Striatal acetylcholine release correlates with behavioral sensitization in rats withdrawn from chronic amphetamine

Stimulant sensitization is defined as an enhancement of the behavioral response to drug after repeated drug exposure. We have examined the relation between the expression of behavioral sensitization and the release of the striatal neurotransmitters acetylcholine (ACh) and dopamine (DA). Rats were treated with amphetamine (4 mg/kg i.p., b.i.d.) for 12 days. The behavioral response to amphetamine challenge was assessed during the chronic treatment, at short withdrawal (2 days) and at long withdrawal (2-3 wk) from the drug. Neurochemical responses to amphetamine challenge were assessed in separate groups of rats at the two withdrawal timepoints using in vivo microdialysis. The expression of behavioral sensitization in response to a low challenge dose of amphetamine (0.5 mg/kg) was only observed after long withdrawal; indeed, tolerance was observed at the short withdrawal timepoint. In contrast, sensitization of the behavioral response to challenge with 4 mg/kg amphetamine developed progressively over the course of drug treatment and continued to increase throughout withdrawal. Striatal ACh release was enhanced by amphetamine challenge (4 mg/kg) in the chronically treated animals and this response also was greater at long withdrawal vs. short withdrawal. However, amphetamine administration had no net effect on striatal ACh release in animals previously given chronic saline injections. Amphetamine challenge increased striatal DA release but this response did not differ between drug- or saline-treated animals at either withdrawal timepoint. Thus, an enhancement of the drug-induced stimulation of striatal ACh release correlates with the temporal profile of the expression of behavioral sensitization to amphetamine. In contrast, amphetamine-induced DA release does not appear to correlate with the expression of behavioral sensitization in the same manner.