Preoccupation/Anticipation Stage

Animal models of the preoccupation/anticipation stage of the addiction cycle include models of drug-, cue-, and stress-induced reinstatement. The reinstatement of heroin self-administration induced by a priming injection of heroin after extinction depends on the activation of μ opioid receptors. μ Opioid receptor agonists reinstate responding when injected systemically or directly into the ventral tegmental area, and these effects are blocked by naloxone. In contrast, cue-induced reinstatement is not blocked by opioid antagonists. A runway model of cue-induced reinstatement with heroin-trained rats found evidence of resistance to dopamine and opioid blockade of olfactory cue-induced reinstatement. Similarly, the dopamine antagonist haloperidol does not block conditioned place preference produced by heroin cues. However, the blockade of glutamate activity attenuates the cue-induced reinstatement of heroin seeking.

The stress of an intermittent footshock reinstates heroin self-administration in nondependent rats after extinction and reactivates opioid-induced place preference after drug-free periods without extinction. These effects are also not readily blocked by opioid or dopamine receptor antagonists. However, CRF can reinstate heroin seeking, and stress-induced reinstatement can be blocked with combination CRF1/CRF2 receptor antagonists and selective CRF1 receptor antagonists. A CRF2 antagonist, however, was ineffective, indicating that the CRF1 subtype is most likely more important for this type of reinstatement. The brain sites critical for the role of CRF in footshock-induced reinstatement include the bed nucleus of the stria terminalis and central nucleus of the amygdala. Reversible functional inactivation of these structures also blocked the footshock-induced reinstatement of heroin seeking.

Similarly, a role for norepinephrine projections that originate in the ventral noradrenergic pathway and project to the bed nucleus of the stria terminalis and central nucleus of the amygdala has also been shown in studies that evaluate footshock-induced reinstatement of opioid seeking. α2 Adrenergic agonists, which are known to inhibit norepinephrine release, block the footshock-induced reinstatement of heroin seeking. The brain sites for these effects appear to be the ventral noradrenergic bundle from the lateral tegmental nucleus that projects to the ventral portion of the forebrain, such as the bed nucleus of the stria terminalis. Lesions of this pathway attenuated the footshock-induced reinstatement of heroin seeking.

Humans with opioid addiction are well known to have a dysregulated hypothalamic-pituitary-adrenal (HPA) stress axis that persists during cycles of addiction. These persistent physiological abnormalities stabilize during methadone maintenance. In an experiment that blocked cortisol synthesis, the reduced HPA axis reserve in individuals with heroin addiction returned to normal and then stabilized during methadone maintenance. Conversely, reactivation of a hyperactive HPA axis occurred during opioid withdrawal. During protracted abstinence, hyper-responsiveness of the cortisol negative feedback system regulates the HPA axis. Cycles of heroin addiction were associated with hyporesponsivity of the temporary shutoff of the negative feedback on the HPA axis produced by the blockade of cortisol synthesis, but this hypoactivity may be paralleled by an ongoing sensitization of CRF systems in the amygdala.

FIGURE 5.19 Plasma corticosterone responses to 15 min and 4 h restraint stress in vehicle- and morphine-treated rats. The arrow indicates the time of the initiation of restraint. The data are expressed as mean ± SEM (n = 5–9). ∗p < 0.05, 15 min restraint vs. no restraint groups; #p < 0.05, 4 h restraint vs. no restraint groups; +p < 0.05, 15 min restraint vs. 4 h restraint groups. These results show that rodents made dependent on opioids have an increased glucocorticoid response to acute opioid withdrawal in unrestrained animals but a blunted glucocorticoid response to restraint stress in protracted abstinence, suggesting dysregulation of the hypothalamic–pituitary–adrenal axis in opioid dependence, similar to the dysregulation observed with chronic administration of other drugs of abuse. [Taken with permission from Houshyar H, Cooper ZD, Woods JH. Paradoxical effects of chronic morphine treatment on the temperature and pituitary-adrenal responses to acute restraint stress: a chronic stress paradigm. Journal of Neuroendocrinology, 2001, (13), 862–874.]

In morphine-dependent rats during opioid dependence and acute withdrawal, a marked increase in basal corticosterone concentrations and exaggerated response to stressors are found (Figure 5.19). Rats that had undergone 12 h withdrawal displayed increased basal corticosterone and a potentiated and prolonged corticosterone response to restraint stress. After eight and 16 day withdrawals, they recovered normal baseline HPA activity and showed a blunted response to a stressor. This reduced response to a stressor was suggested to be attributable to the increased sensitivity of the negative feedback systems to glucocorticoids and reduced CRF function, similar to what is seen in individuals with heroin addiction. Thus, chronic stress exposure and chronic morphine exposure have similar effects in rats, and hormonal stress responses may play a role in the maintenance and relapse to opioid use long after acute withdrawal from opioids.

The protracted abstinence component of the preoccupation/anticipation stage of drug addiction is also accompanied by an attentional bias to drugs and drug-related stimuli that helps to channel an individual’s behavior toward drug seeking. In electrophysiological studies, heroin-dependent subjects had larger slow-wave components of event-related potentials in response to heroin-related stimuli during abstinence, and these observations correlated with post-experiment craving. In animal studies, hippocampal long-term potentiation (in which neurons are turned on and take longer than usual to turn off) was reduced by chronic opioid treatment, and the chronically treated animals showed partial learning deficits in a water maze in which they had to locate a platform hidden beneath the water’s surface. These studies suggest that opioids can impair executive function, and this may contribute to the phenomenon of craving.

FIGURE 5.20 Whether a user is tolerant to a drug or, conversely, sensitized to it, depends in part on the levels of active cyclic adenosine monophosphate response element binding protein (CREB) and ΔFosB in nucleus accumbens cells. Initially, CREB dominates, leading to tolerance and, in the drug’s absence, discomfort that only more drug can alleviate. But CREB activity decreases within days when not boosted by repeated administrations of opioids. In contrast, ΔFosB concentrations stay elevated for weeks after the last drug exposure. As CREB activity declines, the dangerous long-term sensitizing effects of ΔFosB come to dominate. [Adapted with permission from Nestler EJ, Malenka RC. The addicted brain. Scientific American, 2004, (290), 78–85. © Terese Winslow.]

The studies of the opioid regulation of second messenger systems in the nucleus accumbens has led to the identification of long-term changes in molecular elements of the brain motivational circuits associated the protracted abstinence of the preoccupation/anticipation stage. As noted above (see Figure 5.18), heroin exposure increases protein kinase A activity in the nucleus accumbens, and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) in the nucleus accumbens is decreased during chronic morphine exposure, whereas upregulation of cAMP response element (CRE) transcription has been observed in the nucleus accumbens during opioid withdrawal.

Another transcription factor activated by the chronic administration of opioids is ΔFosB. This transcription factor is responsible for persistently high levels of activator protein-1 (AP-1) complexes, which are transcriptionally active dimers of Fos and related Jun-family proteins. ΔFosB overexpression increases an individual’s sensitivity to the rewarding effects of morphine, and expression of the “dominant negative” form of ΔFosB decreases the sensitivity to morphine. Because the effects of drugs of abuse on ΔFosB are stable for weeks to months after the last drug exposure, it may help to initiate and maintain the allostatic state of addiction and may be a common long-term molecular motivational change across drug classes (Figure 5.20).

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