Priming of a D1 dopamine receptor behavioural response is dissociated from striatal immediate-early gene activity.

Repeated administration of direct-acting (apomorphine, SKF-38393, quinpirole) or indirect-acting (amphetamine, cocaine) dopaminergic agonists can produce enhancement of locomotor and sterotypic behaviours in response to subsequent dopamine agonist challenge. This sensitization of dopamine receptors, known as priming or reverse tolerance, is long-lasting and appears to be dependent upon the participation of the N-methyl-D-asparate excitatory amino acid receptor. The mechanism underlying dopamine receptor sensitization is not understood. Mounting evidence suggests that immediate-early genes may provide a link whereby extracellular stimuli are converted into long-term changes in neuronal activity. In the present study, behavioural measurements and immunohistochemical techniques were used to determine whether induction of the immediate-early gene c-fos is critical to the mechanism underlying priming of a D1-mediated behavioural response. It was demonstrated that in drug-naive rats bearing unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway, the mixed D1/D2 agonist apomorphine produced a dramatic increase in the expression of Fos-like immunoreactivity in the ipsilateral caudoputamen, nucleus accumbens and globus pallidus, and was a potent primer of SKF-38393-mediated rotational behaviour. In contrast, saline administration did not increase Fos expression and did not prime SKF-38393-elicited rotation. Preadministration of MK-801 at 0.5 mg/kg significantly reduced apomorphine's effect on Fos expression and prevented apomorphine priming of SKF-38393-induced rotation. However, at a lower dose of 0.1 mg/kg, MK-801 had little effect on apomorphine-mediated Fos expression but did block the priming response. In another experiment, the D2 family-selective agonist quinpirole was found to be an affective primer of SKF-38393-mediated rotation, and to produce increase Fos expression in the ipsilateral globus pallidus only. Preadministration of MK-801 at 0.1 mg/kg blocked quinpirole priming of SKF-38393-mediated rotation and significantly reduced the number of Fos-positive neurons in the ipsilateral globus pallidus. Administration of the indirect dopamine agonist amphetamine increased Fos expression in the intact striatum, but not in the ipsilateral (lesioned) striatum or globus pallidus, and did not sensitize (prime) animals to behavioural effects of SKF-38393. In a separate group of animals. Northern blot analysis demonstrated that a priming dose of apomorphine significantly increased the messenger RNA signals for c-fos, c-jun, ngfi-A and jun-B in denervated striatum. Administration of 0.1 mg/kg MK-801 prior to apomorphine had no significant effect on signal intensities.(ABSTRACT TRUNCATED AT 400 WORDS)