Alcohol Withdrawal and Dependence

In rodents, alcohol withdrawal is characterized by irritability, hyper-responsiveness, abnormal motor responses, anxiety-like responses, and decreased reward, all similar to the human condition. Seizures can also occur at high doses. At high doses, alcohol withdrawal signs in rats become maximal after 3–4 days. The anxiety-like responses and seizures can be “kindled” (that is, they increase with repeated withdrawal; Figure 6.16).

The neurobiological basis for the motivational effects of alcohol withdrawal, in which individuals engage in alcohol-seeking behavior during withdrawal, extends the neuroadaptive concept described above for tolerance to include counteradaptive neurochemical events within the brain’s emotional systems that are normally used to maintain emotional homeostasis. Acute alcohol withdrawal compromises brain reward systems, reflected by an elevation in brain reward thresholds (that is, more electrical current is needed for the animal to perceive the stimulation as rewarding), which is opposite to the threshold-lowering effect of acute alcohol exposure. Rats that are made dependent on alcohol using alcohol vapor or a liquid diet, resulting in blood alcohol levels greater than 0.1 g%, exhibit elevations in reward thresholds during withdrawal from alcohol. This effect has been shown to persist up to 72 h after alcohol exposure (Figure 6.17).

Decreases in neurotransmitter function in the ventral striatum and extended amygdala (e.g., GABA, enkephalins, endorphins, dopamine, and serotonin) associated with the acute reinforcing effects of alcohol and increases in glutamatergic responses represent some of the neurochemical counteradaptations that are motivationally important in the development of alcohol dependence. Rats and mice will drink more and work more for alcohol during withdrawal after becoming dependent. Neuropharmacological studies have shown that the increase in alcohol self-administration during acute withdrawal can be dose-dependently reduced by intracerebral injections of GABAA receptor agonists. Acamprosate, a hypothesized partial agonist or antagonist of brain glutamate systems, also decreases excessive drinking associated with dependence and abstinence in rats (for further reading, see Koob et al., 2009).

Dopaminergic function is also compromised during acute alcohol withdrawal. Dependent animals have decreased extracellular dopamine levels in the nucleus accumbens (Figure 6.18). In contrast to the activation of dopaminergic systems during acute intoxication, dopaminergic activity decreases in the ventral tegmental area during withdrawal. This has been linked to the dysphoria associated with acute and protracted withdrawal. The decrease in dopaminergic activity in the ventral tegmental area is consistent with studies that found decreased dopamine release in the nucleus accumbens during alcohol withdrawal. The reduction of dopaminergic neurotransmission is prolonged, outlasting the physical signs of withdrawal. Similar effects have been observed for virtually all major drugs of abuse. Remarkably, when animals were allowed to self-administer alcohol during acute withdrawal, they self-administered just enough alcohol to return extracellular dopamine levels in the nucleus accumbens back to normal, pre-dependence baseline levels (Figure 6.18). Overall, these findings indicate that the classic neurotransmitters that regulate the positive reinforcing properties of drugs of abuse, including alcohol, are compromised during withdrawal.

Figure 6.16 The progressive development of handling-induced seizures during alcohol withdrawal in male C3H mice. The multiple withdrawal group received three cycles of 16 h alcohol vapor separated by 8 h periods of abstinence. A single withdrawal group received a single bout of alcohol exposure (16 h). A second group experienced a single withdrawal episode after receiving the equivalent amount of alcohol intoxication as the multiple withdrawal group (16 × 3 = 48 h) but received it continuously (uninterrupted). The control group did not receive ethanol. The severity of handling-induced seizures was greatest in the multiple withdrawal group, intermediate for the continuous alcohol-single withdrawal group, and minimal for the single ethanol exposure-single withdrawal group. The incidence of spontaneous handling-induced seizures was virtually negligible in the control group. Peak seizure intensity was reached approximately 6–8 h after withdrawal for all alcohol-exposed groups and generally subsided by 24 h, although withdrawal signs were still evident in the multiple withdrawal and continuous ethanol-single withdrawal groups at this time. These results show that multiple withdrawals from alcohol in mice can produce a “kindling” of seizures (a sensitization of seizures such that seizures are more likely to occur with each successive withdrawal). A similar kindling of anxiety-like responses has been observed in animals. A kindling of both seizures and anxiety has been observed in humans with repeated withdrawal. [Taken with permission from Becker HC, Hale RL. Repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures: an animal model of alcohol withdrawal “kindling.” Alcoholism: Clinical and Experimental Research, 1993, (17), 94–98.]

