Acute pain-related depression of operant responding maintained by social interaction or food in male and female rats.

RATIONALE: Clinically relevant pain is often associated with functional impairment and behavioral depression, including depression of social behavior. Moreover, recovery of function is a major goal in pain treatment. We used a recently developed model of operant responding for social interaction in rats to evaluate the vulnerability of social behavior to an experimental pain manipulation and the sensitivity of pain-depressed social behavior to treatment with clinically effective analgesics. METHODS: Sprague-Dawley male and female rats were trained to lever press for social access to another rat, and responding was evaluated after treatment with (a) intraperitoneal injection of dilute lactic acid (IP acid; 0.18-5.6%) administered alone as a visceral noxious stimulus, (b) the mu-opioid receptor (MOR) agonist morphine (0.32-10 mg/kg) or nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (10 mg/kg) administered alone, or (c) morphine or ketoprofen administered before IP acid. For comparison, the same treatments were evaluated in separate rats trained to lever press for food delivery. RESULTS: Both IP acid alone and morphine alone more potently decreased responding maintained by social interaction than by food, whereas ketoprofen did not affect responding for either reinforcer. In general, analgesics were most effective to rescue operant responding when relatively low IP acid concentrations produced significant but submaximal behavioral depression; however, morphine was not effective to rescue responding for social interaction. CONCLUSIONS: Operant responding maintained by social interaction was more sensitive to pain-related disruption and less responsive to opioid analgesic rescue than food-maintained operant responding. Social behavior may be especially vulnerable to depression by pain states.

Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice.

We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 × C57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 × D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression.

Effect of pharmacological manipulations of neuropeptide Y and corticotropin-releasing factor neurotransmission on incubation of conditioned fear.

We recently developed a procedure to study fear incubation in which rats given 100 tone-shock pairings over 10 days show low fear 2 days after conditioned fear training and high fear after 30 or 60 days. Here, we studied the role of the stress-related peptides, neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), in fear incubation. We gave rats either 10 or 100 30-s tone-0.5-s footshock pairings over 1 day (short training) or 10 days (long training) and then assessed tone-cue-induced conditioned suppression of lever responding 2 days after short training or 2 days and 1 month after long training. Prior to testing, we injected NPY (5-10 microg, i.c.v.), the NPY Y1 receptor antagonist BIBO3304 (20-40 microg, i.c.v.), the NPY Y2 receptor antagonist BIIE0246 (2.5-5 mg/kg s.c.), the non-selective CRF receptor antagonist D-Phe CRF(12-41) (10 microg, i.c.v.), or the CRF1 receptor antagonist MTIP (10-20 mg/kg s.c.). Conditioned suppression after long training was higher after 1 month than after 2 days (fear incubation); conditioned suppression was robustly expressed 2 days after short training (non-incubated fear). Both incubated and non-incubated fear responses were attenuated by NPY. In contrast, D-Phe CRF(12-41), MTIP, BIBO3304, or BIIE0246 had no effect on conditioned fear at the different time points. Results confirm previous work on the potent effect of exogenous NPY administration on conditioned fear, but the negative results with BIBO3304 and BIIE0246 question whether endogenous NPY contributes to incubated (or non-incubated) fear. Results also suggest that CRF receptors are not involved in cue-induced fear in the conditioned suppression procedure.

Toilet reading habits in Israeli adults.

Although toilet reading (TR) is a common habit, the effect of TR on bowel movements is neglected in the medical literature. Our hypothesis was that TR provides a distraction and acts as an unconscious relaxation technique and allows an easier defecation process. The aim of this study was to assess how common is TR and to map the reading/playing toilet habits in the Israeli adult population. In addition, we aimed to explore a possible connection between TR and the nature of bowel habits in general and constipation and haemorrhoids in particular. Five hundred adults who represent the diverse demographic backgrounds have been asked to fill an anonymous short questionnaire. The subjects were questioned regarding their demographic details, their TR and playing habits, their bowel habits, whether they suffer from haemorrhoids and whether they use some sort of faecal softener. We found that TR is common and involves 52.7% of the population. Males, younger age, secular population, higher education level and white collar workers compose the TR profile. Although toilet readers spent significantly more time in the toilets, no differences were noted for the type or frequency of stools. Nevertheless, the TR group considered themselves to be less constipated (8.0%vs 13.7%) and had more haemorrhoids (23.6%vs 18.2%). These differences, however, were not significant. Toilet reading is a common and benign habit. It is involved with a longer time spent in the toilet. It seems to be more for fun and not necessarily to solve or due to medical problems.

