Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter

Mice lacking the dopamine transporter (DAT(-/-)) exhibit high extracellular dopamine levels and marked hyperactivity. This hyperlocomotion is paradoxically decreased by acute administration of amphetamine-like psychostimulants, an effect that has been previously related to the activation of serotonergic neurotransmission.

The goal of the present study was to investigate the effects of acute and daily administration of d-amphetamine on the locomotor activity of DAT(-/-) mice and examine the development of behavioral sensitization. In addition, we tested the implication of the serotonin system in the observed effects.

DAT(+/+), DAT(+/-), and DAT(-/-) mice were injected with acute amphetamine (0, 0.3, 1, 3, or 10 mg/kg, SC), repeated amphetamine (1 mg/kg for 8 days, SC), or with the serotonin reuptake inhibitor fluoxetine (0, 5, 10, or 20 mg/kg, SC) and their locomotor activity was evaluated. Moreover, the expression of the serotonin transporter and 5-HT(1A) receptors in the brain of DAT(-/-) mice was studied using autoradiography.

Acute and repeated d-amphetamine injection (1 mg/kg) induced an hypolocomotor response in DAT(-/-) and DAT(+/-) mice, but only DAT(+/-) mice developed locomotor sensitization to the drug. Acute treatment with fluoxetine decreased locomotion in DAT(-/-) mice in a dose-dependent manner. The common hypolocomotor effect induced by d-amphetamine and fluoxetine in DAT(-/-) mice suggests an action on the serotonin transporter. However, autoradiography of the serotonin transporter and 5-HT(1A) receptors showed normal density and distribution in the brain, suggesting no compensatory effects due to the deletion of the DAT.

These findings indicate that partial or total DAT gene deletion result in decreased locomotion in response to d-amphetamine and modify behavioral sensitization depending on the proportion of DAT removed, suggesting that inhibition of the DAT is necessary for the development of sensitization to psychostimulant drugs.