Drugs for Relapse Prevention of Alcoholism (Milestones in Drug Therapy)
Editors: Spanagel, Rainer; Mann, Karl F.
Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition
Copyright 2005 Springer
> Table of Contents > Dopaminergic compounds: preclinical data
Dopaminergic compounds: preclinical data
Friedbert Weiss
Department of Neuropharmacology, The Scripps Research Institute (CVN 15), 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Introduction
Like other addictive disorders, alcoholism is characterized by long-lasting vulnerability to relapse after cessation of drinking. Increasing attention has, therefore, been directed toward identifying specific risk factors for relapse and to establish the neurobiological mechanisms by which these factors convey vulnerability to relapse. At the same time, relapse prevention has emerged as an important focus of treatment and medication development efforts.
An important neuropharmacological substrate for many of the neurobehavioral effects of ethanol is the mesocorticolimbic dopamine (DA) system. Evidence has accumulated in recent years implicating this system also in a range of behavioral and neurobiological processes relevant for alcohol craving and relapse. These findings identify DA transmission as a possible pharmacotherapeutic target for relapse prevention.
Evidence implicating dopamine neurotransmission as a target for relapse prevention
Craving and relapse associated with ethanol cue exposure
Ethanol acutely increases the activity of the mesolimbic DA reward pathway [1, 2, 3, 4 and 5] and this effect has been widely implicated as a mechanism by which ethanol exerts its reinforcing actions [6, 7, 8 and 9]. However, not only ethanol consumption [5, 10], but also exposure to environmental stimuli associated with ethanol can activate DA transmission in the nucleus accumbens [5, 10, 11 and 12]. Thus, in addition to its role in the reinforcing effects of ethanol, mesolimbic DA transmission may mediate the incentive-motivational effects of ethanol-related environmental stimuli that are thought to be relevant for ethanol-seeking, craving and relapse. The conditioning of ethanol's pharmacological actions with discrete environmental stimuli is a major factor in the abuse potential of this drug [13]. Ethanol cues can evoke drug desire that may lead to the resumption of drinking in abstinent alcoholics [14, 15, 16, 17, 18, 19, 20 and 21]. Drug-related
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stimuli may perhaps also elicit automatic responses that lead to drug-seeking behavior and relapse without the intervention of distinct feelings of craving [22, 23]. A role of DA in such conditioned responses to ethanol cues would be consistent with the established general role of mesocorticolimbic DA transmission in incentive learning and conditioned reinforcement associated with both natural and drug rewards (e.g., [24, 25 and 26]). In support of this possibility, alcohol-related stimuli not only increase accumbal DA release in rats [5, 10, 11 and 12], but activate the ventral striatum (i.e., a DA-rich brain region) in abstinent alcoholics [27]. Consistent with this hypothesis as well, pharmacological activation of DA transmission in the nucleus accumbens enhances the ability of ethanol-paired stimuli to function as conditioned reinforcers [28].
Craving elicited by priming doses of ethanol
It is well established that small doses of drugs of abuse including ethanol, rather than reducing drug desire, elicit further drug craving (e.g., [29, 30]). Moreover, in alcoholics, the first drink after abstinence is often associated with loss of control leading to severe intoxication and return to continued alcohol abuse [30]. A role for DA in this aspect of relapse has emerged in controlled laboratory studies showing that the D2-preferring DA receptor antagonist haloperidol reduces alcohol craving in response to a priming dose of ethanol in alcoholic patients [31]. Haloperidol also blocked the stimulant and euphorigenic effects of ethanol in social drinkers [32]. The attenuation of ethanol's priming effects supports the view that craving and loss of control following resumption of drinking are linked to DA-activating effects of ethanol. More generally, these findings support the wealth of preclinical evidence that has implicated DA as a major neuropharmacological substrate for ethanol reward.
