Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain.
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 prefrontal cortex (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.


CONCLUSIONS
The assessment of DA and 5-HT neuronal tone was restricted to the PFC and the hippocampus, respectively.


CONCLUSIONS
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.
Institute of Mental Health Research, University of Ottawa, Ottawa, Ont. Olga.Chernoloz@rohcg.on.ca
Olga
O
Chernoloz
Mostafa
M
El Mansari
Pierre
P
Blier
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007478:Iontophoresis; D008297:Male; D009434:Neural Pathways / Q000187:drug effects; D000077487:Pramipexole; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*
D052160:Benzothiazoles; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000077487:Pramipexole; D004298:Dopamine