Blockade of neurokinin-3 receptors modulates dopamine-mediated behavioral hyperactivity

Acute activation or blockade of neurokinin-3 (NK-3) receptors has been shown to alter dopamine-mediated function and behaviors, however long-term effects of NK-3 receptor blockade remain largely unknown. The present study investigated whether acute and repeated administration of the NK-3 receptor antagonist SB 222200 altered hyperactivity induced by cocaine, and examined its effects on dopamine D1 receptor density in the striatum. Adult male CD-1 mice received either vehicle or SB 222200 (2.5 or 5 mg/kg, s.c.) 30 min before a cocaine injection (20 mg/kg, i.p.) and behavioral responses were recorded. Mice that were administered SB 222200 had an attenuated stereotypic response to cocaine compared to vehicle treated mice. Mice were also injected once daily with either vehicle or SB 222200 (5 mg/kg, s.c.) for 5 days, and after a 7-day drug-free period they were challenged with either saline, cocaine or the dopamine D1 receptor agonist SKF 82958 (0.125 or 0.25 mg/kg, i.p.). Mice injected with SB 222200 had significantly enhanced hyperactivity when challenged with cocaine or a low dose of SKF 82958 (0.125 mg/kg, i.p.) compared to control mice. Brains of mice administered vehicle or SB 222200 for 5 days were harvested after a 7-day drug-free period for dopamine D1 receptor quantification by radioligand binding. [(3)H] SCH 23390 homogenate binding studies showed a 19.7% increase in dopamine D1 receptor density in the striatum of SB 222200 treated mice. These data suggest that repeated blockade of NK-3 receptors enhances subsequent dopamine-mediated behaviors possibly resulting from dopamine D1 receptor up-regulation in the striatum.