Neuroadaptation induced by chronic ethanol
In contrast to the acute effects of ethanol that activate mesolimbic DA neurotransmission, chronic dependence-inducing ethanol treatments lead to the development of DA hypofunction. Animals chronically exposed to ethanol show impaired DA synthesis (e.g., [33, 34 and 35]) paired with elevated DA transporter levels and, thus, presumably enhanced clearance of synaptic DA [34]. Impairments in mesolimbic DA function are particularly evident during withdrawal with marked decrements in the activity of ventral tegmental DA neurons [36, 37] and reduced extracellular DA levels in the nucleus accumbens [38, 39]. Renewed ethanol administration reverses these functional deficits as well as behavioral signs of withdrawal in rats [39, 40]. Consistent with these findings in animals, the DA D2 agonist bromocriptine ameliorates ethanol
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withdrawal symptoms, including anxiety, depression, and restlessness in alcoholics [41]. Deficient DA function, therefore, is likely to represent a neural basis for the state of dysphoria and negative affect that accompanies ethanol withdrawal such that restoration of normal DA function by appropriate pharmacological agents may be a suitable strategy for relapse prevention.Deficits in DA neurotransmission induced by chronic ethanol appear to be long lasting. Midbrain DA neural activity still shows suppression three days after withdrawal [42]. Measures of accumbal DA synthesis and turnover indicate that the release of DA is deficient as late as two months after withdrawal [43], and impairments in DA D1-mediated signal transduction have been observed as late as four months following withdrawal from long-term ethanol exposure [44]. The persistent impairment in the functioning of mesolimbic DA transmission likely has implications for vulnerability to relapse during protracted ethanol withdrawal. Indeed, clinical studies suggest that retardation in the recovery of impairments in DA receptor function or DA-dependent signal transduction is associated with the risk of early relapse [45, 46]. Relapse risk linked to delayed recovery of DA receptor function may not, however, extend to heightened ethanol cue reactivity or cue-induced craving, since a more recent study failed to demonstrate a relationship between DA receptor sensitivity and craving induced by the smell of alcoholic beverages [47]. A role of deficient DA transmission in the resumption of drinking has also found important indirect support by findings that low endogenous DA function is linked to predisposition for increased alcohol preference and intake [48, 49 and 50], whereas pharmacological enhancement of DA synthesis, inhibition of DA degradation, or overexpression of D2 receptors by adenoviral DRD2 gene delivery exert protective effects reducing ethanol preference and intake [58, 51].
Exacerbation of drinking following ethanol deprivation
A well-described phenomenon in the alcohol literature is a marked increase in ethanol consumption that follows periods of alcohol deprivation [52, 53]. This alcohol deprivation effect (ADE) is considered a measure of motivation for alcohol [52, 54], loss of control [55], or relapse [50, 56]. Similarities exist between the alcohol deprivation effect in animals and human alcohol abuse such as enhanced ethanol consumption after abstinence in social drinkers [57], and aspects of the loss of control phenomenon surrounding the first drink after abstinence in alcoholics [30, 58, 59]. With repeated deprivation and increased length of deprivation periods, this phenomenon becomes resistant to manipulations of ethanol concentration, taste, and environmental factors [55, 60, 61]. Moreover, increases in ethanol intake produced by repeated deprivation outlast long abstinence phases [60] and may become irreversible [55]. The ADE, therefore, provides a model to study compulsive alcohol-seeking behavior and loss of control following resumption of drinking.
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Neurochemical studies implicate dysregulation of mesolimbic DA transmission as a factor contributing to enhanced drinking following alcohol deprivation. DA release in the nucleus accumbens as measured by microdialysis [62] as well as electrically evoked release of [3H]DA from accumbal tissue [63] was increased after 2-3 weeks of ethanol deprivation in alcohol-preferring P and Wistar rats following several weeks of free access to ethanol. In addition, under these conditions the ADE was associated with a reduction of autoregulatory increases on accumbal DA overflow induced by D2 receptor stimulation [62]. The latter finding suggests that increased DA activity resulting from compromised D2 autoreceptor function may play a role in the ADE [62], although this interpretation is difficult to reconcile with the wealth of data showing that increased DA function is associated with decreased ethanol preference and intake whereas preference and intake are increased in animals with low DA function (e.g., [48, 49, 50 and 51]). Data from a model that utilized repeated deprivation to induce high ethanol drinking also implicate impaired D1-mediated signal transduction as reflected by a decrease in the efficacy of DA to stimulate striatal adenylyl cyclase activity in deprivation-induced exacerbation of ethanol intake [44]. Thus, persistent ethanol-induced changes in DA receptor function may be responsible for increased ethanol drinking associated with the ADE.
