Alcohol-seeking Behavior In Rats Research Articles

Blockade of orexin receptors in the infralimbic cortex prevents stress-induced reinstatement of alcohol-seeking behavior in rats with a history of alcohol dependence

Blockade of orexin receptors in the infralimbic cortex prevents stress-induced reinstatement of alcohol-seeking behavior in rats with a history of alcohol dependence

Optogenetic induction of orbitostriatal long-term potentiation in the dorsomedial striatum elicits a persistent reduction of alcohol-seeking behavior in rats

Uncontrolled drug-seeking and -taking behaviors are generally driven by maladaptive corticostriatal synaptic plasticity. The orbital frontal cortex (OFC) and its projections to the dorsomedial striatum (DMS) have been extensively implicated in drug-seeking and relapse behaviors. The influence of the synaptic plasticity of OFC projections to the DMS (OFC→DMS) on drug-seeking and -taking behaviors has not been fully characterized. To investigate this, we trained rats to self-administer 20% alcohol and then delivered an in vivo optogenetic protocol designed to induce long-term potentiation (LTP) selectively at OFC→DMS synapses. We selected LTP induction because we found that voluntary alcohol self-administration suppressed OFC→DMS transmission and LTP may normalize this transmission, consequently reducing alcohol-seeking behavior. Importantly, ex vivo slice electrophysiology studies confirmed that this in vivo optical stimulation protocol resulted in a significant increase in excitatory OFC→DMS transmission strength on day two after stimulation, suggesting that LTP was induced in vivo. Rat alcohol-seeking and -taking behaviors were significantly reduced on days 1–3, but not on days 7–11, after LTP induction. Striatal synaptic plasticity is modulated by several critical neurotransmitter receptors, including dopamine D1 receptors (D1Rs) and adenosine A2A receptors (A2ARs). We found that delivery of in vivo optical stimulation in the presence of a D1R antagonist abolished the LTP-associated decrease in alcohol-seeking behavior, whereas delivery in the presence of an A2AR antagonist may facilitate this LTP-induced behavioral change. These results demonstrate that alcohol-seeking behavior was negatively regulated by the potentiation of excitatory OFC→DMS neurotransmission. Our findings provide direct evidence that the OFC exerts “top-down” control of alcohol-seeking behavior via the DMS.

Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats.

Peroxisome proliferator-activated receptor γ (PPARγ) is an intracellular transcription factor whose signaling activation by the selective agonist pioglitazone reduces alcohol drinking and alcohol-seeking behavior in rats. The present study utilized the two-bottle choice and operant self-administration procedures to investigate neuroanatomical substrates that mediate the effects of PPARγ agonism on alcohol drinking and seeking in msP rats. Bilateral infusions of pioglitazone (0, 5, and 10 μg/μl) in the rostromedial tegmental nucleus (RMTg) decreased voluntary alcohol drinking and alcohol self-administration. Microinjections of pioglitazone in the ventral tegmental area (VTA), central amygdala (CeA), and nucleus accumbens (NAc) shell had no such effect. Notably, water, food, and saccharin consumption was unaltered by either treatment. The yohimbine-induced reinstatement of alcohol seeking was prevented by infusions of pioglitazone (0, 2.5, 5, and 10 μg/μl) in the CeA, VTA, and RMTg but not in the NAc shell. These results emphasize the involvement of mesocorticolimbic circuitries in mediating the effects of PPARγ agonists on alcohol drinking and seeking. These results will facilitate future studies that investigate the pathophysiological role of PPARγ in alcohol use disorder and help clarify the mechanisms by which the activation of this receptor decreases the motivation for drinking.

Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior.

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu5-dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu5 in ex vivo slices significantly reduced KCa2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of KCa2 channel activity by mGlu5 receptors. Additionally, positive modulation of KCa2 channels prevented mGlu5 receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (KCa2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions, an effect that persisted for 3 weeks, but was not observed after apamin microinfusions into the prelimbic PFC. Positive modulation of IL-PFC KCa2 channels significantly attenuated mGlu5-dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu5-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of KCa2 channels. Moreover, these findings demonstrate that KCa2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior.SIGNIFICANCE STATEMENT Alcohol use disorder is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles, and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on relapse in alcoholics.

