Opponent Process/Between-System Neuroadaptations

As defined above, opponent process, between-system neuroadaptations (Table 1) are hypothesized to involve activation of the neurotransmitter systems grouped together in this review as the brain arousal-stress systems. Thus, recruitment of the CRF system occurs during the development of dependence for all drugs of abuse that has motivational significance (Figure 1B above), but additional between-system neuroadaptations associated with motivational withdrawal include activation of the dynorphin/κ opioid system, norepinephrine brain stress system, extrahypothalamic vasopressin system, and possibly the orexin system. Additionally, activation of the brain stress systems may not only contribute to the negative motivational state associated with acute abstinence but also may contribute to the vulnerability to stressors observed during protracted abstinence in humans. However, brain antistress systems, such as NPY and nociceptin, also may be compromised during the development of dependence, thus removing a mechanism for restoring homeostasis (Koob and Le Moal, 2008). These results suggest that the motivation to continue drug use during dependence not only includes a change in the function of neurotransmitters associated with the acute reinforcing effects of drugs of abuse during the development of dependence, such as dopamine, opioid peptides, serotonin, and GABA, but also recruitment of the brain stress systems and/or disruption of the brain antistress systems (Koob and Le Moal, 2005).

The neuroanatomical entity integrating these brain arousal-stress and antistress systems may be the extended amygdala. Thus, the extended amygdala may represent a neuroanatomical substrate for the negative effects on reward function produced by stress that help drive compulsive drug administration (Koob and Le Moal, 2008) (Figure 10). The extended amygdala has a role in integrating emotional states such as the expression of the conditioned fear response in the central nucleus of the amygdala (Phelps and Le Doux, 2005) and emotional pain processing (Neugebauer et al., 2004) (see above). The integration of data from addiction neurobiology and from behavioral neuroscience of fear and pain point to a rich substrate for the integration of emotional stimuli related to the arousal-stress continuum (Pfaff, 2006) and provides insights not only into the mechanisms of emotional dysregulation in addiction but also into the mechanisms of emotions themselves.

The development of the aversive emotional state that drives the negative reinforcement of addiction is hypothesized to involve a long-term, persistent plasticity in the activity of neural circuits mediating motivational systems that derive from recruitment of antireward systems that drive aversive states. The withdrawal/negative affect stage defined above consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards, and is characterized in animals by increases in reward thresholds during withdrawal from all major drugs of abuse. Antireward is a concept based on the hypothesis that brain systems are in place to limit reward (Koob and Le Moal, 1997, 2005, 2008). As dependence and withdrawal develop, brain antireward systems such as CRF, norepinephrine, dynorphin, vasopressin, and possibly orexin are hypothesized to be recruited to produce stress-like aversive states (Koob and Le Moal, 2001; Nestler, 2005; Aston-Jones et al., 1999) (Figure 10). The present thesis also argues that antistress systems, such as NPY and orexin that presumably buffer the stress response, also may be compromised. At the same time, decreases in reward function occur within the motivational circuits of the ventral striatum-extended amygdala (Figure 10). The combination of decreases in reward neurotransmitter function, recruitment of antireward systems, and compromised antistress systems provides a powerful source of negative reinforcement that contributes to compulsive drug-seeking behavior and addiction.

Date: 2016-06-12; view: 479