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.2012 Feb;37(2):113-21.
doi: 10.1503/jpn.110038.

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

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

Olga Chernoloz et al. J Psychiatry Neurosci.2012 Feb.

Abstract

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.

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.

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Figures

Fig. 1
Fig. 1
Assessment of tonic activation of D2 receptors in the prefrontal cortex (PFC). Integrated firing rate histograms of PFC pyramidal neurons illustrating systemic administration of the D2 receptor antagonist haloperidol (HAL; 0.2 mg/kg) in (A) rats subjected to saline (controls) and (B) rats receiving a 14-day regimen of pramipexole (PPX; 1 mg/kg/d). Each bar corresponds to 50-second application of dopamine (DA), and the number above each bar corresponds to the ejection current in nA. The arrow indicates a point of injection of 200 μg/kg of haloperidol. (C) The overall effect of systemic administration of haloperidol on baseline firing of PFC pyramidal neurons in controls and rats receiving PPX (expressed as % of change in basal firing). **p = 0.002.
Fig. 2
Fig. 2
Assessment of dopamine (DA) release in the prefrontal cortex (PFC). Peristimulus time histograms illustrating effects of stimulation of the ascending DA pathway on the firing activity of PFC pyramidal neurons in (A) controls and (B) rats administered pramipexole (PPX) for 14 days. The 2 10-ms bins at time 0 represent the stimulation artifacts. SIL = absolute silence value.
Fig. 3
Fig. 3
Assessment of tonic activation of 5-HT1A receptors in the dorsal hippocampus. Integrated firing rate histograms of dorsal hippocampus CA3 pyramidal neurons illustrating systemic administration of the 5-HT1A receptor antagonist WAY 100 635 in 4 incremental doses of (A) controls treated with 25 μg/kg of saline and (B) rats treated with 14 days of pramipexole (PPX; 1 mg/kg/d). Each bar corresponds to a 50-second application of 5-HT, and the number above each bar corresponds to the ejection current in nA. Each arrow indicates a single injection of 25 μg/kg of WAY 100 635. (C) The overall effect of cumulative systemic administration of WAY 100 635 on baseline firing of CA3 pyramidal neurons in control and PPX-treated rats (expressed as % of change in basal firing). **p = 0.004.
Fig. 4
Fig. 4
Assessment of serotonin (5-HT) release and sensitivity of terminal 5-HT1B receptors. Peristimulus time histograms illustrating effects of stimulation of the ascending 5-HT pathway, with (A) 1 Hz and (B) 5 Hz, on the firing activity of CA3 pyramidal neurons in controls and rats treated with 14 days of pramipexole (PPX). (C) The suppressing effect of the 5-HT pathway stimulations (1 Hz and 5 Hz) on the firing activity of hippocampal neurons in rats administered either NaCl (control) or PPX. Numbers in the boxes indicate the number of assessed neurons. The 10 msec bin at time 0 represents the stimulation artifact. Stimulation at a frequency of 1 Hz is indicated in white and that at 5 Hz in black. *p = 0.023, **p = 0.006. SIL = absolute silence value.
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References

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