Nicotine-induced enhancement of Pavlovian alcohol-seeking behavior in rats.

Nicotine enhances responding elicited by Pavlovian cues that predict positive outcomes. We tested the hypothesis that nicotine acting at nicotinic acetylcholine receptors (nAChRs) would augment Pavlovian alcohol-seeking. Male, Long-Evans rats with unrestricted access to food and water were acclimated to drinking 15% ethanol in their home cages and then given Pavlovian conditioning sessions in which each trial of a 15-s conditioned stimulus (CS, 12 trials/session) was paired with 0.2ml of ethanol (unconditioned stimulus, US, 2.4ml/session). Entries into a port where ethanol was delivered were used to assess conditioning. Control groups received explicitly unpaired trials of the CS and US. In experiment 1, systemic injections of saline (1ml/kg) or nicotine (0.4mg/kg, freebase) were administered before each session. In experiments 2 and 3, an identical regimen of saline or nicotine injections was administered before the start of Pavlovian conditioning sessions. All paired groups acquired conditioned port-entry responding to the CS, indicative of Pavlovian alcohol-seeking, whereas unpaired control group did not. Pre-session nicotine injections increased CS port-entries relative to saline, only in the paired group. This nicotine-induced enhancement of Pavlovian alcohol-seeking was blocked by pre-treatment with the nAChR antagonist mecamylamine. Prior exposure to nicotine did not influence the subsequent acquisition of Pavlovian alcohol-seeking. These findings highlight for the first time that nicotine acting at nAChRs augments Pavlovian alcohol-seeking, specifically in non-restricted rats. Individuals who smoke and drink may thus be particularly susceptible to alcohol cues that could trigger further drinking.

Alcohol seeking by rats becomes habitual after prolonged training.

This study examines the effect of the amount of training on alcohol seeking behavior in rats. Contemporary theories of instrumental learning suggest that habit learning processes are involved in the development of the compulsive drug seeking that characterizes addiction. Wistar rats were trained to perform an instrumental response for a solution of ethanol. In Experiment 1, the rats received 2 instrumental training sessions, whereas animals in Experiment 2 received 2, 8, or 16 sessions. An aversion was then conditioned to ethanol by pairing it with LiCl, and the performance in extinction was subsequently tested. Instrumental responding showed variable sensitivity to outcome devaluation as a function of the length of training. After 2 and 8 training sessions, but not after 16 sessions, drug seeking was influenced by a change in the value of ethanol. The results suggest that alcohol seeking is more flexible and goal-directed in early stages of training, but it becomes habitual and less governed by its consequences with more extended training.

Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats

Sigma-1 receptor (Sig-1R) has been proposed as a novel therapeutic target for drug and alcohol addiction. We have shown previously that Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while Sig-1R antagonists on the other hand block excessive drinking in genetic and environmental models of alcoholism, without affecting intake in outbred non-dependent rats. Even though significant progress has been made in understanding the function of Sig-1R in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. Administration of the selective Sig-1R antagonist BD-1063 dramatically reduced the acquisition of alcohol drinking behavior as well as the preference for alcohol in genetically selected TSRI Sardinian alcohol preferring (Scr:sP) rats; the treatment had instead no effect on total fluid intake, food intake or body weight gain, proving selectivity of action. Furthermore, BD-1063 dose-dependently decreased alcohol-seeking behavior in rats trained under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a conditioned reinforcer. Finally, an innate elevation in Sig-1R protein levels was found in the nucleus accumbens of alcohol-preferring Scr:sP rats, compared to outbred Wistar rats, alteration which was normalized by chronic, voluntary alcohol drinking. Taken together these findings demonstrate that Sig-1R blockade reduces the propensity to both acquire alcohol drinking and to seek alcohol, and point to the nucleus accumbens as a potential key region for the effects observed. Our data suggest that Sig-1R antagonists may have therapeutic potential in multiple stages of alcohol addiction.

