O1

"o 50

"o 50

Control MW - Vehicle MW - MK-801 Withdrawal Group

Threshold Dosage

150-i

150-i

Control MW - Vehicle MW - MK-801 Withdrawal Group

Fig. 2. Effects of treating early alcohol withdrawals with MK-801 on sensitivity to NMDA-induced seizures during a subsequent untreated withdrawal episode. Data are presented as mean ± S.E.M. latency (top) and threshold dosage (bottom) for NMDA-induced clonic seizures. Multiple-withdrawal (MW) groups were injected (ip) with either vehicle (saline) or MK-801 (0.3 mg/kg) at 1 h into each of the first three successive withdrawal cycles. Alcohol-naive controls were given saline injections at the equivalent times. No injections were given on the last (fourth) withdrawal episode. At 8 h following final withdrawal, latency and threshold dosage required for eliciting clonic seizures were determined following iv infusion of NMDA (15 mg/mL; 0.28 mL/min). *Significantly differs from both Control and MW/MK-801 groups (p < 0.05).

Control MW - Vehicle MW - MK-801 Withdrawal Group

Fig. 2. Effects of treating early alcohol withdrawals with MK-801 on sensitivity to NMDA-induced seizures during a subsequent untreated withdrawal episode. Data are presented as mean ± S.E.M. latency (top) and threshold dosage (bottom) for NMDA-induced clonic seizures. Multiple-withdrawal (MW) groups were injected (ip) with either vehicle (saline) or MK-801 (0.3 mg/kg) at 1 h into each of the first three successive withdrawal cycles. Alcohol-naive controls were given saline injections at the equivalent times. No injections were given on the last (fourth) withdrawal episode. At 8 h following final withdrawal, latency and threshold dosage required for eliciting clonic seizures were determined following iv infusion of NMDA (15 mg/mL; 0.28 mL/min). *Significantly differs from both Control and MW/MK-801 groups (p < 0.05).

Additional support for the notion that altered NMDA receptor function may underlie sensitization or kindling of alcohol withdrawal comes from studies demonstrating that pharmacological antagonism of NMDA receptors during early withdrawals may influence the severity of subsequent withdrawal episodes. In our model of repeated withdrawals, dizocilpine (MK-801; 0.1-0.6 mg/kg) was found to significantly reduce alcohol-withdrawal seizures in a dose-dependent manner when administered at the beginning of each of three successive withdrawal episodes. This resulted in a dose-dependent attenuation of seizure activity during a fourth untreated withdrawal cycle (95). Similarly, as shown in Fig. 2, MK-801 treatment of early withdrawals was found to reverse the reduction in NMDA seizure threshold dosage exhibited during a subsequent (untreated) withdrawal episode in mice with multiple-withdrawal experience. However, as a note of caution, although repeated MK-801 treatment for multiple alcohol withdrawals attenuated the early phase of a later untreated withdrawal episode (1-10 h postwithdrawal), this treatment also resulted in an exacerbation of seizure activity at later time-points (10-72 h postwithdrawal) (95). A similar pattern of results was reported when the competitive NMDA receptor antagonis CGP-39551 was administered chronically during the course of alcohol exposure (78). This suggests that repeated (chronic) use of these antagonists for alcohol dependence may increase adaptive changes in NMDA receptors that ultimately contribute to withdrawal-related hyperexcitability.

Evidence for a role of increased NMDA receptor density in alcohol withdrawal sensitization has been mixed. Repeated bouts of heavy alcohol intoxication interspersed by periods of withdrawal did not significantly alter the number of [3H]MK-801-binding sites in the various regions of rat brain (96). However, a small increase in [3H]MK-801-binding sites in the hippocampus and entorhinal cortex was observed in the multiple-withdrawal group that evidenced seizures during prior withdrawal episodes in comparison to multiple-withdrawal rats that did not exhibit such spontaneous seizure activity. In our mouse model of repeated alcohol withdrawals, the density of [3H]MK-801-binding sites did not significantly differ from controls in hippocampus or cortex (unpublished data). In an in vitro model of chronic intermittent alcohol exposure, an upregulation in [3H]MK-801 binding was reported 1 wk following final withdrawal (97). This persistent increase in number of NMDA receptors was accompanied by an increase in the ability of NMDA to stimulate calcium influx in cultured cortical neurons. Different results regarding changes in NMDA receptor density following repeated alcohol withdrawal may depend on the method and intensity of chronic alcohol exposure. Alcohol withdrawal sensitiza-tion also may be associated with changes in the subunit composition of NMDA receptors, which may not be revealed by radioligand-binding studies but, rather, impact on receptor function. Such investigations are currently be conducted by a number of laboratories.

