Glenn R. Valdez

Compulsive Drug‐Seeking Behavior and Relapse

Abstract: The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse. These changes lead to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. Considerable evidence exists implicating perturbations in DA and 5‐HT transmission in the nucleus accumbens—neurochemical systems that are activated by cocaine and ethanol self‐administration and deficient during withdrawal—as potential substrates for these affective changes. In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress‐like consequences of withdrawal that are common to all drugs of abuse. A growing body of evidence also implicates dysregulation of the non‐neuroendocrine CRF stress system within the central nucleus of the amygdala as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse. Moreover, a possible link may exist between long‐lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence. Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug‐related stimuli. The long‐lasting efficacy of drug‐ and alcohol‐associated contextual stimuli in eliciting drug‐seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue‐induced cocaine craving in humans and confirms a significant role of learning factors in the long‐lasting addictive potential of cocaine. With cocaine, D1‐dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala may be important substrates for the motivating effects of drug‐related environmental stimuli. With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug‐seeking behavior. Finally, conditioning factors (i.e., exposure to drug‐associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies.

Stress enhancement of craving during sobriety: a risk for relapse.

This report of the proceedings of a symposium presented at the 2004 Research Society on Alcoholism Meeting provides evidence linking stress during sobriety to craving that increases the risk for relapse. The initial presentation by Rajita Sinha summarized clinical evidence for the hypothesis that there is an increased sensitivity to stress-induced craving in alcoholics. During early abstinence, alcoholics who were confronted with stressful circumstances showed increased susceptibility for relapse. George Breese presented data demonstrating that stress could substitute for repeated withdrawals from chronic ethanol to induce anxiety-like behavior. This persistent adaptive change induced by multiple withdrawals allowed stress to induce an anxiety-like response that was absent in animals that were not previously exposed to chronic ethanol. Subsequently, Amanda Roberts reviewed evidence that increased drinking induced by stress was dependent on corticotropin-releasing factor (CRF). In addition, rats that were stressed during protracted abstinence exhibited anxiety-like behavior that was also dependent on CRF. Christopher Dayas indicated that stress increases the reinstatement of an alcohol-related cue. Moreover, this effect was enhanced by previous alcohol dependence. These interactive effects between stress and alcohol-related environmental stimuli depended on concurrent activation of endogenous opioid and CRF systems. A.D. Lê covered information that indicated that stress facilitated reinstatement to alcohol responding and summarized the influence of multiple deprivations on this interaction. David Overstreet provided evidence that restraint stress during repeated alcohol deprivations increases voluntary drinking in alcohol-preferring (P) rats that results in withdrawal-induced anxiety that is not observed in the absence of stress. Testing of drugs on the stress-induced voluntary drinking implicated serotonin and CRF involvement in the sensitized response. Collectively, the presentations provided convincing support for an involvement of stress in the cause of relapse and continuing alcohol abuse and suggested novel pharmacological approaches for treating relapse induced by stress.

High-priority communication I Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence

One of the most critical attributes of chronic abstinence from alcohol is a state of anxiety, which can lead to mood disturbances and negative affect that can last for months or even years in alcoholics. Within hours after their final exposure to ethanol in experimental conditions, laboratory animals also exhibit an anxiety-like state. This state is accompanied by an enhanced stress response and can persist for weeks after withdrawal. One possible mechanism underlying these behavioral changes observed weeks after withdrawal is increased corticotropin-releasing factor (CRF) activity. In the present study, we sought to examine the role of CRF in the regulation of behavior in the elevated plus-maze during protracted abstinence by using intracerebroventricular administration of the CRF receptor antagonist [D-Phe(12),Nle(21,38),CalphaMeLeu(37)]rCRF((12-41)) (D-Phe-CRF((12-41))). Rats were surgically implanted with a guide cannula aimed at the lateral ventricles and subsequently fed a nutritionally complete ethanol [10% (vol./vol.)] or control liquid diet for 21 days. Rats were further divided into groups receiving microinjections of D-Phe-CRF((12-41)) or vehicle and 15 min of restraint stress, or D-Phe-CRF((12-41)) or vehicle and no restraint. Six weeks after removal of the liquid diet, rats were injected and then placed in a restraint tube or returned to their home cages for 15 min before testing in the elevated plus-maze. Rats with a history of ethanol dependence explored the open arms of the plus-maze significantly less when exposed to restraint stress compared with findings for all other groups, an effect attenuated by pretreatment with D-Phe-CRF((12-41)). Results of the current experiment demonstrated that continuous exposure to ethanol over a 3-week period leads to an increased behavioral responsiveness to stress, which seems to be regulated by CRF.

