Withdrawal/Negative Affect Stage

The response that follows the stage of drug intoxication differs markedly across drugs and is influenced by the chronicity and frequency of its abuse. For some drugs such as opiates, alcohol, and sedative hypnotics, drug discontinuation in chronic drug users can trigger an intense, acute physical withdrawal syndrome that, if not properly managed and when severe, can sometimes be fatal. All drugs of abuse are associated with a motivational withdrawal syndrome characterized by dysphoria, irritability, emotional distress, and sleep disturbances that persist even after protracted withdrawal. The neurobiology of acute withdrawal is distinct from protracted or motivational withdrawal, and both contribute to relapse. Few imaging studies have been carried out during acute withdrawal. One such study that measured changes in dopamine during heroin withdrawal failed to document the dopamine decreases in the nucleus accumbens that had previously been reported with microdialysis in the rodent brain (Wang et al, 1997). From this study, it is unclear whether the results reflect the lack of involvement of striatal dopamine during acute withdrawal in heroin abusers or the limited sensitivity of the positron emission tomography (PET) technology.

The mechanisms underlying acute withdrawal are likely to be drug specific and reflect adaptations in the molecular targets of these drugs. For example, during the first few days of cocaine withdrawal, enhanced sensitivity of the brain to the effects of GABA-enhancing drugs occurs that may reflect the downregulation of this neurotransmitter with chronic cocaine use (Volkow et al, 1998). Similarly, brain imaging studies have also revealed decreases in endogenous opioids during cocaine withdrawal, which may contribute to the irritability, malaise, and dysphoria that occur during this phase of motivational withdrawal (Zubieta et al, 1996).

During protracted withdrawal, once the signs and symptoms of acute withdrawal have subsided, imaging studies have documented hypofunction in dopamine pathways, demonstrated by decreases in D₂ receptor expression and decreases in dopamine release, which may contribute to the anhedonia (ie, decreased sensitivity to rewarding stimuli) and amotivation reported by drug-addicted subjects during protracted withdrawal (Volkow et al, 1997b, 2007; Martinez et al, 2004, 2005). The decreased reactivity of dopamine to reinforcing stimuli is also present after protracted withdrawal from alcohol when acute physical withdrawal has subsided. In contrast to the decreased sensitivity to rewards (including drug rewards), imaging studies have reported that during detoxification, enhanced sensitivity to conditioned cues also occurs. Abstinence from smoking, for example, can dramatically potentiate neural responses to smoking-related cues (McClernon et al, 2009). These conditioned responses sustain the cycle of abstinence and relapse that characterizes substance use disorders (Childress et al, 1988).

In addition, imaging studies evaluating markers of brain function have shown that drug abusers tested during protracted detoxification show evidence of disrupted activity of frontal regions, including dorsolateral prefrontal regions, cingulate gyrus, and orbitofrontal cortex, which is hypothesized to underlie their impaired inhibitory control and impulsivity and contribute to relapse (see the following section for discussion).

Date: 2016-06-12; view: 244