Neuroplasticity in the mesolimbic dopamine system and cocaine addiction.

The main characteristics of cocaine addiction are compulsive drug use despite adverse consequences and high rates of relapse during periods of abstinence. A current popular hypothesis is that compulsive cocaine use and cocaine relapse is due to drug-induced neuroadaptations in reward-related learning and memory processes, which cause hypersensitivity to cocaine-associated cues, impulsive decision making and abnormal habit-like learned behaviours that are insensitive to adverse consequences. Here, we review results from studies on the effect of cocaine exposure on selected signalling cascades, growth factors and physiological processes previously implicated in neuroplasticity underlying normal learning and memory. These include the extracellular signal-regulated kinase (ERK) signalling pathway, brain-derived neurotrophic factor (BDNF), glutamate transmission, and synaptic plasticity (primarily in the form of long-term potentiation and depression, LTP and LTD). We also discuss the degree to which these cocaine-induced neuroplasticity changes in the mesolimbic dopamine system mediate cocaine psychomotor sensitization and cocaine-seeking behaviours, as assessed in animal models of drug addiction. Finally, we speculate on how these factors may interact to initiate and sustain cocaine psychomotor sensitization and cocaine seeking.

Differential effects of the hypocretin 1 receptor antagonist SB 334867 on high-fat food self-administration and reinstatement of food seeking in rats.

BACKGROUND AND PURPOSE: Many studies have demonstrated a role of hypocretin 1 (orexin 1) receptors in home-cage food consumption in rodents. However, the role of these receptors in operant food self-administration or relapse to food seeking in animal models is unknown. EXPERIMENTAL APPROACH: In Experiment 1, we trained food-restricted rats (16-20 g per day) to lever press for high-fat (35%) pellets (3-6 h per day, every other day). We then tested the effect of the hypocretin 1 receptor antagonist SB 334867 (10, 20 mg kg(-1), i.p) on pellet self-administration. In Experiment 2, we trained rats to self-administer the food pellets, and following extinction of the food-reinforced responding, we tested the effect of hypocretin 1 (3 and 6 mug, i.c.v) on reinstatement of food-seeking and the effect of SB 334867 on this reinstatement. In Experiment 3, we tested the effect of SB 334867 on reinstatement induced by non-contingent pellet exposure (pellet-priming) or the pharmacological stressor yohimbine (2 mg kg(-1), i.p). KEY RESULTS: SB 334867 attenuated high-fat pellet self-administration. In contrast, SB 334867 had no effect on reinstatement of lever presses induced by hypocretin 1, pellet-priming or yohimbine. CONCLUSIONS AND IMPLICATIONS: These data indicate that during dieting, hypocretin 1 receptors contribute to operant high-fat pellet self-administration, but not to relapse to food seeking induced by acute re-exposure to the food itself or by the induction of a stress-like state.

Increased vulnerability to nicotine self-administration and relapse in alcohol-naive offspring of rats selectively bred for high alcohol intake.

The prevalence of smoking in human alcoholics is substantially higher than in the general population, and results from twin studies suggest that a shared genetic vulnerability underlies alcohol and nicotine addiction. Here, we directly tested this hypothesis by examining nicotine-taking behavior in alcohol-naive offspring of alcohol-preferring (P) rats and alcohol-nonpreferring (NP) rats that had been selectively bred for high and low alcohol intake. The self-administration of intravenous nicotine (0.015-0.060 mg/kg per infusion) in P rats was more than twice than that of NP rats. Nicotine seeking induced by reexposure to nicotine cues in extinction tests was also substantially greater in P rats than in NP rats. In a subsequent relapse test, priming nicotine injections reinstated drug seeking in P rats but not NP rats. P rats also self-administered higher amounts of oral sucrose (1-20%) than NP rats, a finding consistent with previous reports. In contrast, self-administration of intravenous cocaine (0.1875-1.125 mg/kg per infusion) was remarkably similar in the P and NP rats; however, P-NP differences in cocaine seeking emerged in subsequent extinction and cocaine priming-induced reinstatement tests. In both cases, lever responding was higher in P rats than in NP rats. Thus, alcohol-naive offspring of rats genetically selected for high alcohol intake are highly susceptible to nicotine self-administration and relapse, and this susceptibility is not likely caused by general reward deficits in NP rats. The present findings provide experimental evidence for the hypothesis that a shared genetic determinant accounts for the co-abuse of nicotine and alcohol.

Long-term stability of an area-reversible atom-interferometer Sagnac gyroscope.

