further support the development of JL 13 as a novel atypical antipsychotic drug for the improved treatment of schizophrenia and other idiopathic psychotic disorders.…”

“…In addition, JL 13 also appears to exhibit benign neurological profile, evidenced by its lack of ability to antagonize amphetamine-induced stereotypy or produce catalepsy in rats (Bruhwyler et al 1997) and its low incidence of adverse side effects in non-human primates (Casey et al 2001). In more recent studies, we examined the long-term effects of JL 13 on dopamine (D 1 , D 2 , D 3 , and D 4 ) receptors and serotonin (5-HT 1A and 5-HT 2A ) receptors subtypes in rat forebrain regions and found that this unique compound induced regionally selective changes in tissue levels of specific DA and 5-HT receptor subtypes more closely mimicking those observed with clozapine and other atypical than typical antipsychotics (Moran-Gates et al 2006).…”

“…Similar to NMDA receptors, actions of JL 13 on cortical 5-HT 1A (increases) and 5-HT 2A (decreases) receptors (Moran-Gates et al 2006) may contribute to the increased AMPA receptor binding found in CPu (Table 2). Other studies have provided additional evidence for a direct interaction between 5-HT 1A/2A /AMPA receptors.…”

“…Selected dose of JL 13 is behaviorally, neurochemically, and molecularly active in rats (Invernizzi et al 2000;Ellenbroek and Liégeois 2003;Moran-Gates et al 2006). After 4 weeks of treatment, residual drug solution in each minipump implanted in control-and drug-treated rats was <5% of the original volume, indicating vehicle and JL 13 were adequately delivered.…”