Alterations in D1/D2 synergism may account for enhanced stereotypy and reduced climbing in mice lacking dopamine D2L receptor.

Concurrent activation of dopamine D1 and D2 receptors (D1 and D2) is required for the expression of certain dopamine (DA)-mediated responses, such as climbing and stereotyped behaviors. Such interactions between D1 and D2 (i.e. D1/D2 synergism) represent an important aspect of dopaminergic function and plasticity. The D2 receptor exists in two isoforms: D2L and D2S. We have generated mice that selectively lack D2L (D2L-/-). Here we showed that treatment with the indirect DA agonist amphetamine, the direct DA agonist apomorphine, or combination of D1 and D2 agonists elicited intense climbing in wild type mice (which express predominantly D2L in the striatum), but this behavior was absent or reduced in D2L-/- mice. On the other hand, apomorphine, the D2 agonist quinpirole, or combination of quinpirole and the D1 agonist SKF 81297 induced more stereotyped behavior such as biting or head movements in D2L-/- mice (which express only D2S) than in wild type mice. The D1 receptor functioned normally in D2L-/- mice. Taken together, these results suggest that D2L and D1 interactions may play a greater role in DA agonist-induced climbing, whereas D2S and D1 interactions may have a larger impact on DA agonist-induced stereotypy (and possibly psychosis). DA agonists, which are clinically used to treat Parkinson's disease and attention-deficit hyperactivity disorder (ADHD), are known to induce psychotic side effects. Thus, our findings may provide novel insights for designing anti-parkinsonian, anti-ADHD and antipsychotic drugs with greater therapeutic efficacy and fewer side effects.