We report the first demonstration of a matter-wave interference gyroscope that meets both the short-term noise and long-term stability requirements for high accuracy navigation. This performance level resulted from implementation of a novel technique to precisely reverse the input axis of the gyroscope.

Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats.

RATIONALE AND OBJECTIVES: Alpha-2 adrenoceptors are known to be involved in stress-induced reinstatement of heroin and cocaine seeking in laboratory animals. Here, we studied the involvement of these receptors in stress-induced reinstatement of alcohol seeking by using an agonist (lofexidine) and an antagonist (yohimbine) of these receptors, which inhibit and activate, respectively, noradrenaline transmission. We also tested the effect of lofexidine and yohimbine on alcohol self-administration. Lofexidine is used clinically for treating opiate withdrawal symptoms and yohimbine induces stress-like responses in humans and non-humans. METHODS: Rats were trained to self-administer alcohol (12% w/v, 1 h/day) and after extinction of the alcohol-reinforced behavior, they were tested for the effect of lofexidine (0, 0.05 and 0.1 mg/kg, IP) on reinstatement of alcohol seeking induced by intermittent footshock stress (10 min, 0.8 mA) or for the effect of yohimbine (0, 1.25 and 2.5 mg/kg, IP) on reinstatement of alcohol seeking. Other rats were trained to self-administer alcohol, and after stable responding, the effects of lofexidine and yohimbine on alcohol self-administration were determined. RESULTS: Pretreatment with lofexidine (0.05 mg/kg and 0.1 mg/kg) attenuated stress-induced reinstatement of alcohol seeking and also decreased alcohol self-administration. In contrast, yohimbine pretreatment potently reinstated alcohol seeking after extinction and also induced a profound increase in alcohol self-administration. CONCLUSIONS: Results indicate that activation of alpha-2 adrencoceptors is involved in both stress-induced reinstatement of alcohol seeking and alcohol self-administration. To the degree that the present results are relevant to human alcoholism, alpha-2 adrencoceptor agonists should be considered in the treatment of alcohol dependence.

Effect of blockade of corticotropin-releasing factor receptors in the median raphe nucleus on stress-induced c-fos mRNA in the rat brain.

Using a rat relapse model, we have shown that infusion of a corticotropin-releasing factor (CRF) receptor antagonist into the median raphe nucleus (MRN) blocks footshock stress-induced reinstatement of alcohol seeking in rats. The goal of the present study was to begin identifying brain sites potentially involved in this effect. For this purpose, we measured levels of c-fos mRNA in discrete nuclei of the rat brain following exposure to intermittent footshock, which was preceded by intra-MRN infusions of a CRF receptor antagonist, d-Phe CRF (0 or 50 ng). Exposure to intermittent footshock increased the expression of c-fos mRNA in a number of brain regions previously shown to be responsive to stressful stimuli. Pretreatment with d-Phe CRF in the MRN selectively attenuated the increases in c-fos mRNA induced by footshock in the central nucleus of the amygdala (CeA). These findings are consistent with previous data on the important role for the CeA in stress-induced reinstatement of drug seeking. These results also suggest that inhibition of CeA activity may contribute to the blockade of alcohol-seeking induced by footshock that we have observed following injections of d-Phe into the MRN.

Effect of experimenter-delivered and self-administered cocaine on extracellular beta-endorphin levels in the nucleus accumbens.

Beta-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of beta-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular beta-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on beta-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 microm) and was blocked by coadministration of SCH-23390 (10 microm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular beta-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in beta-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the beta-endorphin neurons within the arcuate nucleus-nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.

Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats.

RATIONALE AND OBJECTIVE: Alcohol and tobacco are often co-abused in humans and previous studies found that nicotine increases alcohol consumption in rats. Here, we studied whether nicotine would reinstate alcohol-taking behavior in drug-free rats and whether this effect would be enhanced by prior exposure to nicotine during alcohol self-administration training. METHODS: Rats were trained to press a lever for alcohol (12% w/v, 1 h/day), and following stable alcohol intake groups of rats ( n=11-12) were given daily vehicle or nicotine (0.2, 0.4 or 0.8 mg/kg, SC) injections just prior to the self-administration sessions for 10 days. Rats were then given 6 days of alcohol self-administration in the absence of nicotine and an additional 5-10 drug-free days during which lever presses were not reinforced (extinction). Subsequently, rats were tested for reinstatement of alcohol seeking following exposure to priming injections of vehicle or nicotine (0.4 mg/kg, SC). RESULTS: Nicotine increased alcohol self-administration in a dose- and time-dependent manner over the 10-day period. Nicotine also reinstated alcohol seeking after extinction of the alcohol-reinforced behavior, and this effect was strongly enhanced by prior nicotine exposure. CONCLUSIONS: The present data extend previous studies on the effect of nicotine on alcohol self-administration, and further indicate that nicotine is an effective stimulus for reinstatement of alcohol seeking during drug-free periods.

