Brain substrates for increased drug seeking during protracted withdrawal
Introduction
Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use. More than 80% of addicts relapse to drug seeking and use after a period of withdrawal and abstinence during what is known as the protracted withdrawal phase. The long-lasting nature of this compulsion and the high rates of recidivism present a challenge for effective treatment. An understanding of the neurobiological basis of drug seeking and relapse is a central issue of addiction research.
We describe here an hypothesis for brain mechanisms that may underlie, at least in part, the increased drug seeking during protracted withdrawal. We propose that two important alterations occur following dependence and withdrawal: (i) Conditioned responses of A1/A2 neurons release norepinephrine (NE) in the extended amygdala. This produces elevated anxiety which, when alleviated by drug administration, generates negative reinforcement that summates with the positive reinforcing qualities of drugs. (ii) Changes occur in the mesocorticolimbic dopamine (DA) system and its afferents that alter hedonic processing and impair either the learning of, or motivation for, natural rewards. At the same time, motivation or learning for drug reward and drug-associated cues is increased.
In support of this hypothesis, we first present our data revealing a prominent role for norepinephrine projections from the A1/A2 neurons of the caudal medulla to the bed nucleus of the stria terminalis (BNST) and central amygdala (CNA) in the affective (aversive) response to acute opiate withdrawal. Next, we review our more recent findings showing that neurons in the extended amygdala respond to drug-associated stimuli during protracted withdrawal in proportion to the preference expressed for these stimuli; the area of the BNST where NE is important in the aversive aspect of withdrawal is prominently implicated in this response as well. We will then briefly review evidence implicating mesocortical limbic and dopamine neurons in the processing of, and motivation for, reward. Finally, we will present results indicating that although preference for drug cues is increased the preference for natural rewards such as food is decreased during protracted withdrawal, indicating a change in overall hedonic processing. Associated changes in Fos expression in the extended amygdala and lateral hypothalamus pinpoint specific areas where altered plasticity in afferents to the VTA may underlie such alterations in hedonic function. Finally, we review our current work showing that plasticity in the VTA itself is important for learning and remembering drug-timulus associations, indicating that plasticity changes within the VTA might also be involved in hedonic changes during protracted withdrawal.
Section snippets
Role of norepinephrine in the extended amygdala in the affective response to opiate withdrawal
Previous studies have shown that NE neurons are strongly activated during opiate withdrawal. Although a great deal has been learned about the mechanisms involved in activation of these cells (Akaoka and Aston-Jones, 1991, Aston-Jones et al., 1993, Aston-Jones et al., 1997, Nestler and Aghajanian, 1997), until recently little was known about where elevated NE acted to produce behavioral symptoms of withdrawal. We noted that the densest NE innervation in the brain occurs in the ventral BNST
Protracted withdrawal: activation of extended amygdala and enhanced drug seeking
Vulnerability to relapse during long-term withdrawal is thought to result in part from adaptive processes within the CNS that oppose the acute actions of drugs of abuse (the homeostatic hypothesis, reviewed in Weiss et al., 2001). These changes may lead to affective changes such as anxiety during withdrawal. Unlike the acute physical withdrawal syndromes that occur during the first 24 h of drug abstinence, these affective changes can persist for considerable periods of time (weeks or longer)
Altered hedonic processing during protracted withdrawal
Other results indicate that altered hedonic processing may also contribute to the increased interest in drugs during prolonged abstinence. Thus, human clinical observations find that addicts have feelings of dysphoria, depression and anhedonia for prolonged periods following abstinence from drugs (Dole et al., 1966, Martin and Jasinski, 1969). Researchers have hypothesized that these symptoms of protracted opiate withdrawal involve dysregulation of hedonic processing due to altered brain
Anxiety during protracted withdrawal and negative reinforcement
In the opponent process view of addiction, abstinence from chronic drug exposure uncovers neuroadaptaions in brain function that contribute to an ill-defined feeling of dysphoria, anxiety or malaise that can only be ameliorated by more drug (Koob and Le Moal, 2001). Continued drug use is thought to be rewarding not only because it stimulates the natural reward circuitry but also because of the reinforcement associated with offsetting the anti-reward response (including stress hyper-responsivity
Acknowledgements
This work was supported by PHS grant R37 DA-06214.
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