Extended Amygdala: Negative Reinforcement Pathways

Compulsive drug use defined by increased intake of drug with extended access is accompanied by a chronic perturbation in brain reward homeostasis using measures of brain stimulation reward thresholds. The differential exposure to drug self-administration has dramatic effects on reward thresholds that progressively increase (ie, decreased reward) in extended-access, but not in limited-access, rats across successive self-administration sessions (Ahmed et al, 2002; Kenny et al, 2006; Wee et al, unpublished results). Animals with extended access to cocaine are more sensitive to the blockade of self-administration by dopamine antagonists and partial agonists (Ahmed and Koob, 2004; Wee et al, 2007), and the opioid partial agonist buprenorphine dose dependently decreased heroin self-administration in extended-access, opioid-dependent rats (Chen et al, 2006b), suggesting that reversal of reward deficits can blunt the motivational drives of drug addiction. This mechanism could underlie the benefit of methadone and buprenorphine treatment in heroin addiction.

As noted above, CRF antagonists blocked the anxiogenic- and aversive-like effects of drug withdrawal, and withdrawal from all drugs of abuse activated CRF in the CeA. These observations led to the hypothesis that activation of CRF, specifically extrahypothalamic CRF in the CeA, contributed to the motivational state driving compulsivity from the negative reinforcement perspective (Koob and Le Moal, 2008). Thus, one would predict that blockade of the brain stress systems in animal models of extended access to drugs may block the motivation for excessive drug intake. CRF antagonists selectively blocked the increased self-administration of drugs associated with extended access to intravenous self-administration of cocaine, nicotine (Koob, 2008), heroin (Greenwell et al, 2009), and alcohol (Koob, 2008). A particularly dramatic example of the motivational effects of CRF in the extended amygdala in dependence can be observed in animal models of ethanol self-administration in dependent animals in which a CRF_1/2 peptide antagonist injected into the amygdala blocked the increase in ethanol self-administration during withdrawal (Funk et al, 2006; Koob, 2008).

Although less well developed, evidence suggests involvement of norepinephrine systems in the extended amygdala in the negative motivational state and increased self-administration associated with dependence (Koob, 2009b). Consistent with the role of the dynorphin-κ opioid system in the aversive effects of drug withdrawal, a κ-opioid antagonist blocked the excessive drinking associated with ethanol withdrawal in dependent rats and selectively blocked the increased progressive-ratio performance in rats with extended access to cocaine (Koob, 2009b; Wee et al, 2009).

Neuropeptide Y has dramatic anxiolytic-like properties localized to the amygdala and has been hypothesized to have effects opposite to CRF in the negative motivational state of withdrawal from drugs of abuse (Heilig et al, 1994; Heilig and Koob, 2007). NPY administered intracerebroventricularly blocked the increased drug intake associated with ethanol dependence (Thorsell et al, 2005a, 2005b). Injection of NPY into the CeA (Gilpin et al, 2008) and viral vector-enhanced expression of NPY in the CeA also blocked the increased drug intake associated with ethanol dependence (Thorsell et al, 2007).

Thus, the CRF increases in the CeA that occur with acute withdrawal from drugs have motivational significance not only for the anxiety/aversive-like effects of acute withdrawal but also for the increased drug intake associated with dependence. Acute withdrawal also may increase the release of norepinephrine in the BNST and dynorphin in the nucleus accumbens, both of which may contribute to the negative emotional state associated with dependence. Decreased activity of NPY in the CeA also may contribute to the anxiety-like state associated with ethanol dependence. Activation of brain stress systems (CRF, norepinephrine, dynorphin), combined with inactivation of brain antistress systems (NPY) in the extended amygdala may elicit powerful emotional dysregulation with motivational significance to addiction. A number of other neurotransmitter systems have been hypothesized to modulate the extended amygdala both from the stress-induction domain (vasopressin, substance P, orexin) and the antistress domain (nociceptin, endocannabinoids; for review, see Koob, 2008). Such dysregulation may be a significant contribution to the between-system opponent processes that help maintain dependence and also sets the stage for more prolonged state changes in emotionality such as protracted abstinence.

Research on negative reinforcement mechanisms in human addiction has been very limited. With cocaine, for example, the amygdala and lateral orbitofrontal cortex were shown to be activated by unexpected but not expected cocaine infusions in active cocaine abusers (Kufahl et al, 2008), but cocaine abstinence was associated with large reductions in the activity of dopamine projection regions, including the amygdala (Tomasi et al, 2007a). In apparent contrast, smoking abstinence was associated with increased cerebral blood flow in the extended amygdala, among other regions (Wang et al, 2007), whereas a nasal nicotine spray reduced regional cerebral blood flow in the right amygdala and left anterior temporal cortex of habitual smokers subjected to 12 h of smoking deprivation (Zubieta et al, 2001).

