Preoccupation/Anticipation (Craving) Stage

The preoccupation/anticipation or craving stage of the addiction cycle has long been hypothesized to be a key element of relapse in humans and defines addiction as a chronic relapsing disorder. Although often linked to the construct of craving, craving per se has been difficult to measure clinically (Tiffany et al, 2000) and often does not correlate well with relapse. Nevertheless, the stage of the addiction cycle in which the individual reinstates drug-seeking behavior after abstinence remains a challenging focus for neurobiological mechanisms and medications development for treatment. Animal models of craving can be divided into two domains: drug-seeking induced by drug or stimuli paired with drug-taking, and drug-seeking induced by an acute stressor or a residual negative emotional state, often a state of stress, termed protracted abstinence (see Transition to addiction: patterns of drug-taking, animal models section).

Much evidence from animal studies suggests that drug-induced reinstatement is localized to the medial prefrontal cortex/nucleus accumbens/ventral pallidum circuit mediated by the neurotransmitter glutamate (McFarland and Kalivas, 2001). In contrast, cue-induced reinstatement appears to involve the basolateral amygdala as a critical substrate with a possible feed-forward mechanism through the prefrontal cortex system involved in drug-induced reinstatement (Everitt and Wolf, 2002; Weiss et al, 2001). The association of previously neutral stimuli paired with precipitated opioid withdrawal (conditioned withdrawal) also depends critically on the basolateral amygdala (Schulteis et al, 2000), and such stimuli may have motivational significance (Kenny et al, 2006). Neurocircuitry changes associated with drug- and cue-induced reinstatement after extinction have been linked to a glutamatergic pathway from the prefrontal cortex to the nucleus accumbens core, the dopamine projection from the VTA to the medial prefrontal cortex, and the GABA projection from the nucleus accumbens to the ventral pallidum (Kalivas and O'Brien, 2008).

In contrast, stress-induced reinstatement of drug-related responding in animal models appears to depend on the activation of both CRF and norepinephrine in elements of the extended amygdala (both the CeA and BNST; for reviews, see Shaham et al, 2003; Shalev et al, 2002). Protracted abstinence, largely described in alcohol dependence models, appears to involve overactive glutamatergic and CRF systems, presumably in the extended amygdala, although to a large extent this remains to be explored (de Witte et al, 2005; Valdez et al, 2002).

Human subjects with cocaine addiction show impaired performance in tasks involving attention, cognitive flexibility, and delayed reward discounting that are mediated by the medial and orbital prefrontal cortices, as well as spatial, verbal, and recognition memory impairments that are mediated by the hippocampus, and these deficits can predict poor treatment outcomes (Aharonovich et al, 2006; Bolla et al, 2003). Parallel animal studies of the orbitofrontal, prefrontal cortex, and hippocampus in addiction using animal models have begun to show some of the deficits reflected in human studies. Experimenter-administered cocaine produced impairments in reversal learning (an orbital frontal task) in rats and monkeys (Jentsch et al, 2002; Schoenbaum et al, 2004; Calu et al, 2007). Perhaps even more compelling, animals allowed extended access, but not limited access, to cocaine showed deficits in working memory (a prefrontal-cortex-dependent task), sustained attention task (a prefrontal-cortex-dependent task), and an object recognition task (a hippocampus-dependent task; Briand et al, 2008a, 2008b; George et al, 2008). In one study (Briand et al, 2008a), these deficits were associated with a significant decrease in dopamine D₂ receptor mRNA in the medial and orbital prefrontal cortices, an observation also consistent with human imaging studies. Thus, animal studies using models of compulsive stimulant administration are beginning to show deficits associated with human cocaine addiction (see Human studies: imaging and neuropsychopharmacology).

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Date: 2016-06-12; view: 225