3.3. Non-NMDA Glutamate Receptors and Alcohol Withdrawal Kindling

Although studies investigating the role of metabotropic glutamate receptors in alcohol actions are rather limited, an emerging body of evidence suggests that non-NMDA ionotropic glutamate receptors (a-amino-3-hydroxy-5-methyl-4-isoxazole propronic acid [AMPA]/kainate receptors) may contribute to both acute and chronic effects of alcohol (50,98). In addition, AMPA/kainate receptors are known to play a significant role in various forms of neuroplasticity (85,87,99). Thus, there is some basis upon which to suspect that these non-NMDA glutamate receptor systems may play a role in mediating kindling or sensitization of alcohol withdrawal.

Alcohol inhibits glutamate-mediated excitatory transmission through AMPA/kainate receptors in a complex fashion, dependent on numerous factors (98). Whereas in vitro studies have demonstrated neuroadaptation to these effects, the effects of chronic in vivo alcohol treatment on AMPA/kainate receptors have been mixed. For example, chronic alcohol exposure did not alter [3H]kainate binding in hippocampus or cortex (58), and expression of GluR1 and GluR2 levels was not altered in various brain regions (75). On the other hand, rats undergoing alcohol withdrawal were reported to exhibit enhanced sensitivity to the convulsant properties of kainate (57).

Few studies have examined whether changes in non-NMDA glutamate receptors accompany enhanced CNS hyperexcitability associated with repeated alcohol withdrawals. In one study, repeated cycles of heavy intoxication and withdrawal in rats resulted in no changes in [3H]kainate binding, but the density of [3H]AMPA-binding sites was decreased in several brain regions (96). This latter effect was suggested to reflect a possible compensatory response to augmented CNS hyperexcitability. In another study, although mice with multiple-withdrawal experience were found to exhibit enhanced sensitivity to NMDA (reduced seizure threshold dosage), the seizure threshold dosage for kainate was significantly elevated (93). Whether this blunted sensitivity to the convulsant properties of kainate represents a compensatory response in these mice is unclear. However, because multiple alcohol withdrawal experience does not appear to uniformly alter sensitivity to all chemoconvulsants, this suggests that exacerbated seizure activity exhibited by animals with such repeated withdrawal experience may not reflect a global non-specific heightening of neural excitation. Additional studies will be needed to more clearly define the role of AMPA/kainate receptors in the alcohol-withdrawal kindling phenomenon.

4. GLUTAMATE AND ALCOHOL WITHDRAWAL KINDLING: IMPLICATIONS FOR NEUROTOXICITY

A dangerous consequence of alcohol withdrawal kindling relates to alcohol-induced neurotoxcity. It has been suggested that multiple alcohol withdrawal experience may render individuals more vulnerable to neurological damage and associated congnitive impairments (13,15). There is both preclini-cal and clinical evidence in support of this notion. For example, chronic intermittent alcohol exposure (i.e., coupled with numerous intervening periods of abstinence) was reported to result in hippocampal cell loss in rats, an effect not observed in animals exposed to alcohol in a continuous fashion (40,100). In a study involving postmortem analysis of alcoholic brains, temporal lobe pathology was reported to be associated with a history of alcohol withdrawal seizures (101). Enhanced vulnerability and susceptibility to alcohol-related neuropathology as a result of multiple-withdrawal experience may, in turn, underlie cognitive deficits associated with chronic bingelike drinking (102). Indeed, there is both clinical (103) and experimental (39) evidence indicating that a history of repeated alcohol withdrawals is associated with greater cognitive dysfunction.

Given the prominent role of glutamate in neurotoxicity and neurodegeneration (104,105), enhanced vulnerability to neuropathologic insult following repeated alcohol withdrawals may be related to an associated upregulation in NMDA receptor function (106,107). In in vitro studies, although acute alcohol has been shown to inhibit NMDA-mediated cell death (108,109), chronic alcohol exposure results in an exacerbation of NMDA ex ci to toxicity in cortical (110-112) and cerebellar granule cells (113,114). Similar results have been reported following chronic alcohol exposure in hippocampal slice explants (115-117). Moreover, chronic alcohol exposure resulted in enhanced NMDA-mediated, but not AMPA- or kainate-mediated excitotoxicity in cultured hippocampal cells (118).

