ReviewBiological substrates of reward and aversion: A nucleus accumbens activity hypothesis
Introduction
The biological basis of mood-related states such as reward and aversion is not understood. Classical formulations of these states implicate the mesocorticolimbic system, comprising brain areas including the NAc, VTA, and PFC, in reward (Bozarth and Wise, 1981, Goeders and Smith, 1983, Wise and Rompré, 1989). Other brain areas, including the amygdala, periaquaductal gray, and the locus coeruleus, are often implicated in aversion (Aghajanian, 1978, Phillips and LePiane, 1980, Bozarth and Wise, 1983). However, the notion that certain brain areas narrowly and rigidly mediate reward or aversion is becoming archaic. The development of increasingly sophisticated tools and methodologies has enabled new approaches that provide evidence for effects that previously would have been difficult (if not impossible) to detect. As one example from our own work, we have found that a prominent neuroadaptation triggered in the NAc by exposure to drugs of abuse (activation of the transcription factor CREB) contributes to depressive-like and aversive states in rodents (for review, see Carlezon et al., 2005). Other work suggests that changes in the activity of dopaminergic neurons in the VTA – which provides inputs to the NAc that are integrated with glutamatergic inputs from areas such as the PFC, AMG, and HIP – can also encode both rewarding and aversive states (Liu et al., in press).
In this review, we will focus on the role of the NAc in simple states of reward and aversion. The role of NAc activity in more complex states such as drug-craving and drug-seeking is beyond the scope of this review, since these states depend upon experience-dependent neuroadaptations and do not easily map onto basic conceptualizations of rewarding and aversive states. An improved understanding of the neurobiology of reward and aversion is critical to the treatment of complex disorders like addiction. This question is particularly important as the field utilizes accumulated knowledge from decades of research on drugs of abuse to move toward the rational design of treatments for addictive disorders. The requirement for new medications goes beyond the mere reduction of drug-craving, drug-seeking, or other addictive behaviors. To be an effective therapeutic, a medication must be tolerated by the addicted brain, or compliance (sometimes called adherence) will be poor. There are already examples of medications (e.g., naltrexone) that would appear on the basis of animal data to have extraordinary potential for reducing intake of alcohol and opiates – except that addicts often report aversive effects and discontinue treatment (Weiss 2004). Methods to predict rewarding or aversive responses in normal and addicted brains would accelerate the pace of drug discovery, medication development, and recovery from addiction. Here we review evidence for the simple working hypothesis that rewarding and aversive states are encoded by the activity of NAc medium spiny GABAergic neurons.
Section snippets
The NAc
The NAc comprises the ventral components of the striatum. It is widely accepted that there are two major functional components of the NAc, the core and the shell, which are characterized by differential inputs and outputs (see Zahm, 1999, Kelley, 2004, Surmeier et al., 2007). Recent formulations further divide these two components into additional subregions (including the cone and the intermediate zone of the NAc shell) (Todtenkopf and Stellar, 2000). As in the dorsal striatum, GABA-containing
Role of the NAc in rewarding states
It is well accepted that the NAc plays a key role in reward. Theories about its role in motivation have been a critical element in our understanding of addiction (e.g., Wise and Bozarth, 1987; Wise and Rompré, 1989). There are three primary lines of evidence implicating the NAc in reward, involving pharmacological, molecular, and electrophysiological approaches.
Role of the NAc in aversive states
The fact that the NAc also plays a role in aversion is sometimes underappreciated. Pharmacological treatments have been used to demonstrate aversion after NAc manipulations. In addition, molecular approaches have demonstrated that exposure to drugs of abuse and stress cause common neuroadaptions that can trigger signs (including anhedonia, dysphoria) that characterize depressive illness (Nestler and Carlezon, 2006), which is often co-morbid with addiction and involves dysregulated motivation.
Testing the model
Based on the evidence described above, our working hypothesis is that rewarding stimuli reduce the activity of NAc MSNs, whereas aversive treatments increase the activity of these neurons. According to this model (Fig. 2), NAc neurons tonically inhibit reward-related processes. Under normal circumstances, excitatory influences mediated by glutamate actions at AMPA and NMDA receptors or dopamine actions at D1-like receptors are balanced by inhibitory dopamine actions at D2-like receptors.
Conclusions
We propose a simple model of mood in which reward is encoded by reduced activity of NAc MSNs, whereas aversion is encoded by elevated activity of these same cells. Our model is supported by a preponderance of evidence already in the literature, although more rigorous tests are needed. It is also consistent with clinical studies indicating reduced numbers of inhibitory dopamine D2-like receptors in the NAc of drug addicts, which may decrease sensitivity to natural rewards and exacerbate the
Acknowledgements
Funded by the National Institute on Drug Abuse (NIDA) grants DA012736 (to WAC) and DA019666 (to MJT) and a McKnight-Land Grant professorship (to MJT). We thank M.J. Kaufman, B. de Frederick, and S.S. Negus for permission to cite unpublished data from their brain imaging studies in monkeys.
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