Withdrawal/Negative Affect Stage

The neuroanatomical entity termed the extended amygdala (Heimer and Alheid, 1991) may represent a common anatomical substrate integrating brain arousal?stress systems with hedonic processing systems to produce the negative emotional states that promote negative reinforcement mechanisms associated with the development of addiction. The extended amygdala is composed of the CeA, bed nucleus of the stria terminalis (BNST), and a transition zone in the medial (shell) subregion of the nucleus accumbens (Figure 2b). Each of these regions has cytoarchitectural and circuitry similarities (Heimer and Alheid, 1991). The extended amygdala receives numerous afferents from limbic structures such as the basolateral amygdala and hippocampus and sends efferents to the medial part of the ventral pallidum and a large projection to the lateral hypothalamus, thus further defining the specific brain areas that interface classical limbic (emotional) structures with the output of extrapyramidal motor system (Alheid et al, 1995). The extended amygdala has long been hypothesized to have a key role not only in fear conditioning (Le Doux, 2000) but also in the emotional component of pain processing (Neugebauer et al, 2004).

Within-system neuroadaptations to chronic drug exposure include decreases in function of the neurotransmitter systems in the neurocircuits implicated in the acute reinforcing effects of drug of abuse. One prominent hypothesis is that dopamine systems are compromised in crucial phases of the addiction cycle, such as withdrawal, and lead to decreased motivation for nondrug-related stimuli and increased sensitivity to the abused drug (Melis et al, 2005; see brain imaging studies below). Psychostimulant withdrawal in humans is associated with fatigue, decreased mood and psychomotor retardation, and in animals is associated with decreased motivation to work for natural rewards (Barr and Phillips, 1999) and decreased locomotor activity (Pulvirenti and Koob, 1993), behavioral effects that may involve decreased dopaminergic function. Animals during amphetamine withdrawal show decreased responding on a progressive-ratio schedule for a sweet solution, and this decreased responding was reversed by the dopamine partial agonist terguride (Orsini et al, 2001), suggesting that low dopamine tone contributes to the motivational deficits associated with psychostimulant withdrawal. Decreases in activity of the mesolimbic dopamine system and decreases in serotonergic neurotransmission in the nucleus accumbens occur during acute drug withdrawal from all major drugs of abuse in animal studies (Rossetti et al, 1992; Weiss et al, 1992, 1996).

A second component of the withdrawal/negative affect stage is a between-system neuroadaptation in which different neurochemical systems involved in stress modulation also may be engaged within the neurocircuitry of the brain stress and aversive systems in an attempt to overcome the chronic presence of the perturbing drug to restore normal function despite the presence of drug. Both the hypothalamic?pituitary?adrenal axis and the brain stress/aversive system mediated by corticotropin-releasing factor (CRF) are activated during withdrawal from chronic administration of all major drugs with abuse potential, with a common response of elevated adrenocorticotropic hormone, corticosterone, and amygdala CRF during acute withdrawal (Koob, 2008; Koob and Kreek, 2007). Acute withdrawal from all drugs of abuse also produces an aversive or anxiety-like state in which CRF and other stress-related systems (including noradrenergic pathways) have key roles.

The aversive stimulus effects of drug withdrawal can be measured using place aversion (Hand et al, 1988), and the opioid partial agonist buprenorphine dose dependently decreased the place aversion produced by precipitated opioid withdrawal. Systemic administration of a CRF₁ receptor antagonist and direct intracerebral administration of a peptide CRF₁/CRF₂ antagonist also decreased opioid withdrawal-induced place aversions (Stinus et al, 2005; Heinrichs et al, 1995). Functional noradrenergic antagonists administered directly into the BNST blocked opioid withdrawal-induced place aversion, implicating the importance of noradrenergic stimulation in the stress responses that follow acute drug withdrawal (Delfs et al, 2000). Indeed, classical medications used to treat physical withdrawal in heroin abusers and alcoholics include α-adrenergic drugs (eg, clonidine) that inhibit noradrenergic release and decrease some symptoms of alcohol and heroin withdrawal.

Another candidate for the aversive effects of drug withdrawal is dynorphin. Much evidence shows that dynorphin is increased in the nucleus accumbens in response to dopaminergic activation and, in turn, that overactivity of the dynorphin systems can decrease dopaminergic function. κ-Opioid agonists are aversive, and cocaine, opioid, and ethanol withdrawal is associated with increased dynorphin in the nucleus accumbens and/or amygdala (Koob, 2008). An exception is salvidorin A, which is a κ-agonist abused by humans, but this may reflect its hallucinogenic effects rather than any pleasurable properties (Gonzalez et al, 2006).

Another common between-system response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like responses. For example, withdrawal from repeated administration of cocaine produces an anxiogenic-like response in the elevated plus maze and defensive burying test, both of which are reversed by CRF antagonists. Similarly, ethanol withdrawal produces anxiety-like behavior that is reversed by intracerebroventricular administration of CRF₁/CRF₂ peptidergic antagonists, systemic administration of a small molecule CRF₁ antagonist, and microinjection of a peptidergic CRF₁/CRF₂ antagonist into the amygdala (Funk et al, 2006; Koob, 2008). CRF antagonists injected intracerebroventricularly or systemically also block the potentiated anxiety-like responses to stressors observed during protracted abstinence from chronic ethanol, and the effects of CRF antagonists have been localized to the CeA (Koob, 2008). Precipitated withdrawal from nicotine produces anxiety-like responses that are also reversed by CRF antagonists (Tucci et al, 2003; George et al, 2007).

Thus, acute withdrawal is associated with within-system changes reflected in a decrease in dopaminergic activity in the mesolimbic dopamine system and with between-system recruitment of neurotransmitter systems that convey stress and anxiety-like effects such as CRF and dynorphin. Other neurotransmitter systems known to be involved in emotional dysregulation of the motivational effects of drug withdrawal include norepinephrine, substance P, vasopressin, neuropeptide Y (NPY), endocannabinoids, and nociceptin (Koob, 2008).

Date: 2016-06-12; view: 227