Effect of cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement, and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats.

Lever pressing during tests for resistance to extinction and cue-induced reinstatement of cocaine seeking in rats progressively increases over the first 2 months of withdrawal. In the present report, we investigated the generality of these findings in rats trained to self-administer sucrose, a non-drug reinforcer. We also examined whether the time-dependent changes in cocaine seeking correlate with the levels of the dopamine transporter (DAT) and tyrosine hydroxylase (TH) proteins in the amygdala, nucleus accumbens, prefrontal cortex and orbitofrontal cortex. Rats were trained to self-administer cocaine (0.5 mg/kg/i.v. infusion) or 10% sucrose (0.2 ml/infusion into a liquid drop receptacle) for 10 days (6 h/day); each reward delivery was paired with a tone+light cue. Tests for cocaine seeking were conducted following 1 or 15 reward-free days. On the test day, rats were initially tested for resistance to extinction during 6-7 60-min extinction sessions in the absence of the tone-light cue, until they reached the extinction criterion of less than 15 responses/60 min. Subsequently, rats were tested for cue-induced reinstatement during a 60-min session in which each lever press led to a contingent presentation of the tone-light cue. Lever pressing during the tests for reward seeking was significantly greater on day 15 than on day 1 following withdrawal from both cocaine and sucrose self-administration training. The levels of DAT, but not TH, were greater in the prefrontal cortex of cocaine-trained rats than in sucrose-trained rats on both days 1 and 15 of withdrawal. The levels of DAT and TH in other brain areas were not altered following withdrawal from cocaine or sucrose self-administration. These data suggest that the withdrawal can modulate reward seeking of both drug and non-drug reinforcers, and that alterations in DAT and TH levels in the brain regions examined do not mediate this effect.

The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol.

Using an animal model of drug relapse, we found that intermittent footshock stress reinstates alcohol seeking, an effect attenuated by the 5-HT reuptake blocker fluoxetine and by corticotropin-releasing factor (CRF) receptor antagonists. Here we studied the role of the 5-HT cell body region of the median raphe nucleus (MRN) and CRF receptors in this site in reinstatement of alcohol seeking. Rats were given alcohol in a two-bottle choice procedure (water vs alcohol) for 25 d and were then trained for 1 hr/d to press a lever for alcohol (12% w/v) for 23-30 d. Subsequently, lever pressing for alcohol was extinguished by terminating drug delivery for 5-9 d. Tests for reinstatement of alcohol seeking were then performed under extinction conditions. Intra-MRN infusions of 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] (a 5-HT1A agonist that decreases 5-HT cell firing and release) reinstated alcohol seeking. Reinstatement of alcohol seeking also was observed after intra-MRN infusions of low doses of CRF (3-10 ng), which mimicked the effect of ventricular infusions of higher doses of the peptide (300-1000 ng). Finally, intra-MRN infusions of the CRF receptor antagonist d-Phe CRF (50 ng) blocked the effect of intermittent footshock (10 min) on reinstatement. These data suggest that an interaction between CRF and 5-HT neurons within the MRN is involved in footshock stress-induced reinstatement of alcohol seeking.

Neurobiology of relapse to alcohol in rats.

Relapse to alcohol use after prolonged withdrawal periods is the major problem in the treatment of alcohol dependence in humans. However, until recently, relatively few preclinical studies concentrated on the elucidation of the neurochemical events underlying relapse to alcohol. In this article we will review recent data from studies in which alcohol-deprivation and reinstatement models were used to determine the mechanisms underlying relapse to alcohol in rats. In the alcohol-deprivation model, the intake of alcohol is determined after prolonged periods of forced abstinence in drug-experienced rats. In the reinstatement model, the ability of acute non-contingent exposure to drug or non-drug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies, which used these preclinical models, on the effect of specific pharmacological agents on relapse to alcohol seeking induced by re-exposure to alcohol and to alcohol-associated cues and by exposure to stress. Subsequently, we will describe potential neuronal circuits that may underlie relapse to alcohol. Finally, future directions and clinical implications of the study of relapse to alcohol in laboratory animals will be discussed briefly.

A cannabinoid mechanism in relapse to cocaine seeking.

Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction. The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system and has rewarding effects in preclinical models of drug abuse. We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.

