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 D1 agonist SKF-38393 (0.01-1.0 microgram/side), the D2/3 agonist quinpirole (0.1-1.0 microgram/side) or saline was infused once daily over 3 days into either the ventral tegmental area (VTA) or the nucleus accumbens shell. Relative to saline controls, intra-VTA SKF-38393 administration did not influence behavior during the treatment regimen, whereas the higher dose of quinpirole produced a significant suppression of locomotor activity after the third daily administration. Infusion of 1.0 microgram/side SKF-38393 into the nucleus accumbens shell produced marked behavioral hyperactivity after both the first and last daily infusions, with no significant difference between the behavioral responses on these days. In contrast, quinpirole did not influence behavior after its infusion into the nucleus accumbens shell. Two weeks after the last daily intracranial drug infusion, all animals were administered cocaine (15 mg/kg, i.p.) and behavioral activity was monitored. The repeated administration of SKF-38393 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 D1 agonist administration influenced dopamine release in the nucleus accumbens shell, in vivo microdialysis was performed in this structure after three daily intra-VTA infusions of saline or 0.1 microgram/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 the repeated intra-VTA administration of a D1 agonist mimics the sensitization process produced by repeated cocaine administration.