J Psychiatry Neurosci 2012;37(2):113-21
Olga Chernoloz, BSc Pharm; Mostafa El Mansari, PhD; Pierre Blier, MD, PhD
Chernoloz, El Mansari, Blier — Institute of Mental Health Research, University of Ottawa; Blier — Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ont.
Background: Long-term administration of the dopamine (DA) D2-like (D3/2) receptor agonist pramipexole (PPX) has been previously found to desensitize D2 autoreceptors, thereby allowing a normalization of the firing of DA neurons and serotonin (5-HT)1A autoreceptors, permitting an enhancement of the spontaneous firing of 5-HT neurons. We hypothesized that PPX would increase overall DA and 5-HT neurotransmission in the forebrain as a result of these changes at the presynaptic level.
Methods: Osmotic minipumps were implanted subcutaneously in male Sprague-Dawley rats, delivering PPX at a dose of 1 mg/kg/d for 14 days. The in vivo electrophysiologic microiontophoretic experiments were carried out in anesthetized rats.
Results: The sensitivity of postsynaptic D2 receptors in the prefrontalcortex (PFC) remained unaltered following PPX administration, as indicated by the unchanged responsiveness to the microiontophoretic application of DA. Their tonic activation was, however, significantly increased by 104% compared with the control level. The sensitivity of postsynaptic 5-HT1A receptors was not altered, as indicated by the unchanged responsiveness to the microiontophoretic application of 5-HT. Similar to other antidepressant treatments, long-term PPX administration enhanced the tonic activation of 5-HT1A receptors on CA3 pyramidal neurons by 142% compared with the control level.
Limitations: The assessment of DA and 5-HT neuronal tone was restricted to the PFC and the hippocampus, respectively.
Conclusion: Chronic PPX administration led to a net enhancement in DA and 5-HT neurotransmission, as indicated by the increased tonic activation of postsynaptic D2 and 5-HT1A receptors in forebrain structures.
Submitted Apr. 21, 2011; Revised Aug. 19, 2011; Accepted Aug. 22, 2011.
Acknowledgments: This study was supported by the Canadian Institutes of Health Research grant to P. Blier. The authors thank Boehringer Ingelheim Pharmaceuticals for providing pramipexole. P. Blier received support for investigator initiated grants, and/or honoraria for advisory boards and/or speaking engagements from AstraZeneca, Biovail, Bristol Myers Squibbs, Eli Lilly & Company, Janssen Pharmaceuticals, Labopharm, Lundbeck, Pfizer, Schering-Plough/Merck, Servier, Takeda and Wyeth
Competing interests: As above for P. Blier. None declared for O. Chernoloz and M. El Mansari.
Contributors: P. Blier designed the study. O. Chernoloz acquired the data, which all authors analyzed. O. Chernoloz wrote the article, which M. El Mansari and P. Blier reviewed. All authors approved its publication.
Correspondence to: O. Chernoloz, University of Ottawa Institute of Mental Health Research, 1145 Carling Ave., Ottawa ON K1Z7K4; Olga.Chernoloz@rohcg.on.ca