Repeated lofexidine treatment attenuates stress-induced, but not drug cues-induced reinstatement of a heroin-cocaine mixture (speedball) seeking in rats.

Alpha-2 adrenoceptor agonists (lofexidine, clonidine) are used to alleviate short-term opioid withdrawal in humans. In rats, acute injections of these agents attenuate stress-induced reinstatement of heroin and cocaine seeking at time points that are beyond the acute drug withdrawal phase. Here, we studied whether exposure to lofexidine would attenuate reinstatement of a heroin-cocaine mixture (speedball) seeking induced by exposure to stress or to drug-associated cues. Rats were trained to lever press for speedball for 10 days, and the drug-reinforced behavior was then extinguished for 11 days in the presence (Experiment 1) or the absence (Experiment 2) of the drug cues. Subsequently, rats were tested for reinstatement of drug seeking after exposure to intermittent footshock stress (5-15 min; Experiment 1) or the drug cues (Experiment 2). Starting on day 7 of training, rats received daily injections of saline or lofexidine (0.1 or 0.2 mg/kg). Repeated lofexidine treatment significantly attenuated footshock-induced reinstatement, but did not alter drug cues-induced reinstatement of speedball seeking. In addition, lofexidine did not have a consistent effect on speedball self-administration and extinction behavior. Results extend previous reports with acute drug injections, indicating that lofexidine maintains its effect on stress-induced reinstatement after repeated treatment. The present data also suggest that the neurochemical events underlying stress- and drug cues-induced relapse are not identical.

Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats.

RATIONALE AND OBJECTIVES: Footshock stress reliably reinstates heroin seeking in rats, but the time course of the development of this effect following drug withdrawal is not known. Here we studied the effect of intermittent footshock stress on reinstatement of heroin seeking following different withdrawal periods (1-66 days). We also studied whether changes in corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) are correlated with this reinstatement after 1 day and 6 days of heroin withdrawal. METHODS: Rats were trained to self-administer heroin (9 h/day; 0.1 mg/kg per infusion) for 10 days. Tests for extinction behavior and footshock-induced reinstatement of heroin seeking were then conducted after 1, 6, 12, 25, or 66 days of heroin withdrawal. On the test day, rats were given five to ten 60-min extinction sessions until they reached the extinction criterion of less than 15 responses per 60 min on the lever previously associated with heroin. Rats were then exposed to intermittent foot-shock (0.8 mA; 10 min), and lever-pressing behavior was recorded for 120 min. RESULTS: Reinstatement of lever-pressing behavior by footshock followed an inverted U-shaped curve with maximal responding after 6 days and 12 days of heroin withdrawal. Surprisingly, foot-shock did not reinstate lever-pressing behavior on day 1 of withdrawal. Lever pressing during extinction, prior to exposure to footshock, also followed an inverted U-shaped curve, with higher responding after 6, 12, and 25 days of heroin withdrawal. Finally, compared with control groups not exposed to shock, CRF mRNA levels in response to footshock were increased in the CeA (day 1 of withdrawal) and the dorsal BNST (day 1 and day 6), but not in the ventral BNST. CONCLUSIONS: The duration of the heroin withdrawal period is an important factor in the manifestation of (1) footshock stress-induced reinstatement of heroin seeking and (2) extinction of the heroin-reinforced behavior. Finally, the time-dependent changes in footshock stress-induced reinstatement following withdrawal from heroin were not correlated with alterations in CRF mRNA in the CeA and BNST.

The role of corticotropin-releasing factor in drug addiction.

The goal of this article is to summarize available data examining the physiological significance of brain corticotropin-releasing factor (CRF) systems in mediating the behavioral and physiological effects of several classes of abused drugs, including opioid and psychostimulant drugs, alcohol and sedative hypnotics, nicotine, and cannabinoids. An initial discussion of CRF neurobiology is followed by consideration of the role of CRF in drug-induced activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, the behavioral effects of drugs (e.g., locomotor activity, anxiogenic-like responses), drug self-administration, drug withdrawal, and relapse to drug-seeking. Subsequently, neurochemical changes in brain CRF in response to acute and chronic drug exposure are examined. A major conclusion derived from the data reviewed is that extrahypothalamic brain CRF systems are critically involved in behavioral and physiological manifestations of drug withdrawal and in relapse to drug-taking behavior induced by environmental stressors. On the other hand, it appears that hypothalamic CRF, via its action on the HPA axis, is involved in the reinforcing effects of cocaine and alcohol, and the locomotor activating effects of psychostimulant drugs. These preclinical data may provide a rationale for the development of CRF-based pharmacotherapies for the treatment of compulsive drug use in humans.