A Procedure to Observe Context-induced Renewal of Pavlovian-conditioned Alcohol-seeking Behavior in Rats

Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian discrimination training (PDT) in conditioning chambers. In each daily (Mon-Fri) PDT session, 16 trials each of two different 10 sec auditory conditioned stimuli occur. During one stimulus, the CS+, 0.2 ml of 15% ethanol is delivered into a fluid port for oral consumption. The second stimulus, the CS-, is not paired with ethanol. Across sessions, entries into the fluid port during the CS+ increase, whereas entries during the CS- stabilize at a lower level, indicating that a predictive association between the CS+ and ethanol is acquired. During PDT each chamber is equipped with a specific configuration of visual, olfactory and tactile contextual stimuli. Following PDT, extinction training is conducted in the same chamber that is now equipped with a different configuration of contextual stimuli. The CS+ and CS- are presented as before, but ethanol is withheld, which causes a gradual decline in port entries during the CS+. At test, rats are placed back into the PDT context and presented with the CS+ and CS- as before, but without ethanol. This manipulation triggers a robust and selective increase in the number of port entries made during the alcohol predictive CS+, with no change in responding during the CS-. This effect, referred to as context-induced renewal, illustrates the powerful capacity of contexts associated with alcohol consumption to stimulate alcohol-seeking behavior in response to Pavlovian alcohol cues.

A procedure to observe context-induced renewal of pavlovian-conditioned alcohol-seeking behavior in rats.

Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian discrimination training (PDT) in conditioning chambers. In each daily (Mon-Fri) PDT session, 16 trials each of two different 10 sec auditory conditioned stimuli occur. During one stimulus, the CS+, 0.2 ml of 15% ethanol is delivered into a fluid port for oral consumption. The second stimulus, the CS-, is not paired with ethanol. Across sessions, entries into the fluid port during the CS+ increase, whereas entries during the CS- stabilize at a lower level, indicating that a predictive association between the CS+ and ethanol is acquired. During PDT each chamber is equipped with a specific configuration of visual, olfactory and tactile contextual stimuli. Following PDT, extinction training is conducted in the same chamber that is now equipped with a different configuration of contextual stimuli. The CS+ and CS- are presented as before, but ethanol is withheld, which causes a gradual decline in port entries during the CS+. At test, rats are placed back into the PDT context and presented with the CS+ and CS- as before, but without ethanol. This manipulation triggers a robust and selective increase in the number of port entries made during the alcohol predictive CS+, with no change in responding during the CS-. This effect, referred to as context-induced renewal, illustrates the powerful capacity of contexts associated with alcohol consumption to stimulate alcohol-seeking behavior in response to Pavlovian alcohol cues.

The Effects of Xenon and Nitrous Oxide Gases on Alcohol Relapse

In recent years, the glutamate theory of alcoholism has emerged as a major theory in the addiction research field and N-methyl-d-aspartate (NMDA) receptors have been shown to play a major role in alcohol craving and relapse. The NMDA receptors are considered as the primary side of action of the anesthetic gases xenon (Xe) and nitrous oxide (N2 O). Despite the rapid on/off kinetics of these gases on the NMDA receptor, a brief gas exposure can induce an analgesic or antireward effect lasting several days. The aim of this study was to examine the effect of both Xe and N2 O on alcohol-seeking and relapse-like drinking behavior (measured as the alcohol deprivation effect) in Wistar rats. We used 2 standard procedures-the alcohol deprivation model with repeated deprivation phases and the cue-induced reinstatement model of alcohol seeking-to study the effect of 2 brief gas exposures of either Xe, N2 O, or control gas on relapse-like drinking and alcohol-seeking behavior. Here, we show that exposure to Xe during the last 24hours of abstinence produced a trend toward reduced ethanol intake during the first alcohol re-exposure days. In addition, Xe gas exposure significantly decreased the cue-induced reinstatement of alcohol-seeking behavior. N2 O had no effect on either behavior. Xe reduces alcohol-seeking behavior in rats and may therefore also interfere with craving in human alcoholics.

Current approaches to the laboratory assessment of abuse potential

Current approaches to the laboratory assessment of abuse potential

P01-84 Disrupting reconsolidation of alcohol memories reduces cue-induced alcohol seeking behavior in rats

In humans alcohol seeking behavior is frequently evoked by the retrieval of memories associated with an alcohol experience. Consolidated memories can become labile if reactivated by reexposure. The aim of our study was to examine whether the behavioral impact of previously conditioned alcohol associated cues is significantly reduced by blocking the reconsolidation of the previously learned alcohol associations that are retrieved by reexposition. For this purpose we applied an animal model for cue-induced relapse to alcohol-seeking behavior. We show that post-retrieval i.p.-administration of 0.1 mg/kg of the NMDA antagonist MK-801 (n=8-10 per group) significantly reduced alcohol seeking behavior during the following test day as compared to vehicle treated animals. Similarly, memory reconsolidation was disrupted by ICV administration of 400 μg of the protein synthesis inhibitor anisomycin (n=9-11 per group). Pharmacological disruption of reconsolidation of alcohol-associated memories may thus provide a potential therapeutic strategy for the prevention of relapse in alcohol addiction.