The amygdala may be equally important for processing positive reward (Murray, 2007) and reward expectancy (Holland and Gallagher, 2004), similar to processing negative reward. Particularly interesting in the context of brain imaging research will be to understand the function of the amygdala in generating the anxiety and negative emotion frequently seen during abstinence.

A recent report highlighted the importance in addiction of the interoceptive circuit that most likely interfaces with the extended amygdala and ventral striatum. The study showed that smokers with damage to their insula (but not smokers with extrainsular lesions) were able to stop smoking easily and without experiencing either cravings or relapse (Naqvi et al, 2007). The insula, particularly its more anterior regions, is reciprocally connected to several limbic regions (eg, ventromedial prefrontal cortex, amygdala, and ventral striatum) and appears to have an interoceptive function, integrating the autonomic and visceral information with emotion and motivation and providing conscious awareness of these urges (Naqvi and Bechara, 2009). Indeed, brain lesion studies suggest that the ventromedial prefrontal cortex and insula are necessary components of the distributed circuits that support emotional decision-making (Clark et al, 2008). Consistent with this hypothesis, many imaging studies show differential activation in the insula during craving (Naqvi and Bechara, 2009). The reactivity of this brain region has been suggested to serve as a biomarker to help predict relapse.

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MOLECULAR TARGETS FOR NEUROPLASTICITY: BINGE/INTOXICATION, WITHDRAWAL/NEGATIVE AFFECT, AND PREOCCUPATION/ANTICIPATION (CRAVING)

The focus of the present review is on the neurocircuitry of addiction. However, parallel to the neuroplasticity of the neurocircuitry are the molecular changes that occur in these same structures. Chronic exposure to opiates and cocaine leads to activation of cyclic adenosine monophosphate response-element binding protein (CREB) in the nucleus accumbens and CeA (Shaw-Lutchman et al, 2002; Edwards et al, 2007). CREB can be phosphorylated by protein kinase A and by protein kinase regulated by growth factors, putting it at a point of convergence for several intracellular messenger pathways that can regulate gene expression. Activation of CREB in the nucleus accumbens with psychostimulant drugs is linked to the motivational symptoms of psychostimulant withdrawal, such as dysphoria, possibly through induction of the opioid peptide dynorphin, which binds to κ-opioid receptors and has been hypothesized to represent a mechanism of motivational tolerance and dependence (Nestler, 2005). Repeated CREB activation promotes dynorphin expression in the nucleus accumbens, which in turn decreases dopaminergic activity, both of which can contribute to negative emotional states. Extracellular signal-regulated kinase is another key element of intracellular signaling considered a key component in the plasticity associated with repeated administration of cocaine, specifically behavioral sensitization, cocaine reward, and time-dependent increases in cocaine-seeking after withdrawal (ie, incubation effect; Lu et al, 2006; Li et al, 2008).

Another molecular target for regulating the plasticity that leads to addiction is dysregulation of cystine?glutamate exchange, which is hypothesized to promote pathological glutamate signaling related to several components of the addiction cycle. Here, repeated administration of cocaine blunts cystine?glutamate exchange, leading to reduced basal and increased cocaine-induced glutamate in the nucleus accumbens that persists for at least 3 weeks after the last cocaine treatment (Baker et al, 2003). Most compelling is the observation that treatment with N-acetylcysteine, by activating cystine?glutamate exchange, prevented cocaine-induced escalation and behavioral sensitization, restored the ability to induce LTP and long-term depression in the nucleus accumbens, and blunted reinstatement in animals and conditioned reactivity to drug cues in humans (Moussawi et al, 2009; LaRowe et al, 2007; Madayag et al, 2007).

CREB and other intracellular messengers can activate transcription factors, which can change gene expression and produce long-term changes in protein expression, and, as a result, neuronal function. Although acute administration of drugs of abuse can cause a rapid (within hours) activation of members of the Fos protein family, such as c-fos, FosB, Fra-1, and Fra-2 in the nucleus accumbens, other transcription factors, isoforms of ΔFosB, a highly stable form of FosB, have been shown to accumulate over longer periods of time (days) with repeated drug administration (Nestler, 2005). Animals with activated ΔFosB have exaggerated sensitivity to the rewarding effects of drugs of abuse, and ΔFosB may be a sustained molecular ?switch' that helps to initiate and maintain a state of addiction (McClung et al, 2004). Whether (and how) such transcription factors influence the function of the brain stress systems, such as CRF and those described above, remains to be determined.

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Date: 2016-06-12; view: 270