Human urocortin II: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide

Recently, human urocortin II (hUcn II), a member of the corticotropin-releasing factor (CRF) peptide family, was identified. The following experiments sought to compare the effects of this novel CRF-related peptide versus those of ovine CRF (oCRF) on locomotor activation and anxiety-related behavior, using the locomotor activity test and the elevated plus maze, respectively. To examine locomotor activity during the active (dark) and inactive (light) phases, rats were intracerebroventricularly (i.c.v.) injected with 0, 0.1, 1.0 or 10 microg of hUcn II (n=8/group active; n=6-9/group inactive) or oCRF (n=8/group active; n=8/group inactive) 2 h after the onset of their respective testing phase and monitored for 3 (inactive) or 5 (active) h. To compare the effects of CRF-related peptides on exploration of the elevated plus maze, rats were pretreated (i.c.v. 0, 0.1, 1.0 or 10 microg) with hUcn II (n=7-11/group) or oCRF (n=7-10/group), 10 min prior to testing. Delayed effects in the elevated plus maze were examined in rats injected with 1.0 microg of hUcn II (n=8/group) or oCRF (n=6-8/group), or vehicle (n=8/group) 1, 4 or 6 h before testing. In contrast to the activational effects of oCRF, hUcn II mildly suppressed locomotor activity during the inactive phase. hUcn II did not acutely affect open arm exploration in the elevated plus maze, whereas oCRF decreased this measure. However, hUcn II increased open arm exploration 4 h after injection. Thus, hUcn II exhibits mild motor suppressive effects and delayed anxiolytic-like effects, suggesting a time-dependent role for hUcn II in the regulation of stress-related behavior.

Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist

Murine urocortin 3 (mUcn 3), a member of the corticotropin releasing factor (CRF) peptide family, was recently identified. Of known agonists, this neuropeptide displays the highest degree of selectivity in binding to the CRF(2) receptor. These experiments sought to test the hypothesis that CRF(2) receptors have a role in modulating stress by examining intracerebroventricular (i.c.v.) administration of mUcn 3 in animal models of activation and anxiety. To investigate the effects of mUcn 3 on motor activity, rats were injected with mUcn 3 (0, 0.1, 1.0 or 10 microg, i.c.v.) 10 min prior to testing and activity was monitored for 6 h. To determine changes in novelty-induced exploration, rats were injected with mUcn 3 (0, 0.1, 1.0 or 10 microg, i.c.v.) 10 min prior to testing and examined in the elevated plus maze. Finally, delayed effects of mUcn 3 were tested in rats injected with 1.0 microg of mUcn 3 or vehicle 30 or 60 min prior to testing in the elevated plus maze. Injections of mUcn 3 significantly decreased locomotor activity in rats during the first hour of testing. In the elevated plus maze, mUcn 3 injections significantly increased open arm preference compared to vehicle when tested using a 10-min pretreatment interval. mUcn treated rats tested in the elevated plus maze following the delayed pretreatment interval did not differ from controls. These data demonstrate that injection of mUcn 3 leads to acute locomotor suppressive effects and decreases in stress-like behaviors, indicating an anxiolytic-like action for mUcn 3, and suggests a possible role of the CRF(2) receptor in the regulation of stress-related behavior.

Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism

Alcoholism is a chronic relapsing disorder, accompanied by alterations in psychological and physiological functioning, which reaches an addictive state where an individual demonstrates uncontrollable compulsive alcohol drinking and impairment in social and occupational functioning. Withdrawal is one of the defining characteristics of dependence, characterized by impaired physiological function and enhanced negative affect, and is thought to be a major contributing factor to relapse. The negative emotional aspects of withdrawal appear to be more involved in continued alcohol craving because physical withdrawal symptoms are not highly correlated with relapse in alcoholics. Allostasis describes maintaining stability outside the homeostatic range by varying the internal milieu to match environmental demands. This concept has been applied to neurobiological models of drug addiction and is thought to contribute to the vulnerability of drug addicts to relapse, as addicts continue to use drugs in order to maintain their psychological state within a homeostatic range. With regard to alcohol, two neuropeptides appear to be involved in the regulation of alcohol-related stress, corticotropin-releasing factor (CRF), which is associated with an increased stress response and negative affect, and neuropeptide Y (NPY), a neuropeptide with anxiolytic properties. The hypothesis to be developed in the present review is that a dysregulation of the CRF and NPY systems significantly contributes to the motivational basis of continued alcohol-seeking behavior during alcohol dependence. It appears that increases in CRF contribute to the negative affective state that is strongly associated with alcohol withdrawal, and NPY provides a motivational basis to consume alcohol because the anxiolytic effects of alcohol, which are strongly associated with relapse, appear to be regulated in part by this neuropeptide.