In summary, the literature points toward a prominent role for mesolimbic DA transmission in behavioral and neurobiological processes relevant for alcohol relapse risk. Despite this evidence, only few preclinical studies have explicitly tested the effects of pharmacological manipulation of DA neurotransmission on relapse. The following review will therefore extend beyond data from strict animal models of relapse to include a wider spectrum of experimental approaches relevant for evaluating the potential of DA transmission as a treatment target for relapse prevention. Findings covered by this review are summarized in Figure 1.
Manipulation of dopamine receptors and ethanol-seeking behavior
Conditioned ethanol-seeking behavior
A dopaminergic role in drug-related learning and the potential of DA antagonists to reverse ethanol-seeking induced by alcohol cues has been studied in several animal models. These models have in common that they measure behavior controlled by the incentive-motivational or conditioned reinforcing effects of alcohol-associated environmental stimuli. These models differ, however, in terms of whether or not abstinence or extinction of ethanol-reinforced behavior is imposed before testing for conditioned ethanol-seeking, and whether or not conditioning occurs in conjunction with involuntary or self-administration of ethanol.
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Figure 1. Conditioned reinstatement by olfactory discriminative stimuli associated with ethanol availability (S+) versus nonreward (S-), and modification of this effect by the D1 antagonist SCH23390 and the D2 antagonist eticlopride. Rats were treated with DA antagonists 30 min before reinstatement tests. Panels A, C: Total number of responses. For comparison, the figures show also the mean ( SEM) number of responses during ethanol self-administration (??) and nonreward (??) conditioning sessions collapsed across the last three days of the conditioning phase (SA), as well as the mean ( SEM) number of responses across the last three days of the extinction phase (EXT). * p < 0.05, ** p < 0.01 different from extinction baseline; + p < 0.05, different from vehicle. Panels B, D: Latency to initiate responding. * p < 0.05, ** p < 0.01 different from vehicle. + p < 0.05, ++ p < 0.01 different from 5 g/kg. p < 0.01 different from 10 g/kg. Modified from Ref. 54 (with permission) |
Conditioned reinstatement
In the context of the drug addiction literature, conditioned reinstatement refers to the resumption of extinguished instrumental responding induced by noncontingent exposure to a drug-related cue (for review see [64, 65]). Ethanol-associated contextual stimuli reliably elicit recovery of responding at a previously ethanol-paired lever following extinction without further alcohol availability [66, 67, 68, 69, 70, 71 and 72]. Moreover, the behavioral effects of these stimuli are remarkably
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resistant to extinction in that recovery of ethanol-seeking does not diminish when these cues are presented repeatedly under non-reinforced conditions [73].Reinstatement of ethanol-seeking by ethanol-associated contextual stimuli is sensitive to antagonism of DA transmission [74]. Rats operantly self-administering 10% ethanol in daily 30-min sessions were trained to associate distinct olfactory discriminative stimuli with the availability of ethanol or absence of reward. Following subsequent extinction of ethanol-reinforced responding the animals were exposed to the discriminative stimuli previously predictive of ethanol or no reward. Presentation of the ethanol-associated stimulus reinstated responding at the previously active lever. Both the DA D1-selective antagonist SCH 23390, and the DA D2-selective antagonist eticlopride, dose-dependently attenuated this effect by increasing the latency to initiate responding and decreasing the number of responses (Fig. 1). Similar effects were obtained in rats with a history of ethanol dependence, tested three weeks following withdrawal from a 12-day ethanol vapor inhalation procedure. Interestingly, the dose-effect curve for SCH 23390 and eticlopride in these animals was shifted to the left, resulting in an overall greater inhibition of reinstatement responses at lower doses of these agents (Fig. 2). These findings suggest that in both non-dependent and previously dependent rats, blockade of D1 or D2 receptors attenuates the conditioned incentive effects of ethanol-related contextual stimuli. A likely explanation for the increased DA antagonist potency in previously dependent rats involves the DA hypoactivity produced by chronic ethanol as discussed above. Specifically, reduced synaptic availability of DA at the time of testing may have been a factor contributing to the increased DA antagonist potency in rats with a history of ethanol dependence.
