Reinforcing properties of Pramipexole in normal and parkinsonian rats

Neurobiol Dis. 2013 Jan;49:79-86. doi: 10.1016/j.nbd.2012.08.005. Epub 2012 Aug 23.

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: 6-OHDA; D2/3 agonist; Dopamine agonist; Dopamine replacement therapy; Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / administration & dosage*
  • Benzothiazoles / administration & dosage*
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiopathology
  • Dopamine Agonists / pharmacology*
  • Drug-Seeking Behavior / physiology*
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology
  • Immunohistochemistry
  • Male
  • Motor Activity / physiology
  • Oxidopamine
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / physiopathology
  • Pramipexole
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats, Wistar
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D3 / agonists
  • Receptors, Dopamine D3 / metabolism
  • Reinforcement Schedule
  • Self Administration
  • Substance-Related Disorders / physiopathology*

Substances

  • Antiparkinson Agents
  • Benzothiazoles
  • Dopamine Agonists
  • Fosb protein, rat
  • Proto-Oncogene Proteins c-fos
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Pramipexole
  • Oxidopamine