PPARα Regulates Cholinergic-Driven Activity of Midbrain Dopamine Neurons via a Novel Mechanism Involving α7 Nicotinic Acetylcholine Receptors

Abstract

Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the ␤2 subunit (␤2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-␣ (PPAR␣) tonically regulate ␤2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPAR␣ endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of ␣7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the ␤2 subunit of nAChRs and the levels of two PPAR␣ endogenous ligands in a Ca 2ϩ -dependent manner. Accordingly, in vivo production of endogenous PPAR␣ ligands, triggered by ␣7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPAR␣ ligands are effectors of ␣7-nAChRs and that their neuromodulatory properties depend on phosphorylation of ␤2*-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPAR␣ signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPAR␣ as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: Implications for the heightened adolescent susceptibility to nicotine addiction

“…Functionally-relevant connectivity of the LDT to the VTA has been established (Forster and Blaha, 2000; Lammel et al, 2012; Lodge and Grace, 2006) and ACh-containing LDT neurons provide the major cholinergic input to DA-containing, mesoaccumbal projecting VTA neurons (Oakman et al, 1995; Omelchenko and Sesack, 2005; Omelchenko and Sesack, 2006). Further, the asymmetric nature of these cholinergic synapses (Omelchenko and Sesack, 2006) and the role of endogenous ACh in increasing firing of DA-VTA cells (Mameli-Engvall et al, 2006; Melis et al, 2013) indicate that LDT-mediated cholinergic input to DA-VTA cells is excitatory. Activation of the mesoaccumbal pathway including excitation of DA-VTA cells plays a deterministic role in development of drug dependency (Corrigall et al, 1994; Corrigall et al, 1992) and input from the LDT influences the excitability of DA-VTA neurons (Lammel et al, 2012).…”

“…Large effluxes of DA from VTA cells at terminals within the nucleus accumbens (NAcc) are believed to signal relevancy of behaviourally-motivating stimuli, such as drugs of abuse. Cholinergic input to the VTA, probably arising in large part from the LDT (Omelchenko and Sesack, 2005; Omelchenko and Sesack, 2006) is predominately excitatory (Mameli-Engvall et al, 2006; Melis et al, 2013), acting at nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs) demonstrated on DA-containing cells (Miller and Blaha, 2005; Pidoplichko et al, 2004). Supporting the conclusion that the LDT-VTA pathway is functionally important, inactivation of the LDT prohibits the DA-containing VTA neurons from burst firing (Lodge and Grace, 2006), a firing pattern required for behaviorally relevant release of DA from these cells (Floresco et al, 2003; Grace and Onn, 1989).…”

A threshold model for opposing actions of acetylcholine on reward behavior: Molecular mechanisms and implications for treatment of substance abuse disorders

“…After relatively high levels of ACh, choline, or nicotinic agonist; α7-mediated reductions in dopamine release may underlie reward inhibition, serving an auto inhibitory role [93]. This may occur through phosphorylation of β2* receptors, associated with attenuated nicotine-induced increases in the firing of VTA dopaminergic neurons [94]. …”

The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats

“…Administration of the endogenous PPARα ligand, OEA, decreases food consumption and reinforcement that is mediated by central DA neurotransmission (Fu et al, 2003; Plaza-Zabala et al, 2010; Rodriguez de Fonseca et al, 2001; Tellez et al, 2013). Further, increasing endogenous levels of ligands for PPARα or administration of agonists decrease activation of the mesolimbic DA system and attenuate the behavioral effects of nicotine and morphine (Fernandez-Espejo et al, 2009; Luchicchi et al, 2010; Mascia et al, 2011; Melis et al, 2010; Melis et al, 2008; Melis et al, 2013b; Panlilio et al, 2012). Accordingly, evidence indicates that PPARα agonists reduce voluntary ethanol (EtOH) self-administration in rodents; however, results have not been consistent.…”