Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure

Abstract

Addictive substances are known to increase dopaminergic signaling in the mesocorticolimbic system. The origin of this dopamine (DA) signaling originates in the ventral tegmental area (VTA), which sends afferents to various targets, including the nucleus accumbens, the medial prefrontal cortex, and the basolateral amygdala. VTA DA neurons mediate stimuli saliency and goal-directed behaviors. These neurons undergo robust drug-induced intrinsic and extrinsic synaptic mechanisms following acute and chronic drug exposure, which are part of brain-wide adaptations that ultimately lead to the transition into a drug-dependent state. Interestingly, recent investigations of the differential subpopulations of VTA DA neurons have revealed projection-specific functional roles in mediating reward, aversion, and stress. It is now critical to view drug-induced neuroadaptations from a circuit-level perspective to gain insight into how differential dopaminergic adaptations and signaling to targets of the mesocorticolimbic system mediates drug reward. This review hopes to describe the projection-specific intrinsic characteristics of these subpopulations, the differential afferent inputs onto these VTA DA neuron subpopulations, and consolidate findings of drug-induced plasticity of VTA DA neurons and highlight the importance of future projection-based studies of this system.

Figure 1

In vivo firing characteristics of VTA DA neurons. Active VTA DA neurons transition between two states of firing modes in vivo: (a) low-frequency tonic, single-spike firing and (b) high-frequency burst firing (inset shows expanded view of burst with onset occurring when two spikes fire within <80 ms and termination ending after >160 ms of silence). VTA DA neurons have a waveform shape under filter conditions. (c) Demonstration of a single recorded VTA DA neuron under three different filters used in electrophysiology. DA, dopamine; VTA, ventral tegmental area.

Figure 2

Schematic representation of VTA input and output. Amyg, amygdala; BNST, bed nucleus of stria terminalis; LH, lateral hypothalamus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; LHb, lateral habenula; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; OFC, orbitofrontal cortex; PPTg, pedunculopontine tegmental nucleus (aka PPN); RMTg, rostral medial tegmental nucleus; VP, ventral pallidum; vSub, ventral subiculum; VTA, ventral tegmental area.

Figure 3

Known inputs onto I_h-positive VTA DA neurons. VTA DA neurons that project to specific regions of the mesocorticolimbic system can often be identified by the presence and absence of an I_h current. This figure shows I_h-positive circuits. BNST, bed nucleus of stria terminalis; DA, dopamine; I_h, hyperpolarization-activated cation channel current; LDT, laterodorsal tegmental nucleus; LHb, lateral habenula; NAc, nucleus accumbens; RMTg, rostral medial tegmental nucleus; VTA, ventral tegmental area.

Figure 4

Known inputs onto I_h-negative VTA DA neurons. This figure shows known direct synaptic inputs onto I_h-negative neurons and their projection targets. Amyg, amygdala; BNST, bed nucleus of stria terminalis; DA, dopamine; I_h, hyperpolarization-activated cation channel current; LDT, laterodorsal tegmental nucleus; LHb, lateral habenula; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; RMTg, rostral medial tegmental nucleus; VTA, ventral tegmental area.

Figure 5

Drugs of abuse act in different ways to increase DA concentrations in downstream targets of the VTA. Pictured here is a VTA DA neuron projecting to the NAc. Ethanol acts directly on VTA DA neurons to increase VTA cell firing, increase I_h, and increase GIRK activity. This increase in activity leads to increased DA release. Ethanol also has effects on VTA GABA interneurons. Nicotine acts on VTA DA neurons themselves through the ligand-gated ion channel, nAChRs. Nicotine also has effects on GABA interneurons and glutamatergic afferents. Morphine acts indirectly through GABA interneurons to increase VTA DA activity. Morphine binds to MORs to decrease IPSC frequency and decrease GABAergic cell firing. This decrease in GABAergic tone disinhibits VTA DA neurons, increasing DA concentrations in the NAc. Cocaine increases concentrations of DA in the NAc by inhibiting DAT function at the VTA DA terminal. Interestingly, acute administration of ethanol, morphine, and cocaine was shown to enhance glutamatergic synaptic strength, as seen through an increase AMPA/NMDA ratio. DA, dopamine; DAT, dopamine transporter; GIRK, G protein-coupled inwardly rectifying potassium channels; I_h, hyperpolarization-activated cation channel current; IPSC, inhibitory post-synaptic current; MOR, μ-opioid receptor; NAc, nucleus accumbens; VTA, ventral tegmental area.