Elsevier

Biological Psychiatry

Volume 68, Issue 3, 1 August 2010, Pages 256-264
Biological Psychiatry

Archival Report
Peroxisome Proliferator-Activated Receptors-Alpha Modulate Dopamine Cell Activity Through Nicotinic Receptors

https://doi.org/10.1016/j.biopsych.2010.04.016Get rights and content

Background

Modulation of midbrain dopamine neurons by nicotinic acetylcholine receptors (nAChRs) plays an important role in behavior, cognition, motivation, and reward. Specifically, nAChRs containing β2 subunits (β2-nAChRs) switch dopamine cells from a resting to an excited state. However, how β2-nAChRs can be modulated and thereby how dopamine firing activity is affected remains elusive. Because changes in dopamine cell activity are reflected in the dynamics of microcircuits generating altered responses to stimuli and inputs, factors regulating their state are fundamental. Among these, endogenous ligands to the nuclear receptor-transcription factor peroxisome proliferator-activated receptors type-alpha (PPARα) have been recently found to suppress nicotine-induced responses of dopamine neurons.

Methods

We used both in vitro and in vivo electrophysiological techniques together with behavioral analysis to investigate on the effects of modulation of PPARα in Sprague–Dawley rat and C57BLJ/6 mouse dopamine neurons and their interactions with β2-nAChRs. To this aim, we took advantage of a selective reexpression of β2-nAChR exclusively in dopamine cells by stereotaxically injecting a lentiviral vector in the mouse ventral tegmental area.

Results

We found that activation of PPARα decreases in vitro both dopamine cell activity and ventral tegmental area net output through negative modulation of β2-nAChRs. Additionally, PPARα activation in vivo reduces both the number of spontaneously active dopamine neurons and nicotine-induced increased locomotion.

Conclusions

Our combined findings suggest PPARα ligands as important negative modulators of β2-nAChRs on dopamine neurons. Thus, PPARα ligands might prove beneficial in treating disorders in which dopamine dysfunction plays a prominent role, such as schizophrenia and nicotine addiction.

Section snippets

Methods and Materials

All procedures were performed in accordance with the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research Council 2004), EEC Council Directive (219/1990 and 220/1990) and approved by Animalerie Centrale and Médecine du Travail, Institut Pasteur. We made all efforts to minimize pain and suffering and to reduce the number of animals used.

The PPARα Antagonist MK886 Enhances DA Neuron Spontaneous Activity

To characterize the postsynaptic effects on DA neurons, all experiments were performed in the presence of CNQX (10 μmol/L), D-AP5 (100 μmol/L), and picrotoxin (100 μmol/L) to block alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-, N-methyl-D-aspartate-, and gamma-aminobutyric acidA-mediated postsynaptic responses. Whole-cell current- and voltage-clamp recordings were performed from medial posterior VTA DA neurons in rat horizontal slices containing the midbrain. The DA cells displayed

Discussion

Here we show that PPARα significantly contributes to the effects of endogenous cholinergic transmission mediated by β2-nAChRs on DA neuron excitability and to the effects of nicotine on locomotor activity, a DA associated behavior. The changes in number of spontaneously active DA neurons in vivo following PPARα activation are consistent with both the decreased spontaneous activity of individual VTA DA neurons and the diminished VTA net output observed in vitro. A functional consequence of

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