Appetitive ethanol-seeking behavior
Recently, an ethanol self-administration model has been developed [75, 76 and 77] that dissociates ethanol-reinforced consummatory behavior (i.e., ethanol drinking) from appetitive ethanol-seeking responses (i.e., behavior induced and maintained by the incentive-motivational effects of ethanol-associated contextual cues present in the self-administration environment). In this procedure, rats must complete a set of responses at a lever during which time ethanol is not available (appetitive phase). Completion of a given response requirement within a specified time results in retraction of the lever and presentation of a sipper tube containing 10% ethanol from which rats are then allowed to freely drink (consummatory phase). Although this procedure is not, strictly speaking, a model of relapse because no significant period of abstinence is imposed before tests, responding during the appetitive phase provides a measure of the day-to-day strength of animals' motivation to initiate and engage in ethanol-seeking behavior when exposed to the ethanol-predictive stimulus environment of the operant conditioning chamber. Thus, pharmacological
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interventions that attenuate appetitive responding in this model may provide relevant leads as to potential treatment targets for conditioned ethanol-seeking and craving.Figure 2. Dose-effect curves for the attenuation of conditioned reinstatement by SCH 23390 and eticlopride in nondependent rats and rats with a history of prior ethanol dependence. Tests were conducted in nondependent rats prior to a 12-day ethanol vapor inhalation procedure and, again, beginning on day 21 after termination of ethanol vapor exposure (Postdependent). Drug effects are expressed as mean ( SEM) percent inhibition of S+-induced responding compared to the effects of vehicle injection. * p < 0.05 ** p < 0.01 different from Nondependent. Reproduced from Ref. 51 (with permission). |
Data generated with this model have revealed that appetitively motivated responding preceding the availability of ethanol is more sensitive to reversal by dopamine D2-selective antagonists than actual ethanol intake [78, 79].
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Raclopride, microinjected into the nucleus accumbens, delayed the onset of appetitive responding and decreased the total number of responses. In contrast, only a single high dose of raclopride reduced the consummatory response. Systemic administration of another D2 antagonist, remoxipride, produced even more selective effects on appetitive ethanol-seeking by dose-dependently decreasing the number of appetitive responses, while having no effect on ethanol consumption.The findings above demonstrate that both conditioned reinstatement and appetitive ethanol-seeking behavior are sensitive to reversal by DA antagonists. A role of DA in cue-controlled ethanol-seeking is supported further by a study that examined the effects of the D2 antagonist haloperidol on responding maintained by a conditioned stimulus (CS) that had been discretely paired with ethanol-reinforced responses [80]. Haloperidol significantly reduced conditioned responding at a previously active lever. Only a single dose was tested. However, the effects of this dose were selective for responding at the lever paired with the ethanol cue and responding at a control lever remained unaltered. This observation, therefore, lends additional support for the conclusion that DA transmission participates in mediating ethanol-seeking behavior initiated and maintained by ethanol-related environmental stimuli.
Expression of conditioned place preference
Place conditioning procedures permit examination of neuropharmacological substrates involved in the acquisition and expression of the conditioned reinforcing effects of ethanol. In this model, manipulations that interfere specifically with the expression of conditioned place preference (CPP), once acquired, provide information on the neuropharmacological basis of conditioned ethanol-seeking behavior, whereas interference with the acquisition of CPP is relevant for the understanding of mechanisms mediating the acute reinforcing effects of ethanol or the learning of Pavlovian associations. Like the model of appetitive ethanol-seeking behavior, studies on the expression of ethanol CPP have not involved imposition of abstinence and, thus, have limitations with respect to providing a measure of relapse. Nonetheless, the degree of preference for a previously ethanol-paired environment provides an index of the strength of ethanol-seeking associated with the incentive-motivational effects of an alcohol-associated stimulus context.