Alcohol is also a powerful modulator of stress systems. Dysregulation of the brain’s stress systems has been hypothesized to be another neurochemical counteradaptation that is motivationally significant during the development of alcohol dependence, an effect that may be crucial for understanding dependence and relapse. Two other brain stress systems have prominent roles in mediating the stress-like effects of alcohol withdrawal and the compulsive-like drinking associated with alcohol dependence. Although less well-developed, evidence supports a role for norepinephrine systems in the extended amygdala in the negative motivational state and increased self-administration associated with dependence. Substantial evidence has accumulated that suggests that in animals and humans, central noradrenergic systems are activated during acute withdrawal from alcohol and alcohol withdrawal in rats and humans by noradrenergic blockade. In dependent rats, the α1 receptor antagonist prazosin selectively blocked the increased drinking associated with acute withdrawal. Dynorphin, an opioid peptide that binds to κ opioid receptors, is activated by chronic psychostimulant and opioid administration, and κ opioid receptor agonists produce aversive effects in animals and humans. κ Opioid antagonists also block the excessive drinking associated with alcohol withdrawal and dependence, and this effect appears to be mediated by the shell of the nucleus accumbens.

Figure 6.17 Time-dependent elevation of intracranial self-stimulation thresholds in rats during alcohol withdrawal. Mean blood alcohol levels were 197.29 mg%. The data are expressed as the mean percentage of baseline threshold. Asterisks (%) indicate thresholds that were significantly elevated above control levels at 2–48 h post-alcohol (p < 0.05). Open circles indicate the control condition. Closed circles indicate the ethanol withdrawal condition. These data show that animals made dependent on alcohol using an alcohol vapor procedure and withdrawn from the alcohol show elevations in reward thresholds measured by intracranial self-stimulation. These increases can be interpreted as dysphoric-like effects. [Taken with permission from Schulteis G, Markou A, Cole M, Koob G. Decreased brain reward produced by ethanol withdrawal. Proceedings of the National Academy of Sciences USA, 1995, (92), 5880–5884.]

Figure 6.18 Effects of operant alcohol self-administration in nondependent and dependent rats (alcohol liquid diet) that underwent alcohol withdrawal on dopamine efflux in the nucleus accumbens. Dialysate neurotransmitter levels were compared with those in alcohol-naive rats trained to self-administer water. Average water intake in this group was negligible (< 0.8 ml) and is not shown. (A) Changes in neurotransmitter output from levels recorded during the last hour of withdrawal. The data are expressed as a percentage of baseline values calculated as the average of three 20 min samples collected during hour 8 of withdrawal (shown in B–D). The corresponding dialysate neurotransmitter concentrations are shown in B (Ethanol-Naive), C (Nondependent), and D (Dependent). To illustrate the changes in neurotransmitter efflux over the various experimental phases, B–D also show pre-withdrawal (BSL) and withdrawal (WD) dialysate concentrations of dopamine during hour 8 of withdrawal. Dashed lines represent the mean pre-withdrawal dialysate dopamine concentrations. (E) Amounts of self-administered alcohol (10% w/v) during 10 min intervals in the dependent (solid bars) and nondependent (open bars) groups. Alcohol self-administration in dependent rats restored dopamine levels to pre-withdrawal values. These data show that ethanol-dependent rats exhibit a decrease in the release of dopamine in the nucleus accumbens during withdrawal. However, if the rats are given access to alcohol self-administration during withdrawal, then they drink a sufficient amount to restore extracellular dopamine levels to pre-withdrawal levels. Notice that the nondependent rats exhibit an increase in dopamine release in the nucleus accumbens independent of withdrawal. This reflects extracellular dopamine efflux in the nucleus accumbens that parallels both positive and negative reinforcement. [Taken with permission from Weiss F, Parsons LH, Schulteis G, Hyytia P, Lorang MT, Bloom FE, Koob GF. Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. Journal of Neuroscience, 1996, (16), 3474–3485.].

