Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use--when a drug is voluntarily taken because it has reinforcing, often hedonic, effects--through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.

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Neural systems of reinforcement for drug addiction: from actions to habits to compulsion

Converging findings of animal and human studies provide compelling evidence that the amygdala is critically involved in enabling us to acquire and retain lasting memories of emotional experiences. This review focuses primarily on the findings of research investigating the role of the amygdala in modulating the consolidation of long-term memories. Considerable evidence from animal studies investigating the effects of posttraining systemic or intra-amygdala infusions of hormones and drugs, as well as selective lesions of specific amygdala nuclei, indicates that (a) the amygdala mediates the memory-modulating effects of adrenal stress hormones and several classes of neurotransmitters; (b) the effects are selectively mediated by the basolateral complex of the amygdala (BLA); (c) the influences involve interactions of several neuromodulatory systems within the BLA that converge in influencing noradrenergic and muscarinic cholinergic activation; (d) the BLA modulates memory consolidation via efferents to other brain regions, including the caudate nucleus, nucleus accumbens, and cortex; and (e) the BLA modulates the consolidation of memory of many different kinds of information. The findings of human brain imaging studies are consistent with those of animal studies in suggesting that activation of the amygdala influences the consolidation of long-term memory; the degree of activation of the amygdala by emotional arousal during encoding of emotionally arousing material (either pleasant or unpleasant) correlates highly with subsequent recall. The activation of neuromodulatory systems affecting the BLA and its projections to other brain regions involved in processing different kinds of information plays a key role in enabling emotionally significant experiences to be well remembered.

The amygdala modulates the consolidation of memories of emotionally arousing experiences

A neurobiological model of the brain emotional systems has been proposed to explain the persistent changes in motivation that are associated with vulnerability to relapse in addiction, and this model may generalize to other psychopathology associated with dysregulated motivational systems. In this framework, addiction is conceptualized as a cycle of decreased function of brain reward systems and recruitment of antireward systems that progressively worsen, resulting in the compulsive use of drugs. Counteradaptive processes, such as opponent process, that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to repeatedly drive the allostatic state. Excessive drug taking thus results in not only the short-term amelioration of the reward deficit but also suppression of the antireward system. However, in the long term, there is worsening of the underlying neurochemical dysregulations that ultimately form an allostatic state (de...

Addiction and the Brain Antireward System

Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a ‘dark side’—a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction. Drug addiction has been conceptualized as a progression from impulsive to compulsive behavior, ending in chronic, relapsing drug taking. Patients with impulse control disorders experience an increasing sense of tension or arousal before committing an impulsive act; pleasure, gratification or relief at the time of committing the act; and then regret, selfreproach or guilt after the act 1 . In contrast, patients with compulsive disorders experience anxiety and stress before committing a compulsive repetitive behavior, then relief from the stress by performing the behavior 1 . In addiction, drug-taking behavior progresses from impulsivity to compulsivity in a three-stage cycle: binge/intoxication, withdrawal/negative affect and preoccupation/anticipation 2 . In the impulsive stage, the drive for the drug-taking behavior is positive reinforcement, in which stimuli increase the probability of the response. As individuals move to the compulsive stage, the drive transitions to negative reinforcement, in which removal of the aversive state increases the probability of the response. Different theoretical perspectives from experimental psychology (positive and negative reinforcement framework), social psychology (self-regulation failure framework) and neurobiology (counteradaptive and sensitization framework) can be superimposed on the stages of the addiction cycle 2 . These stages are thought to feed into each other, becoming more intense and ultimately leading to the pathological state known as addiction. Our thesis is that addiction involves a longterm, persistent plasticity in the activity of neural circuits mediating two different motivational systems: decreased function of brain reward systems driven by natural rewards, and recruitment of anti-reward systems that drive aversive states. The concept of anti-reward is based on the hypothesis that there are brain systems in place to limit reward (see footnote in ref. 2), an ‘opponent process’ concept that is a general feature of biological systems 3 . From a neurobiological perspective, progression through the three stages of the addiction cycle induces plasticity in neural circuitry that drives compulsive drug taking, narrowing the behavioral repertoire to drug seeking. Animal models have been developed that have face validity (resembles the human condition) and some construct validity (possesses explanatory power) for all three stages of the addiction cycle and the transition to drug addiction. Acute selfadministration of drugs (intravenous and oral) has construct validity for drug intoxication and elements of drug binges in humans. Self-stimulation and place conditioning (learning to avoid a location previously paired with an aversive stimulus or state) are sensitive measures of ‘motivational’ withdrawal. Cue-induced or

http://dept.wofford.edu/neuroscience/NeuroSeminar/pdfFall2009/a6.pdf

Plasticity of reward neurocircuitry and the 'dark side' of drug addiction.

Extinction is a form of inhibitory learning that suppresses a previously conditioned response. Both fear and drug seeking are conditioned responses that can lead to maladaptive behavior when expressed inappropriately, manifesting as anxiety disorders and addiction, respectively. Recent evidence indicates that the medial prefrontal cortex (mPFC) is critical for the extinction of both fear and drug-seeking behaviors. Moreover, a dorsal-ventral distinction is apparent within the mPFC, such that the prelimbic (PL-mPFC) cortex drives the expression of fear and drug seeking, whereas the infralimbic (IL-mPFC) cortex suppresses these behaviors after extinction. For conditioned fear, the dorsal-ventral dichotomy is accomplished via divergent projections to different subregions of the amygdala, whereas for drug seeking, it is accomplished via divergent projections to the subregions of the nucleus accumbens. Given that the mPFC represents a common node in the extinction circuit for these behaviors, treatments that target this region may help alleviate symptoms of both anxiety and addictive disorders by enhancing extinction memory.

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Extinction circuits for fear and addiction overlap in prefrontal cortex

The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats.

Evidence has extensively implicated the amygdala in the associative learning process for appetitive reinforcers. Recent interest has focused on the role of the amygdala in the learned associations that occur during the process of drug addiction and relapse. Using an animal model of relapse after chronic cocaine self-administration, we found that rats reinstate extinguished lever responding for conditioned stimuli (tone + light) previously paired with cocaine or heroin ("conditioned-cued reinstatement"). The basolateral amygdala (BLA) complex plays a critical role in this behavior, because permanent lesions or reversible pharmacologic inactivation of the BLA attenuates conditioned-cued reinstatement without affecting cocaine self-administration or cocaine-primed reinstatement. Conditioned-cued reinstatement appears to be mediated in part by dopamine inputs to the BLA, as intra-BLA infusion of a dopamine D1 receptor antagonist blocks reinstatement, whereas intra-BLA infusion of amphetamine potentiates reinstatement. Furthermore, the BLA is also necessary for acquisition of associative learning with cocaine-paired stimuli. Disruption of neural activity within the BLA by sodium channel blockade or muscarinic receptor blockade just before acquisition of stimulus-cocaine associations blocks the ability of conditioned stimuli to elicit conditioned-cued reinstatement after extinction. Together, these results reveal the importance of the amygdala as part of a corticolimbic circuit mediating both the acquisition and the expression of conditioning that plays a critical role in relapse to drug-seeking behavior.

Christopher C Ledford

Papers

The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats.

Drug Addiction, Relapse, and the Amygdala

Potentiated reinstatement of cocaine-seeking behavior following D-amphetamine infusion into the basolateral amygdala.