Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

Abstract

Nicotine and alcohol addiction are leading causes of preventable death worldwide and continue to constitute a huge socio-economic burden. Both nicotine and alcohol perturb the brain's mesocorticolimbic system. Dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to multiple downstream structures, including the nucleus accumbens, prefrontal cortex, and amygdala, are highly involved in the maintenance of healthy brain function. VTA DA neurons play a crucial role in associative learning and reinforcement. Nicotine and alcohol usurp these functions, promoting reinforcement of drug taking behaviors. In this review, we will first describe how nicotine and alcohol individually affect VTA DA neurons by examining how drug exposure alters the heterogeneous VTA microcircuit and network-wide projections. We will also examine how coadministration or previous exposure to nicotine or alcohol may augment the reinforcing effects of the other. Additionally, this review briefly summarizes the role of VTA DA neurons in nicotine, alcohol, and their synergistic effects in reinforcement and also addresses the remaining questions related to the circuit-function specificity of the dopaminergic system in mediating nicotine/alcohol reinforcement and comorbidity.

Keywords: alcohol; circuit; dopamine; electrophysiology; heterogeneity; nicotine; reinforcement; ventral tegmental area.

Figure 1:. Schematic of the acute and chronic action of nicotine (left, green) and alcohol (right, blue) on VTA DA neurons.

VTA DA neurons receive glutamatergic inputs from: PFC, LHb, PPTg and LDTg, ACh inputs from PPTg and LDTg, and GABA inputs from local VTA GABA neurons, VP, NAc and RMTg. VTA neurons expresses a large portfolio of nAChRs (α4β2, α4α5β2, α7, α6β3, α6β4). Acute nicotine acts directly on VTA DA and GABA neurons, and potentiates the glutamatergic and GABA synaptic inputs, and overall increases the tonic and bursting activity of VTA DA neurons. Chronic nicotine exposure decreases the GABA synaptic inputs onto VTA DA neurons, and increases the expression and function of α4β2nAChRs and α7nAChRs, respectively. Voluntary chronic exposure to nicotine increases VTA DA neuron activity. Acute alcohol potentiates GABA and Glycine receptors, inhibits VTA GABA neurons, and has differing effects on K⁺ and HCN channels. Specifically, alcohol increases the function of HCN and BK channels, whereas SK channels are inhibited. SK channel inhibition persists after chronic exposure, and is thought to underlie increased bursting activity of VTA DA neurons in response to ethanol over time. Chronic alcohol exposure increases excitatory transmission onto VTA DA neurons, although this may be due to withdrawal effect. Abbreviations: DA, dopamine neurons; nAChRs, nicotinic receptors; ACh, Acetylcholine; LDT, laterodorsal tegmentum, PPTg, pedonculopontine tegmentum; PFC, prefrontal cortex; Lateral habenula, LHb; RMTg, rostromedial tegmental nucleus; VP, ventral pallidum; NAc, nucleus accumbens; Big potassium channels, BK; Small-conductance activated channels; SK; Hyperpolarization-activated cyclic nucleotide-gated channels, HCN.

Figure 2:. Dopaminergic circuit heterogeneous reinforcing effect of nicotine and alcohol.

(A) Schematic of VTA DA subnuclei and preferential projections. Recent studies using cell-specific tracing techniques established topographic preferential projection: from a medial to lateral axis, VTA DA neurons preferentially project to the mPFC, then the NAc, then the AMG and finally the NAcsh. (B) Schematic of VTA DA heterogenous neural and the consecutive behavioral response to nicotine (left, green) and alcohol (right, blue). Both nicotine and alcohol establish strong reinforcing effects when infused in the pVTA compared to the aVTA. VTA DA neurons display distinct activity in response to nicotine. Lateral VTA DA neurons are activated (+) by i.v. nicotine injection, medial VTA DA neurons are inhibited (−). VTA DA neurons have an increased sensitivity to alcohol across the medial/lateral axis (+, +). Abbreviations: AMG, Amygdala; aVTA, anterior ventral tegmental area; BNST, bed nucleus of the stria terminalis; CPu, caudate putamen; CP, cerebral peduncle; IF, interfascicular nucleus; IL, infralimbic cortex; IPn, interpeduncular nucleus; LHb, lateral habenula; mHb, medial habenula; ml, medial lemniscus; mPFC, medial prefrontal cortex; NAcc, nucleus accumbens core; NAcsh, nucleus accumbens shell; PBP, parabrachial pigmented nucleus; PN, paranigral nucleus; pVTA, posterior ventral tegmental area; RN, red nucleus; RLi, rostral linear nucleus; SN, substantia nigra.

Figure 3:. Network nicotine and alcohol modulation of VTA DA neurons.

(A) Network modulation onto VTA DA neurons in response to nicotine. The IL-BNST-VTA circuit (green) increases the spontaneous VTA DA activities following voluntary nicotine consumption. mHb-IPn circuit decreases the reinforcing properties of high concentration of nicotine by encoding aversive signal. The precise modulation of this pathway onto VTA DA neurons remains poorly understood. LHb-RMTg-VTA circuit requires further investigation to fully characterize its function in nicotine reinforcement. While LHb-RMTg activation inhibits VTA DA neurons, nicotine activation of RMTg neurons does not affect VTA DA neural response to nicotine. (B) Network modulation onto VTA DA neurons in response to alcohol. Activation of DA receptors in the NAcsh, VP, and PFC are involved in mediating the reinforcing effects of ethanol and inhibitory projections from the VP to the VTA may control alcohol seeking and reinstatement. The LHb-RMTg-VTA circuit has been hypothesized to contribute to aversive conditioning of ethanol response and may account for individual differences in drinking behaviors. Stress and withdrawal affects of chronic alcohol exposure are highly controlled by the connections between VTA and AMG. Abbreviations: AMG, Amygdala; BNST, bed nucleus of the stria terminalis; CPu, caudate putamen; IL, infralimbic cortex; IPn, interpeduncular nucleus; LHb, lateral habenula; mHb, medial habenula; mPFC, medial prefrontal cortex; NAcc, nucleus accumbens core; NAcsh, nucleus accumbens shell.