REPEATED INTRA-VENTRAL TEGMENTAL AREA ADMINISTRATION OF SKF-38393 INDUCES BEHAVIORAL AND NEUROCHEMICAL SENSITIZATION TO A SUBSEQUENT COCAINE CHALLENGE

To assess the role of dopamine receptor subtypes in the initiation of behavioral sensitization to cocaine, the partial D-1 agonist SKF-38393 (0.01-1.0 mu g/side), the D-2/3 agonist quinpirole (0.1-1.0 mu g/side ) or saline was infused once daily over 3 days into either the ventral tegmental area (VTA) or the nucleus accumbens shell. Relative to sali ne controls, intra-VTA SKF-38393 administration did not influence beha vior during the treatment regimen, whereas the higher dose of quinpiro le produced a significant suppression of locomotor activity after the third daily administration., Infusion of 1.0 mu g/side SKF-38393 into the nucleus accumbens shell produced marked behavioral hyperactivity a fter both the first and last daily infusions, with no significant diff erence between the behavioral responses on these days. In contrast, qu inpirole did not influence behavior after its infusion into the nucleu s accumbens shell. Two weeks after the last daily intracranial drug in fusion, all animals were administered cocaine (15 mg/kg, i.p.) and beh avioral activity was monitored. The repeated administration of SKF-383 93 into the VTA resulted in sensitization to the locomotor-activating effects of cocaine, No other drug pretreatment influenced the cocaine- induced behavioral response. To determine whether repeated D-1 agonist administration influenced dopamine release in the nucleus accumbens s hell, in vivo microdialysis was performed in this structure after thre e daily intra-VTA infusions of saline or 0.1 mu g/side SKF-38393. The increase in dopamine levels in the nucleus accumbens shell induced by cocaine was significantly greater among rats pretreated with repeated SKF-38393 administration. Taken together,these results indicate that t he repeated intra-VTA administration of a D-1 agonist mimics the sensi tization process produced by repeated cocaine administration.