The strongest evidence in favor of a dopaminergic role in ethanol CPP comes from knockout studies. Mice deficient in either D1 or D2 receptors as well as mice lacking DARPP-32 (a phosphoprotein regulating D1 receptor function) show reduced ethanol-induced conditioned place preference [81, 82, 83 and 84]. In contrast to these findings, antagonists of the D1 (SCH 23390) or D2 (raclopride, haloperidol) receptor failed to alter the expression of ethanol conditioned place preference (CPP) [85, 86]. The D3-preferring antagonist U99194A was shown to enhance the acquisition of ethanol CPP [87, 88], an
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effect that may depend on an additive interaction with ethanol because this D3 antagonist alone can produce CPP in rats [89]. The facilitating effects of U99194A in pharmacological studies are difficult to reconcile with data from D3 knockout mice that showed no change in ethanol CPP [90]. More importantly, U99194A failed to prevent the expression of ethanol CPP [30] indicating that blockade of D3 receptors does not interfere with the conditioned reinforcing effects of ethanol. In interpreting these CPP data it is important to consider that effects in knockout models may depend on life-long loss of DA receptor function, resulting in behavioral consequences different from those produced by acute DA receptor blockade. Also, use of knockout preparations leaves unclear whether the deficit in the targeted DA receptor population compromises the acquisition of ethanol CPP because ethanol is not reinforcing in these animals, whether these animals are unable to learn Pavlovian associations, or whether deficiency in a particular DA receptor population interferes with the expression of CPP.As outlined earlier, the CPP data that pertain most directly to the question as to whether DA plays a role in the conditioned incentive effects of ethanol-paired environments are those that have examined whether the expression of CPP is sensitive to pharmacological manipulation of DA neurotransmission. In the studies that have taken this approach, neither D1 nor D2-selective antagonists altered ethanol CPP [85, 86], findings that are in clear contradiction with the attenuation of ethanol-seeking behavior by D1 or D2 antagonists in models of conditioned reinstatement [74], appetitively-motivated responding [78, 79], and conditioned reinforcement [80]. Several factors may account for these discrepancies. First, CPP studies typically employ involuntary administration of ethanol. The reinforcing actions of ethanol under these conditions may differ from those associated with voluntary oral self-administration. As a result, the strength or nature of associations that are formed between ethanol and environmental stimuli may differ in CPP versus self-administration procedures. Importantly, as well, the number of learning trials in models of ethanol-seeking that involve the conditioning of the effects of self-administered ethanol with environmental stimuli is typically greater than in the CPP procedure. Associations that are produced between specific environmental stimuli and ethanol therefore presumably are weaker in the CPP model. Due to these differences, the expression of conditioned ethanol-seeking responses may be differentially sensitive to DA antagonists in CPP vs. self-administration models. Lastly, it cannot be ruled out that different neural substrates are involved in contextual conditioning in the case of CPP as opposed to stimuli associated with active self-administration.
With these considerations in mind, data from behavioral models that involve the conditioning of self-administered ethanol with environmental stimuli consistently confirm that DA antagonists attenuate the motivating effects of ethanol-related environmental stimuli. What limits this information with respect to the potential of DA transmission to serve as a treatment target for the prevention of cue-induced craving and relapse is that the great majority of
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data has been generated in ethanol nondependent animals. In addition to its positive reinforcing effects, alcohol serves as a negative reinforcer during the development of dependence by alleviating aversive withdrawal symptoms (e.g., [91]). This type of drug-related learning may increase the salience of ethanol as a reinforcer and consequently craving or drug-seeking produced by ethanol cues compared to nondependent subjects for which the drug serves as a positive reinforcer only. Additionally, ethanol-seeking in individuals with a history of dependence is likely to be modified by neuroadaptive changes. Chronic ethanol exposure alters DA function and these changes may modify the effects of DA antagonist treatments on ethanol-seeking behavior as illustrated, for example, by the finding that the potency with which D1 and D2 antagonists suppress conditioned reinstatement is increased in previously ethanol-dependent rats [74]. Thus, it will be important to more systematically evaluate the role of DA in conditioned ethanol-seeking using animals with a history of ethanol dependence and withdrawal.
