Role of the cAMP Pathway and CREB in the Nucleus Accumbens

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As stated earlier, the mesolimbic dopamine system is a major neural substrate for the motivational and rewarding effects of opiates. This occurs via two mechanisms (3). Opiates increase dopaminergic transmission to the NAc by activating VTA dopamine neurons. This occurs indirectly through opiate inhibition of GABAergic interneurons within the VTA that inhibit the dopamine neurons. Opiates also act directly on opioid receptors expressed by NAc neurons. The rewarding effects of other drugs of abuse are mediated via similar actions in the VTA-NAc pathway, although each drug produces these effects via drug-specific mechanisms (1,24). In addition, the mesolimbic dopamine system appears to be play a similar role in mediating the actions of natural reinforc-ers, such as food, drink, sex, and social interactions.

It is interesting, therefore, that chronic administration of opiates or several other drugs of abuse up-regulates the cAMP pathway in the NAc (4). The upregulation, similar to that observed in the LC, involves increased levels of adenylyl cyclase and PKA, although the specific isoforms of adenylyl cyclase that are induced have not yet been identified. In addition, the drugs decrease levels of Gai/o, which would further augment

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Fig. 2. Regulation of CREB by drugs of abuse. The figure shows a VTA dopamine (DA) neuron innervating a class of NAc GABAergic projection neuron that expressed dynorphin (dyn). Dynorphin serves a negative feedback mechanism in this circuit: dynorphin, released from terminals of the NAc neurons, acts on D-opioid receptors located on nerve terminals and cell bodies of the DA neurons to inhibit their functioning. Chronic exposure to cocaine or opiates up-regulates the activity of this negative feedback loop via upregulation of the cAMP pathway, activation of CREB, and induction of dynorphin (4)

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Fig. 2. Regulation of CREB by drugs of abuse. The figure shows a VTA dopamine (DA) neuron innervating a class of NAc GABAergic projection neuron that expressed dynorphin (dyn). Dynorphin serves a negative feedback mechanism in this circuit: dynorphin, released from terminals of the NAc neurons, acts on D-opioid receptors located on nerve terminals and cell bodies of the DA neurons to inhibit their functioning. Chronic exposure to cocaine or opiates up-regulates the activity of this negative feedback loop via upregulation of the cAMP pathway, activation of CREB, and induction of dynorphin (4)

activity of the cAMP pathway. As would be expected, chronic opiate or cocaine administration also causes a sustained increase in the functional activity of CREB in the NAc (25,26).

Insight into the functional consequences of the up-regulated cAMP pathway in the NAc has come from several studies. Infusion of inhibitors of the cAMP pathway (e.g., PKA inhibitors) directly into the NAc makes animals less responsive to the rewarding effects of cocaine and, possibly, opiates (27,28). Conversely, infusion of activators of the cAMP pathway (e.g., adenylyl cyclase or PKA activators) have the opposite effects. Consistent with these findings are observations obtained from direct manipulation of CREB within the NAc by use of viral-mediated gene transfer. Overexpressing CREB specifically within the NAc decreases the rewarding effects of cocaine and opiates, whereas expressing a dominant negative inhibitor of CREB (termed mCREB) increases the drugs' rewarding effects (29).

This action of CREB appears to be mediated in part via regulation of dynorphin gene transcription (Fig. 2). Dynorphin is an opioid peptide expressed in a subset of NAc neurons. Dynorphin acts on D-opioid receptors to inhibit dopamine neuron cell bodies in the VTA and their terminals in the NAc, and thereby inhibits drug reward (30). The dynorphin gene has been shown to be a target for CREB both in vitro and within the NAc in vivo (25,29). Moreover, the effect of increased CREB activity in the NAc on drug reward can be completely blocked by a K-receptor antagonist (29). Thus, it appears that CREB negatively regulates drug reward by increasing the gain of the dynorphin feedback loop.

Recent work has provided a more complete understanding of the behavioral pheno-type mediated by CREB activity in the NAc. Not only does CREB activity decrease sensitivity to drug reward, it also renders an animal less sensitive to a range of external stimuli, including both natural rewards (e.g., sucrose preference) and aversive stimuli (e.g., anxiogenic, aversive, and nociceptive stimuli) (31,32). Based on these data, our hypothesis is that upregulation of the cAMP pathway induced in the NAc by chronic drug exposure numbs an animal's emotional responsiveness. This state presumably contributes to part of the negative emotional state that occurs during drug withdrawal and helps drive relapse to drug use.

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