Interactions between cannabinoids and alcohol

Event Abstract Back to Event Interactions between cannabinoids and alcohol Fernando Rodriguez-de-Fonseca1* 1 Hospital Carlos Haya, Avenida Carlos Haya 82, Laboratorio de Medicina Regenerativa, Fundación IMABIS, Spain The endogenous cannabinoid anandamide participates in the neuroadaptations associated with chronic ethanol exposure and serves as a link between exogenous cannabinoid administration and alcohol actions. While cannabinoid exposure favors alcohol intake, cannabinoid CB1 receptor antagonist reduces both alcohol intake and cue-induced relapse to alcohol selfadministration. Thus, intraperitoneal administration of the cannabinoid CB1 receptor antagonist SR141716A (0.03, 1.0 and 3.0 mg/kg) markedly inhibits ethanol selfadministration and conditioned reinstatement of ethanol-seeking behavior in both Wistar and Marchegian-Sardinian Alcohol preferring rats (mSp). ED50 analysis showed significantly higher sensitivity (p<0.05) to the effect of SR141716A in msP rats compared to heterogeneous Wistar rats. On the other side, acute peripheral administration of ethanol (4 gr/kg, i.p.) decreased anandamide in the cerebellum, the hippocampus and the ventral striatum, as well as in plasma and adipose tissue. Parallel decreases of a second acylethanolamide, palmithylethanolamide were observed in the brain. Effects were observed 45-90 min after ethanol administration. In vivo studies revealed that anandamide decreases were associated with a remarkable inhibition of the release of both anadamide and glutamate release in the ventral striatum. There were no changes in the expression and enzimatic activity of the main enzyme that degradates anandamide, the fatty acid amidohydrolase. Acute ethanol did not change neither the activity of n-acyltransferase, the enzyme that catalyzes the synthesis of the anandamide precursor, nor the expression of NAPE-PLD, the enzyme that releases anandamide from membrane phospholipid precursors. These results suggest that receptor-mediated release of acylethanolamide is inhibited by the acute administration of ethanol, and that this effect is not derived of increased fatty acid ethanolamide degradation. In conclusion, we provide clear evidence that the endogenous cannabinoid system participates in alcohol-seeking behavior in rats, and that alcohol directly modulates endocannabinoid production. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 02 – Cannabinoids and brain reward processes Citation: Rodriguez-de-Fonseca F (2009). Interactions between cannabinoids and alcohol. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.009 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Nov 2009; Published Online: 18 Nov 2009. * Correspondence: Fernando Rodriguez-de-Fonseca, Hospital Carlos Haya, Avenida Carlos Haya 82, Laboratorio de Medicina Regenerativa, Fundación IMABIS, 13331 Marseille, Spain, fernando.rodriguez@ibima.eu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Fernando Rodriguez-de-Fonseca Google Fernando Rodriguez-de-Fonseca Google Scholar Fernando Rodriguez-de-Fonseca PubMed Fernando Rodriguez-de-Fonseca Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The anandamide transport inhibitor AM404 reduces ethanol self‐administration