Studies employing in vivo microdialysis techniques have demonstrated increased extracellular glutamate levels in striatum (119,120), nucleus accumbens (121,122), and hippocampus (123) during withdrawal from chronic alcohol exposure in rats. Similarly, elevated levels of glutamate were reported in cerebrospinal fluid (CSF) from alcoholic patients for as long as 1 mon following abstinence (107). Withdrawal-related increases in glutamate release presumably result in increased activation of NMDA receptors, which may relate to reported increased in vivo sensitivity to NMDA-mediated exci-totoxic damage in the hippocampus of rats undergoing alcohol withdrawal (83,124).

Whether sensitivity to glutamate-related excitotoxicity is enhanced as a function of repeated alcohol withdrawals has not been extensively explored. In one study, repeated alcohol withdrawals resulted in a decrease (toward baseline), rather than a further increase, in extracellular glutamate levels in the hippocampus (123). Because there was a robust increase in glutamate release following the first withdrawal period, it is not clear if this represents some protective response that serves to dampen further neural damage during subsequent withdrawals. In contrast, repeated in vitro exposure and withdrawal from alcohol in rat hippocampal slices was reported to enhance sensitivity to NMDA excitotoxicity (125,126). Furthermore, this enhanced sensitivity to the excitotoxic effects of NMDA challenge was greatest in hip-pocampal cultures exposed to the greatest number of withdrawal (washout) periods interspersed between alcohol exposures (125). Given the serious clinical implications of alcohol-related neuropathology damage and cognitive impairment, the potential for multiple-withdrawal experience to exacerbate these effects, possibly through enhancement of glutamate function, remains an area of active investigation.

5. SUMMARY

A growing body of clinical and experimental evidence indicates that multiple alcohol withdrawal experiences may result in more severe and complicated future withdrawal episodes. It has been postulated that this progressive intensification of withdrawal symptoms may reflect a kindling-like phenomenon. Thus, CNS hyperexcitability that normally accompanies alcohol withdrawal (but does not necessarily result in severe or even noticeable symptoms) may progressively magnify over successive withdrawal episodes, ultimately being manifested as an exaggerated ("kindled") withdrawal response. Although the pathophysiological mechanisms underlying withdrawal sensitization or kindling are not well understood, there is evidence that neuroadaptive changes in glutamate-mediated excitatory neurotransmission may play a significant role in the phenomenon. This notion is further bolstered by the fact that glutamate is known to play a prominent role in various forms of neuroplasticity, many of which bear great resemblance to a kindlinglike process.

A convergent body of evidence from behavioral, biochemical, electrophysiological, and molecular studies has demonstrated that enhanced glutamatergic activity, primarily through increased density and/or function of NMDA receptors, underlies CNS hyperexcitability associated with alcohol withdrawal. There is some evidence indicating that these neuroadaptive changes (enhanced NMDA receptor function) may become further magnified as a consequence of repeated alcohol-withdrawal experience. Although non-NMDA receptors (AMPA/kainate receptors) have been shown to be responsive to acute and chronic alcohol exposure, their role in withdrawal kindling has been less extensively studied. Of course, compensatory changes in other excitatory systems (e.g., voltage-gated calcium channels) as well as inhibitory systems (e.g., GABA, adenosine) undoubtedly contribute to exaggerated CNS hyperexcitability and the expression of sensitized or kindled withdrawal symptoms. These changes may occur either upstream or downstream from upregulated glutamate function. Elucidation of the complex changes in brain function following chronic alcohol exposure as well as the dynamic alterations that are associated with repeated cycles of alcohol intoxication and withdrawal is an area of active investigation.

Aside from the potentially life-threatening consequences of augmented withdrawal-related CNS hyperexcitability (seizures), another serious concern regarding abusive alcohol consumption and a history of multiple-withdrawal experience is enhanced potential for neurotoxicity. Indeed, there is both clinical and preclinical evidence that suggests neurological damage and associated cognitive deficits are more extensive as a result of multiple-withdrawal experience. Glutamate-mediated neurotransmission, particularly through NMDA receptor activation, has been shown to play a prominent role in neu-rotoxicity and neurodegradation. Several studies have demonstrated chronic alcohol exposure and withdrawal result in enhanced NMDA-mediated excitotoxicity, and there is some evidence to suggest that this effect is further enhanced following intermittent alcohol exposure that involves repeated withdrawals. The clinical significance of alcohol-induced neuropathology and cognitive impairment, as well as the manifestations of withdrawal-related CNS hyperexcitability add further relevance to understanding the potential for repeated withdrawals to exacerbate these deleterious consequences through alterations in glutamate-mediated neurotransmission. Further elucidation of the role of glutamate in mediating the alcohol-withdrawal kindling phenomenon could provide the necessary insight needed for the development of more targeted and effective pharmacotherapy treatment strategies for alcohol detoxification, as well as the long-term management of alcohol dependence and alcoholism.

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