Both acute and chronic alcohol activate the hypothalamic-pituitary-adrenal (HPA) axis, which appears to be the result of the release of corticotropin-releasing factor (CRF) in the hypothalamus that, in turn, activates the neuroendocrine stress response. However, abstinent individuals with alcoholism are well known to have persistently impaired HPA function, reflected by low basal cortisol levels and blunted adrenocorticotropic hormone and cortisol responses to CRF. Similar results have been observed in animal studies. Functional changes in the CRF system in the paraventricular nucleus may be a mechanism by which the HPA system becomes dysregulated in alcoholism. However, the acute and chronic activation of the HPA system sensitizes the extensive extra-hypothalamic, extra-neuroendocrine CRF system implicated in behavioral responses to stress. Chronic alcohol produces anxiogenic-like responses during acute and protracted withdrawal, which can be reversed by intracerebral administration of a CRF receptor antagonist directly into the central nucleus of the amygdala and systemic administration of CRF1 antagonists. Increases in extracellular levels of CRF are observed in the amygdala and bed nucleus of the stria terminalis during alcohol withdrawal (Figure 6.19). Even more compelling, a competitive CRF receptor antagonist that normally has no effect on alcohol self-administration in nondependent rats eliminates excessive drinking in dependent rats when injected into the central nucleus of the amygdala (Figure 6.20; for further reading, see Koob, 2008).

Acute withdrawal from alcohol also decreases neuropeptide Y levels in the central and medial nuclei of the amygdala and piriform cortex (for further reading, see Koob, 2008). When administered intracerebroventricularly or directly into the central nucleus of the amygdala, neuropeptide Y decreases alcohol intake. Other neurochemical systems that are potentially involved in the anxiety-inducing effects of alcohol withdrawal that also can modulate excessive drinking are norepinephrine, vasopressin, dynorphin, nociceptin, and endocannabinoids (Table 6.9).

The facilitation of GABA interneuron neurotransmission in the central nucleus of the amygdala is enhanced in dependent animals, a physiological effect that has been confirmed by directly measuring GABA levels in awake, freely moving animals (Figure 6.21). However, both the acute alcohol and chronic alcohol effects do not occur in neurons in knockout mice that lack the CRF1 receptor. Several selective CRF1 receptor antagonists block the effects of alcohol in rats and mice. Such studies suggest that the GABA facilitation in the central nucleus of the amygdala observed during acute ethanol exposure may rely on an interaction with CRF neurons. Thus, CRF activity increases at the system level during alcohol withdrawal and thus may be an early neuroadaptation of the brain to the effects of alcohol.

Figure 6.19 Effects of alcohol withdrawal on corticotropin-releasing factor immunoreactivity (CRF-IR) levels in the rat amygdala as determined by microdialysis. Dialysate was collected over four 2 h periods that regularly alternated with nonsampling 2 h periods. The four sampling periods corresponded to the basal collection (before removal of ethanol) and 2–4, 6–8, and 10–12 h after withdrawal. Fractions were collected every 20 min. The data are expressed as means (n = 5 per group). Significant differences were observed between groups over time (p < 0.05). These data show that rats made dependent on alcohol using an alcohol liquid diet exhibit an increase in the release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala measured by in vivo microdialysis. Notice that this increase in CRF occurs during a period of withdrawal characterized by a decrease in the release of dopamine and serotonin in the nucleus accumbens and increases in reward thresholds. [Taken with permission from Merlo-Pich E, Lorang M, Yeganeh M, Rodriguez de Fonseca F, Raber J, Koob GF, Weiss F. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. Journal of Neuroscience, 1995, (15), 5439–5447.]

In summary, acute withdrawal from alcohol increases CRF in the central nucleus of the amygdala, which has motivational significance for the anxiety-like effects of acute withdrawal from alcohol and the increased drug intake associated with dependence. Acute withdrawal may also increase the release of norepinephrine in the bed nucleus of the stria terminalis and dynorphin in the nucleus accumbens, both of which may contribute to the negative emotional state associated with dependence. Decreased activity of neuropeptide Y in the central nucleus of the amygdala may contribute to the anxiety-like state associated with ethanol dependence. Activation of brain stress systems (CRF, norepinephrine, dynorphin) combined with inactivation of brain anti-stress systems (neuropeptide Y) elicits powerful emotional dysregulation in the extended amygdala (Table 6.9). Such dysregulation of emotional processing may significantly contribute to between-system opponent processes that maintain dependence and set the stage for more prolonged state changes in emotionality, such as in protracted abstinence.

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