The alcohol deprivation effect
Despite growing evidence of a dopaminergic role in the exacerbation of ethanol intake following deprivation, only few studies have examined whether the ADE is sensitive to pharmacological manipulation of DA receptors. In one study [92], haloperidol administered daily during 14 days of deprivation following six weeks of free access to ethanol reversed the ADE measured on the first post-treatment day in mice. The reduction in drinking was most pronounced during the first 1.5 h of renewed access, a time period during which ethanol intake was greatest in vehicle-treated controls. A proportionally smaller, but significant reduction was observed during the remaining 22.5 h of the first post-deprivation day, suggesting that drinking during the early and late phases of the ADE is differentially sensitive to chronic haloperidol. Nonetheless, the reversal of the ADE during the first hour of renewed access may be indicative of protective effects of chronic D2 antagonist treatments against loss of control. This effect may be mediated via haloperidol-induced upregulation of postsynaptic D2 receptors and consequently enhanced DA transmission, in agreement with the literature implicating D2 deficits in alcohol preference (e.g., [48, 49 and 50]). In a second study, lisuride, an ergot derivative acting as a D2 agonist, failed to reduce ethanol intake in rats tested in a long-term free-access model that utilizes repeated brief deprivation periods to induce high ethanol intake [44]. In fact, lisuride slightly increased consumption in high ethanol drinking as well as previously ethanol-na ve rats, presumably as a result of autoregulatory decreases in DA activity produced by the D2 agonist (see e.g., [93]), a condition that has been linked to increased ethanol preference and intake [48, 49, 50 and 51].
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Is dopamine neurotransmission a promising treatment target?
As elaborated above, the neurobiological literature reveals a significant role for DA in relapse risk associated with alcohol cue exposure as well as neuroadaptive changes in DA function. Preclinical data from studies targeting DA receptors to attenuate ethanol-seeking behavior are largely consistent with this literature and implicate DA neurotransmission as a treatment target. Controlled laboratory studies in humans further support this possibility with findings that blockade of D2 receptors reduces craving induced by an ethanol priming dose, blocks the stimulant and euphorigenic effects of ethanol, and reduces ethanol intake. While the latter findings provide excellent support for a role of DA in acute ethanol reinforcement in humans it remains questionable whether direct pharmacological manipulation of DA transmission represents a promising pharmacotherapeutic approach for relapse prevention.
First, although preclinical evidence strongly suggests a potential for DA antagonists in preventing or ameliorating craving and relapse associated with alcohol cue exposure, the expectation of sustained therapeutic benefits with DA antagonist treatments is fraught with the complication that such treatments would exacerbate the DA hypoactivity that accompanies acute and protracted withdrawal, and that has been linked to increased relapse risk. Second, DA agonist treatments that, based on the preclinical literature, would be predicted to reduce susceptibility to relapse by ameliorating DA hypofunction are problematic as well. The D2 agonist bromocriptine administered during the acute ethanol withdrawal phase reduced craving, anxiety, restlessness and depression in hospitalized alcoholics [41]. Longer bromocriptine treatment (six weeks) reduced craving and anxiety as well, particularly in alcoholics with the D2 receptor A1 allele, but this treatment regimen failed to significantly reduce attrition rates [94]. Similarly, a long-acting bromocriptine preparation (Parlodel-LAR ) proved ineffective in reducing relapse rates in detoxified alcoholics [95], and chronic treatment with another D2 agonist, lisuride, actually enhanced proclivity to relapse by decreasing the latency to resume drinking [93]. This effect, and the lack of anti-relapse efficacy of D2 agonists in general, appears to be a consequence of DA autoregulatory changes associated with chronic DA agonist administration. More specifically, neuroendocrine measures of dopaminergic responsivity to D2 stimulation in alcoholics suggest that chronic lisuride produces an autoinhibitory reduction in dopaminergic tone that likely exacerbates DA hypoactivity, thereby increasing the likelihood of relapse [93].
