Repeated antipsychotic drug exposurein developing rats: Dopamine receptor effects

Abstract

Antipsychotic drugs are often prescribed to juvenile psychiatric patients, though their cerebral effects during development are incompletely described. Accordingly, we studied the effects of repeated treatment with dissimilar antipsychotic drugs on dopamine (DA) receptors in juvenile vs. adult rats. Tissue levels of DA receptor types (D1, D2, D3, and D4) in forebrain regions of juvenile rats were quantified after 3 weeks of daily treatment with representative first- (fluphenazine) and second-generation (clozapine and olanzapine) antipsychotics, and compared with similarly treated adult rats examined in previous studies. Fluphenazine, clozapine, and olanzapine all decreased D1 receptors in dorsolateral frontal and medial prefrontal cortex (MPC) of juvenile, but not adult rats. Conversely, all three test agents increased D2 labeling in MPC of adult, but not young animals. Fluphenazine and olanzapine, but not clozapine, also increased D2 receptor levels in hippocampus, and D4 levels in nucleus accumbens (NAc) and caudate-putamen (CPu) in both juvenile and adult brain. D3 receptors were not altered by any treatment in any brain region at either age. Only some DA receptor adaptations to antipsychotic treatment are shared by developing and mature animals. Developmental differences in DA receptor responses may account for differences in clinical effects of antipsychotic drugs between young and adult psychiatric patients.

Olanzapine Sensitization and Clozapine Tolerance: From Adolescence to Adulthood in the Conditioned Avoidance Response Model

“…For instance, Moran-Gates et al (2006) found that repeated administration of OLZ (5 mg/kg, once daily) and CLZ (20 mg/kg, twice daily) from P 22 to P 42, all decreased D 1 receptors in dorsolateral frontal and medial prefrontal cortex of adolescent, but not adult rats. In contrast, both drugs increased D 2 receptors in the medial prefrontal cortex of adult, but not adolescent rats (Moran-Gates et al, 2006). OLZ, but not CLZ, also increased D 2 receptor levels in hippocampus, and D 4 levels in nucleus accumbens and caudate-putamen in both juvenile and adult rats.…”

“…One is the age difference in psychopharmacological responsiveness and brain responses to antipsychotics between adolescent animals and adult ones (Spear and Brake, 1983;Moran-Gates et al, 2006;Wiley, 2008;Choi et al, 2010). The common approach is to compare animals in different age groups on their behavioral responses (eg, locomotor activity, catalepsy; Wiley and Evans, 2008) and brain responses (eg, dopamine and 5-HT receptors; Moran-Gates et al, 2006;Choi et al, 2010) to various antipsychotic treatments, without tracking changes across the different development stages. The second issue of interest is the long-term behavioral and brain consequences of antipsychotic treatment in adolescence (Llorente-Berzal et al, 2012).…”

“…For example, adolescents tend to overexpress various neuroreceptors (eg, dopaminergic, adrenergic, serotonergic) followed by pruning to adult levels (an inverted U-shape curve of development). Both dopamine receptors (eg, D 1 , D 2 ) and serotonergic receptors (eg, 5-HT 1A , 5-HT 2A ) that are implicated in the mechanisms of action of antipsychotic drugs are reported to be expressed at higher levels in various brain areas (eg, cerebral cortex, hippocampus, dorsal and ventral striatum, and septum) during adolescence than in adulthood (Lidow et al, 1991;Teicher et al, 1995;Tarazi et al, 1998;Andersen et al, 2000), and antipsychotic exposure alters these neuroreceptors in unique ways not seen in adult animals (Moran-Gates et al, 2006;Choi et al, 2009;Choi et al, 2010). For instance, Moran-Gates et al (2006) found that repeated administration of OLZ (5 mg/kg, once daily) and CLZ (20 mg/kg, twice daily) from P 22 to P 42, all decreased D 1 receptors in dorsolateral frontal and medial prefrontal cortex of adolescent, but not adult rats.…”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…Similarities of findings on dopamine receptors (a reduced D1 binding in MPC and increased D2 binding in NAc) at both proximal to (Moran-Gates et al 2006) and long after chronic adolescent exposure as in the above two studies suggest that these changes may indeed persist from adolescence to adulthood. Moreover, chronic olanzapine treatment in adolescence has also been reported to induce a long-lasting reduction in levels of glutamate and GABA in the NAc (Xu et al 2015).…”

“…binding in the NAc induced by olanzapine treatment appear to persist from adolescence to adulthood given reports of these changes both proximal to (Moran-Gates et al 2006) and long after chronic exposure . Chronic adolescent olanzapine administration could also induce long-lasting changes in the NAc such as reduced D1 receptor binding, increased D2 receptor binding, decreased evoked DA release ) and reduced levels of glutamate and GABA (Xu et al 2015).…”