The associative type of sensitization to d-amphetamine is expressed as an NO-dependent dramatic increase in extracellular dopamine in the nucleus accumbens

After repeated administration of psychomotor-stimulant drugs such as d-amphetamine, a sensitization to its stimulant effects such as locomotor activity and stereotyped behaviour can be observed depending on the treatment schedule. It was the aim of the present study to test whether (1) associative (conditioning) and non-associative (pseudoconditioning) types of sensitization differ in the corresponding alterations in extracellular dopamine in the nucleus accumbens, and (2) the inhibitor of nitric oxide synthase (NOS), N(G)-nitro-L-arginine methyl ester (L-NAME), influences the two types of sensitization in a different way. Rats were treated with d-amphetamine (1 mg/kg i.p.) on days 1, 3, 5 and 7 and alternatively with saline on days 2, 4 and 6 under associative or non-associative conditions, respectively. A third (saline control) group was treated with saline daily for 7 days. Subsequently, probes for microdialysis were implanted into the nucleus accumbens. After a drug-free period of 10 days, on day 17, the increase in extracellular dopamine produced by 1 mg/kg d-amphetamine was much more pronounced in associative (conditioned) than in non-associative (pseudoconditioned) or naive rats. Pretreatment with L-NAME (100 mg/kg i.p.) on day 17 did not significantly alter the baseline concentrations of dopamine, but it inhibited the dopamine increase much more in associative than in naive rats and did not significantly affect it in non-associative rats. The results suggest that (1) associative sensitization to d-amphetamine leads to the most pronounced increase in extracellular dopamine in the nucleus accumbens, and (2) NO is very much involved in the expression of the associative increase in extracellular dopamine in the nucleus accumbens.