Previous exposure to amphetamine enhances the subsequent locomotor response to a D1 dopamine receptor agonist when glutamate reuptake is inhibited.

The role of nucleus accumbens (NAcc) glutamate (GLU) and D(1) dopamine (DA) receptor activation in the expression of locomotor sensitization to amphetamine (AMPH) was investigated in rats. Rats were preexposed to either AMPH or saline, and 2 weeks later their locomotion was assessed after a microinjection into the NAcc of the selective glutamate reuptake blocker l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) (10 nmol per side), the D(1)-like DA receptor agonists SKF82958 (2.4 nmol per side) and SKF38393 (3.1 nmol per side), the D(2)-like DA receptor agonist quinelorane (3.1 nmol per side), or AMPH (6.8 nmol per side). All compounds other than quinelorane increased locomotion when infused into the NAcc. Only AMPH, however, produced enhanced locomotion in AMPH relative to saline-preexposed rats. When additional rats were tested after NAcc infusions of PDC together with either SKF82958 or quinelorane, enhanced locomotion was observed in AMPH relative to saline-preexposed rats after NAcc PDC + SKF82958. These results suggest that in the NAcc, increased GLU neurotransmission and activation of D(1) DA receptors, neither of which is by itself sufficient, together contribute to the expression of locomotor sensitization by AMPH. They stress, with other findings, the importance of GLU-DA interactions in the NAcc not only in the generation of acute stimulant drug effects but in sensitized responding to these drugs as well.