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Review
, 56 Suppl 1 (Suppl 1), 122-32

Biological Substrates of Reward and Aversion: A Nucleus Accumbens Activity Hypothesis

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Review

Biological Substrates of Reward and Aversion: A Nucleus Accumbens Activity Hypothesis

William A Carlezon Jr et al. Neuropharmacology.

Abstract

The nucleus accumbens (NAc) is a critical element of the mesocorticolimbic system, a brain circuit implicated in reward and motivation. This basal forebrain structure receives dopamine (DA) input from the ventral tegmental area (VTA) and glutamate (GLU) input from regions including the prefrontal cortex (PFC), amygdala (AMG), and hippocampus (HIP). As such, it integrates inputs from limbic and cortical regions, linking motivation with action. The NAc has a well-established role in mediating the rewarding effects of drugs of abuse and natural rewards such as food and sexual behavior. However, accumulating pharmacological, molecular, and electrophysiological evidence has raised the possibility that it also plays an important (and sometimes underappreciated) role in mediating aversive states. Here we review evidence that rewarding and aversive states are encoded in the activity of NAc medium spiny GABAergic neurons, which account for the vast majority of the neurons in this region. While admittedly simple, this working hypothesis is testable using combinations of available and emerging technologies, including electrophysiology, genetic engineering, and functional brain imaging. A deeper understanding of the basic neurobiology of mood states will facilitate the development of well-tolerated medications that treat and prevent addiction and other conditions (e.g., mood disorders) associated with dysregulation of brain motivation systems.

Figures

Fig. 1
Fig. 1
Schematic illustrating the subunit composition of AMPA (glutamate) receptors. For simplicity, the receptors are depicted with 2 subunits. GluR2 contains a motif that blocks Ca2+ flux through the receptor, and thus heteromeric receptors that contain at least one GluR2 subunit are Ca2+-impermeable. Conversely, high expression of GluR1 subunits favors formation of high conductance, Ca2+-permeable AMPA receptors. Increased intracellular Ca2+ has important effects on neuronal functions such as depolarization, and has been implicated in neuroplasticity involving altered gene transcription.
Fig. 2
Fig. 2
Schematic depicting a simple working hypothesis of how the nucleus accumbens (NAc) may regulate rewarding and aversive states. (a) NAc neurons tonically inhibit reward-related processes. Under normal circumstances, there is a balance between cortical (PFC, AMG) excitatory (+) influences mediated by glutamate actions at AMPA and NMDA receptors, and midbrain (VTA) inhibitory (−) influences mediated by dopamine actions at D2-like receptors. NAc neurons have low baseline rates of firing, and depolarization-mediated influx of Ca2+ through NMDA receptors and calcium channels is not sufficient to alter gene expression. (b) Depolarization of NAc neurons containing D2-like receptors and enkephalin inhibits downstream areas implicated in reward (e.g., vental pallidum) which is encoded as aversion. It also leads to elevated Ca2+ influx, which may trigger experience-dependent neuroadaptations (e.g., activation of CREB, elevated expression of GluR1) can produce feed-forward effects that dysregulate the system. AMG, amygdala; Ca, calcium channel; Ca2+, calcium; CREB, cAMP response element binding protein; D2, dopamine D2-like receptor; DA, dopamine; ENK, enkephalin; G1/G2, AMPA glutamate receptor containing GluR1 and GluR2; GABA, gamma-aminobutyric acid; GLU, glutamate; N, NMDA receptor; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area
Fig. 3
Fig. 3
Intravenous infusions of the μ-opioid agonist fentanyl and the κ-opioid agonist U69,593 induce overlapping but anatomically selective blood oxygen level dependent functional MRI (BOLD fMRI) responses in alert male cynomolgus monkeys (N=3). Results are from duplicate scans with each drug condition in each subject. Fentanyl induced positive BOLD fMRI responses in the caudate nucleus and bilaterally in putamen, amygdala, and insula. An equipotent dose of U69,593 induced positive BOLD fMRI responses in caudate nucleus and bilateral insula, but also induced positive responses in bilateral nucleus accumbens (NAc) and ventral striatum. Crosshairs are centered on the NAc. (From Kaufman, M.J., Frederick, B.deB., Negus, S.S., et al., in preparation; used with permission).

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