Effects of antalarmin, a CRF type 1 receptor antagonist, on anxiety-like behavior and motor activation in the rat

Molecular studies point to a role for the type 1 corticotropin-releasing factor receptor (CRF(1)) in anxiogenic-like and activating effects of CRF and stress. However, CP-154,526, a selective CRF(1) antagonist, has yielded mixed results in such tests. Few studies have examined the behavioral effects of other CRF(1) antagonists. Therefore, we examined the effects of antalarmin, a structurally related analog of CP-154,526, on anxiety-like behavior and motor activation. Antalarmin blocked the anxiogenic-like effect of CRF in the elevated plus maze, without affecting anxiety-like behavior in vehicle-treated animals. Antalarmin decreased spontaneous defensive withdrawal behavior in a novel, brightly illuminated open field. Finally, antalarmin blocked the activating effects of CRF, but not D-amphetamine, without producing motor sedation. These findings indicate that the CRF(1) receptor mediates anxiogenic-like effects of novelty stress and the anxiogenic-like and activating effects of CRF and support the hypothesis that CRF(1) antagonists may be useful for the pharmacotherapy of pathological anxiety.

Increased Anxiety‐Like Behavior and Ethanol Self‐Administration in Dependent Rats: Reversal via Corticotropin‐Releasing Factor‐2 Receptor Activation

BACKGROUND Corticotropin-releasing factor (CRF) has been hypothesized to be one of the main regulators of the stress response observed during alcohol withdrawal. The CRF receptor subtypes seem to have a differential role in the regulation of stress-related behavior. Given the behavioral characterization of these receptors, the objective of the following experiments was to characterize the role of CRF2 receptors in the interaction between alcohol and stress by examining the effects of CRF2 receptor activation in the behavioral stress response and ethanol self-administration during early ethanol withdrawal in dependent rats. METHODS Male Wistar rats were made dependent on ethanol via chronic exposure to an ethanol containing liquid diet. Behavior in the elevated plus maze and ethanol self-administration were measured at 2 hr after removal of the diet. The role of the CRF2 receptor in the regulation of these behaviors during the early stages of withdrawal was examined via central injection of the highly selective CRF2 receptor agonist urocortin 3. RESULTS Rats showed decreased exploration of the open arms of the elevated plus maze, an indication of a heightened behavioral stress response, after chronic ethanol exposure. This effect was attenuated by central injection of urocortin 3. In addition, urocortin 3 injections reversed the increase in ethanol self-administration observed during early withdrawal in dependent rats. CONCLUSIONS Reversal of the increased stress-related behavior in the elevated plus maze observed after injections of urocortin 3 indicates that the decreased responding for ethanol also seen after urocortin 3 administration is likely due to a diminished anxiety-like state. These data suggest that activation of the CRF2 receptor may provide a novel target in the attenuation of the stress response characteristic of the early stages of ethanol withdrawal.

κ Agonist-Induced Reinstatement of Cocaine Seeking in Squirrel Monkeys: A Role for Opioid and Stress-Related Mechanisms

κ Opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that κ agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the κ agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the α2-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of κ opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by κ agonists.

Subtype-Selective Corticotropin-Releasing Factor Receptor Agonists Exert Contrasting, but Not Opposite, Effects on Anxiety-Related Behavior in Rats

The corticotropin-releasing factor (CRF) system mediates stress responses. Extrahypothalamic CRF1 receptor activation has anxiogenic-like properties, but anxiety-related functions of CRF2 receptors remain unclear. The present study determined the effects of intracerebroventricular administration of a CRF2 agonist, urocortin 3, on behavior of male Wistar rats in the shock-probe, social interaction, and defensive withdrawal tests of anxiety-like behavior. Equimolar doses of stressin1-A, a novel CRF1 agonist, were administered to separate rats. The effects of pyrazolo[1,5-a]-1,3,5-triazin-4-amine,8-[4-(bromo)-2-chlorophenyl]-N, N-bis(2-methoxyethyl)-2,7-dimethyl-(9Cl) (MJL-1-109-2), a CRF1 antagonist, on behavior in the shock-probe test also were studied. Stressin1-A increased anxiety-like behavior in the social interaction and shock-probe tests. Stressin1-A elicited behavioral activation and defensive burying at lower doses (0.04 nmol), but it increased freezing, grooming, and mounting at 25-fold higher (1-nmol) doses. Conversely, systemic administration of MJL-1-109-2 (10 mg/kg) had anxiolytic-like effects in the shock-probe test. Unlike stressin1-A or MJL-1-109-2, i.c.v. urocortin 3 infusion did not alter anxiety-like behavior in the shock-probe test across a range of doses that reduced locomotion and rearing and increased grooming. Urocortin 3 also did not decrease social interaction, but it decreased anxiety-like behavior in the defensive withdrawal test at a 2-nmol dose. Thus, i.c.v. administration of CRF1 and CRF2 agonists produced differential, but not opposite, effects on anxiety-like behavior. Urocortin 3 (i.c.v.) did not consistently decrease or increase anxiety-like behavior, the latter unlike effects seen previously after local microinjection of CRF2 agonists into the septum or raphe. With increasing CRF1 activation, however, the behavioral expression of anxiety qualitatively changes from “coping” to “noncoping” and offensive, agonistic behaviors.