Where and how does d-amphetamine act to reveal antipsychotic-induced dopamine supersensitivity in rats?

Antipsychotic treatment can produce a dopamine supersensitive state. In both schizophrenia patients and rodents, this is linked to antipsychotic treatment failure. In rodents, dopamine supersensitivity is often confirmed by an exaggerated behavioural response to the indirect monoamine agonist, d-amphetamine, after discontinuation of antipsychotic treatment. Here we investigated where and how d-amphetamine acts to trigger behavioural expression of dopamine supersensitivity, as this could uncover pathophysiological mechanisms underlying this supersensitivity. First, we examined the contributions of a central increase in dopamine/monoamine activity. Haloperidol-treated rats showed a potentiated psychomotor response to systemic d-amphetamine, confirming dopamine supersensitivity. However, they showed a normal psychomotor response to an increase in ventral midbrain dopamine impulse flow or to intracerebroventricular injection of d-amphetamine. This suggests that d-amphetamines peripheral effects are required for a supersensitive response. Second, we determined the specific contributions of dopamine neurotransmission. The D2 agonist quinpirole, but not the D1 agonist SKF38393 or the dopamine reuptake blocker GBR12783 produced a supersensitive psychomotor response in haloperidol-treated rats. In these rats, the D1 antagonist SCH39166 decreased d-amphetamine-induced psychomotor activity, whereas the D2 antagonist sulpiride enhanced it. Thus, when d-amphetamine triggers a supersensitive response, this involves both D1- and D2-mediated transmission. Finally, we measured d-amphetamine-induced changes in D1- and D2-mediated intracellular signalling pathways in the striatum. In haloperidol-treated rats, a supersensitive response to d-amphetamine was linked to enhanced GSK3{beta} activity and suppressed ERK1/2 activity in the nucleus accumbens, suggesting increased D2-mediated signalling. These findings provide new insights into the neurobiology of antipsychotic-evoked dopamine supersensitivity.