Dopamine D4 receptor-deficient mice, congenic on the C57BL/6J background, are hypersensitive to amphetamine.

Mice lacking the dopamine D4 receptor subtype (D4R-/-) are supersensitive to methamphetamine and cocaine. We sought to expand and refine earlier experiments performed on F2 generation D4R-/- mice by lengthening the behavioral session, utilizing an N10 D4R-/- incipient congenic C57BL/6J line (D4R-/- mice backcrossed with wildtype C57BL/6J mice for 10 successive generations), and investigating whether dopamine D4Rs are necessary for the expression of behavioral sensitization to amphetamine. The D4R-/- mice demonstrated an enhanced and dose-dependent increase in amphetamine-stimulated activity compared to wildtype mice following acute administrations of amphetamine. For the behavioral sensitization experiments, separate groups of mice received either repeated administrations of the same dose of amphetamine or a subthreshold dose of amphetamine (2 mg/kg) 28 days following pretreatment with either saline, 1.0, 3.0, or 10.0 mg/kg amphetamine. The D4R-/- mice displayed an enhanced dose-dependent sensitized response to repeated amphetamine administrations compared to their wildtype littermates in both behavioral sensitization paradigms. Our present results further support the importance of dopamine D4Rs in psychostimulant-mediated locomotion and neural plasticity. Copyright 2004 Wiley-Liss, Inc.