The endocannabinoid system mediates in the pharmacological actions of ethanol and genetic studies link endocannabinoid signaling to alcoholism. Drugs activating cannabinoid CB1 receptors have been found to promote alcohol consumption but their effects on self-administration of alcohol are less clear because of the interference with motor performance. To avoid this problem, a novel pharmacological approach to the study of the contribution of the cannabinoid system in alcoholism may be to use drugs that locally amplify the effects of alcohol on endogenous cannabinoids. In the present study we addressed this model by studying the effects of the anandamide transport inhibitor N-(4-hydroxyphenyl) arachidonoyl-ethanolamide (AM404) on both ethanol self-administration and reinstatement of alcohol-seeking behavior in rats. The results show that AM404 significantly reduced ethanol self-administration in a dose-dependent manner but failed to modify reinstatement for lever pressing induced by the stimulus associated with alcohol. This effect was not due to a motor depressant effect and was not related to a decrease in general motivational state, as it was not effective in other reward paradigms such as lever pressing for a saccharin solution. The mechanism of action of AM404 does not involve cannabinoid CB1 receptors as the CB1-selective antagonist SR141716A did not block the reduction of ethanol self-administration induced by the anandamide uptake blocker. Moreover, 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol (HU-210), a classical cannabinoid receptor agonist, did not affect ethanol self-administration. The effects of AM404 are not mediated by either vanilloid VR1 receptors or cannabinoid CB2 receptors because it is not antagonized by either the VR1 receptor antagonist capsazepine or the CB2 antagonist AM630. These results indicate that AM404 may be considered as an innovative approach to reduce alcohol consumption.

Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol‐seeking behavior in rats

The endocannabinoid system is involved in a variety of effects of drugs of misuse, and blockade of the cannabinoid CB1 receptor by selective antagonists elicits marked reductions in opioid and alcohol self-administration. The present study was designed to extend our knowledge of the role of the cannabinoid CB1 receptor in the modulation of alcohol misuse vulnerability in rats. Accordingly, using nonselected Wistar rats and genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, we investigated the effect of the CB1 antagonist SR141716A on operant alcohol self-administration and on reinstatement of alcohol-seeking behavior by environmental conditioning factors. In addition, in situ hybridization studies in both strains were performed to measure cannabinoid CB1 receptor mRNA in different brain areas of these animals. Results showed that intraperitoneal administration of SR141716A (0.03, 1.0 and 3.0 mg/kg) markedly inhibits ethanol self-administration and conditioned reinstatement of ethanol-seeking behavior in both strains of rats. ED50 analysis showed significantly higher sensitivity (P < 0.05) to the effect of SR141716A in msP rats than in heterogeneous Wistar rats. In situ hybridization studies revealed that, compared with Wistar rats, msP animals have consistently greater cannabinoid CB1 receptor mRNA expression in a number of brain areas, including the frontoparietal cortex, caudate-putamen and hippocampus (CA1 and dentate gyrus areas). In conclusion, we provide clear evidence that blockade of CB1 receptors reduces both ethanol self-administration and conditioned reinstatement of alcohol-seeking behavior in rats. In addition, current pharmacological and neuroanatomical data suggest that an altered function of the CB1 receptor system exists between genetically selected alcohol-preferring msP rats and a heterogeneous animal population.

The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats.

Intermittent footshock stress reliably reinstates extinguished alcohol-taking behavior in drug-free rats, but the neurochemical events involved in this effect are not known. We studied here whether two main modulators of stress responses, corticotropin-releasing factor (CRF) and corticosterone, are involved in reinstatement of alcohol seeking induced by the intermittent footshock stressor. METHDOS: Rats were given alcohol in a two-bottle choice procedure (water versus alcohol) for 30 days and were then trained for 60 min per day to press a lever for alcohol (12% w/v) for 24-30 days in operant conditioning chambers. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished by terminating drug delivery for 5-8 days. Reinstatement of alcohol seeking was then determined after exposure to intermittent footshock (0.8 mA; 10 min) in different groups of rats that were pretreated with CRF receptor antagonists or underwent adrenalectomy (ADX) to remove endogenous corticosterone from the body. The CRF receptor antagonists, d-phe-CRF (0.3 or 1.0 microg; ICV) and CP-154,526 (15, 30 or 45 mg/kg; IP) attenuated footshock-induced reinstatement of alcohol seeking in a dose dependent manner. In contrast, the removal of circulating corticosterone by ADX had no effect on footshock stress-induced reinstatement of alcohol-taking behavior. In addition, the prevention of the footshock-induced rise in corticosterone while maintaining basal levels of the hormone by providing adrenalectomized rats with corticosterone pellets (50 mg/kg per day), had no effect on stress-induced reinstatement. These data suggest that CRF contributes to stress-induced relapse to alcohol seeking via its actions on extra-hypothalamic sites. The present data, and previous data with heroin- and cocaine-trained rats, point to a general role of CRF in relapse to drugs induced by stressors.