Dysregulation of gene induction in corticostriatal circuits after repeated methylphenidate treatment in adolescent rats: differential effects on zif 268 and homer 1a

Abstract

Psychostimulants and other dopamine agonists produce molecular changes in neurons of cortico-basal ganglia-cortical circuits, and such neuronal changes are implicated in behavioural disorders. Methylphenidate, a psychostimulant that causes dopamine overflow (among other effects), alters gene regulation in neurons of the striatum. The present study compared the effects of acute and repeated methylphenidate treatment on cortical and striatal gene regulation in adolescent rats. Changes in the expression of the immediate-early genes zif 268 and homer 1a were mapped in 23 striatal sectors and 22 cortical areas that provide input to these striatal sectors, in order to determine whether specific corticostriatal circuits were affected by these treatments. Acute administration of methylphenidate (5 mg/kg, i.p.) produced modest zif 268 induction in cortical areas. These cortical zif 268 responses were correlated in magnitude with zif 268 induction in functionally related striatal sectors. In contrast, after repeated methylphenidate treatment (10 mg/kg, 7 days), cortical and striatal gene induction were dissociated. In these animals, the methylphenidate challenge (5 mg/kg) produced significantly greater gene induction (zif 268 and homer 1a) in the cortex. This enhanced response was widespread but regionally selective, as it occurred predominantly in premotor, motor and somatosensory cortical areas. At the same time, striatal gene induction was partly suppressed (zif 268) or unchanged (homer 1a). Thus, repeated methylphenidate treatment disrupted the normally coordinated gene activation patterns in cortical and striatal nodes of corticostriatal circuits. This drug-induced dissociation in cortical and striatal functioning was associated with enhanced levels of behavioural stereotypies, suggesting disrupted motor switching function.