A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats: A role of inhibitory dopamine d_1/5 receptors in the prefrontal cortex?

The behavioral and biochemical effects of the full dopamine D _1/5 receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6- dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg^-1, s.c.) and dihydrexidine (0-8.0 mg kg^-1, s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D_1/5 receptor antagonist R(+)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 μg kg^-1, s.c.), but not by the selective dopamine D _2/3 receptor antagonist raclopride (0-25.0 μg kg^-1, s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg^-1, s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D_1/5 receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D_1/5 receptors in schizophrenia, such inhibitory actions of dopamine D_1/5 receptor stimulation on psychomotor activation mya have interesting clinical implications in the treatment of schizophrenia.