Reinforcing properties of Pramipexole in normal and parkinsonian rats

Abstract

Striatal D2 and D3 dopamine receptors are involved in mediating the reinforcing properties of natural rewards and drugs. In Parkinson's disease, while D2/3 dopamine agonists alleviate motor symptoms, behavioral addictions and withdrawal syndrome are reported in up to 15% of patients. The origin of such adverse effects is poorly understood but suggests that D2/3 agonists could possess reinforcing properties. We evaluated the reinforcing properties of the widely used D2/3 agonist, Pramipexole (PPX), in normal and parkinsonian rats. Intracerebroventricular injections of 6-OHDA induced a bilateral loss of tyrosine hydroxylase-positive cells in the substantia nigra (−51%) and ventral tegmental area (−31%). The animals were then allowed to self-administer intravenous PPX under fixed ratio and progressive ratio (PR) reinforcement schedules before being tested for extinction of PPX seeking. While parkinsonian were slower than sham rats in acquiring self-administration behavior, they later reached the same level of intake. The reinforcing value of PPX, as assessed during PR and extinction, was moderate in both groups. PPX heightened ∆FosB expression in dorsal striatum of lesioned rats and similar PR results involved different striatal subregions between groups. Altogether, our results show that drug-naïve rats self-administer PPX and that the dopaminergic lesion does not affect its reinforcing effects. While PPX reinforcing value was moderate in most rats, a subset of animals displayed a high number of responses and appeared to be particularly sensitive to this drug. These data suggest that PPX may not be responsible for the reported side-effects but rather call for further investigating the differential vulnerability among individuals.

Keywords

• Parkinson's disease
• Dopamine agonist
• D2/3 agonist
• Dopamine replacement therapy
• 6-OHDA