As more extensively discussed in the Chapter by Carai et al., these clinical findings provide further support for the hypothesis that DA transmission is an important player in the regulation of ethanol-seeking, but illustrate also that direct manipulation of this system, particularly in the context of chronic treatments likely to be required for relapse prevention, is associated with complications that limit therapeutic promise. It remains to be determined whether low-dose D1 antagonist treatments or agents that act as partial agonists at the D2
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receptor may prove beneficial. The latter class of agents that exert functional agonist effects under conditions of low dopaminergic activity but exert antagonist actions when dopaminergic activity is high may offer some promise by ameliorating chronic ethanol-induced DA deficits while at the same time attenuating DA surges associated with ethanol cue exposure. Partial agonists including terguride and SDZ 208-911 reduce ethanol intake in rats with both acute and chronic administration [96], but a possible anti-relapse potential of these agents has not yet been established in appropriate animal models.To properly evaluate the significance and potential of DA neurotransmission to serve as a target for anti-relapse medications, it is important to bear in mind that indirect modification of DA activity through agents that act on other neurochemical systems may perhaps provide an effective approach, eliminating problematic side- and secondary effects associated with chronic DA agonist or antagonist treatments. In fact, as briefly discussed below, regulation or modification of DA activity by other neurochemical systems is likely to contribute to the therapeutic actions of agents with established anti-craving or anti-relapse efficacy.
Effects of indirect manipulation of dopamine transmission on ethanol-seeking
Opiate antagonists
The nonselective opiate receptor antagonist naltrexone as well as mu-opioid and delta-opioid-selective antagonists effectively reverse the behavioral effects of ethanol-related stimuli in conditioned reinstatement [68, 70, 71, 97] and CPP [98, 99] tests. Paralleling these findings, naltrexone attenuates cue-induced ethanol craving [100, 101] and lowers relapse rates in alcoholic populations ([102, 103, 104, 105, 106 and 107]; see also Chapters by Cowen and O'Brien et al.).
Opiate antagonists blunt the stimulatory effects of systemically and self-administered ethanol on DA release in the nucleus accumbens [10, 108, 109 and 110]. Interference with ethanol-induced activation of mesolimbic DA transmission and, consequently, ethanol reward has therefore been implicated as a mechanism by which opiate antagonists reduce ethanol intake. This naltrexone-induced decrease in the rewarding efficacy of ethanol also may limit ethanol intake during a lapse in abstinent alcoholics and thereby lower the incidence of full-blown relapse.
A second mechanism for the therapeutic effects of naltrexone involving interactions with DA transmission may be interference with the neurochemical effects of alcohol cues hypothesized to underlie conditioned cue reactivity and craving. Anticipation of ethanol and exposure to alcohol-related contextual stimuli can increase extracellular DA levels in the nucleus accumbens [5, 10, 11 and 12], and alcohol cue exposure activates DA-rich brain regions in abstinent alcoholics [27]. In view of the ability of opiate antagonists to block ethanol-induced
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stimulation of DA release, it is possible that these agents also interfere with the DA-activating actions of ethanol cues. Direct evidence supporting this hypothesis is still lacking. However, it is not unlikely that such effects may contribute to the anti-craving effects of opiate antagonists in humans and their inhibitory effects on conditioned ethanol-seeking behavior in animals.
Acamprosate
Acamprosate reduces relapse during ethanol withdrawal in humans and lowers ethanol-seeking and intake in animal models (e.g., [111, 112]; see also Chapters by de Witte et al. and Mann). The mechanism(s) underlying these effects are not well understood, but are thought to involve reduction of neural hyperexcitability associated with ethanol withdrawal via restoration of normal N-methyl-D-aspartate receptor function [112, 113 and 114]. Recent evidence indicates, however, that acute acamprosate treatment also dose-dependently delays and suppresses ethanol's stimulatory effects on DA release in the nucleus accumbens [115]. This suggests that acamprosate may reduce relapse during withdrawal by attenuating the ability of ethanol to activate the mesolimbic DA reward pathway. Acamprosate, however, did not attenuate appetitive-phase responding (i.e., ethanol-seeking elicited and maintained by the incentive-motivational effects of a drug-related environment) in rats [116]. Thus, the DA inhibitory effect of acamprosate and its consequences on ethanol intake may be limited to the direct pharmacological actions of ethanol, without interfering with the presumably DA-mediated effects of alcohol-related environmental stimuli on ethanol-seeking behavior and craving.
Acknowledgements
The author would like to thank Mike Arends for his editorial assistance.
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