The effects of lamotrigine on alcohol seeking and relapse

Lamotrigine is a clinically used drug, which inhibits Na⁺ channel activity that in turn reduces glutamate release. Its downstream activity on other neurotransmitter systems such as serotonergic and dopaminergic has also been reported. Since both glutamate and monoamines might be involved in alcohol craving and relapse, our aim was to examine the effects of lamotrigine on alcohol seeking and relapse-like drinking behaviour. Thus, lamotrigine (5 and 15 mg/kg) was tested in two behavioural models for alcohol seeking and relapse – the model of cue-induced reinstatement of alcohol-seeking behaviour and the alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats. Administration of 5 mg/kg of lamotrigine caused a significant decrease of cue-induced reinstatement of alcohol-seeking behaviour. The ADE was significantly reduced with both doses tested. However, the highest dose of lamotrigine produced sedation. The ability of lamotrigine to reduce alcohol seeking as well as relapse-like drinking behaviour provides further support for the proposed involvement of the glutamatergic and dopaminergic/serotonergic systems in alcohol craving and relapse, hence suggesting a good rationale for pharmacological intervention that may reduce craving and relapse in alcohol dependent patients.     

mGlu1 receptor blockade attenuates cue- and nicotine-induced reinstatement of extinguished nicotine self-administration behavior in rats

Glutamatergic neurotransmission is believed to be critically involved in the acquisition and maintenance of drug addiction. The present study evaluated the role of metabotropic glutamate (mGlu) 1 receptors in the reinstatement of nicotine-seeking behavior. Rats were trained to nose-poke to receive response-contingent intravenous infusions of nicotine (0.01 mg/kg/infusion, free base). Following the subsequent extinction phase, reinstatement tests were conducted in animals that were exposed either to response-contingent presentations of the nicotine-associated discrete light cues or to non-contingent nicotine priming injection (0.3mg/kg, s.c., salt) just prior to the test session. In a separate experiment, rats were subjected to the nearly identical response-reinstatement procedure but operant responding was established using food pellets instead of nicotine infusions. Pretreatment with the mGlu1 receptor antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) significantly inhibited cue-induced reinstatement of nicotine-seeking behavior (5 and 10, but not 2.5 mg/kg). EMQMCM (5 mg/kg) also prevented nicotine priming-induced reinstatement of nicotine-seeking behavior. At the highest tested dose only (10 mg/kg), EMQMCM attenuated cue-induced reinstatement of food-seeking behavior. Taken together with the previous reports, the present findings further suggest that blockade of mGlu1 receptors may be beneficial for preventing relapse to tobacco smoking in nicotine-dependent individuals.     

Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats

Rationale and objectives We and others have shown that a stressor commonly used in laboratory studies, intermittent footshock, reinstates alcohol seeking in a rat relapse model. The effects of more ethologically relevant stressors on reinstatement have not been examined. Here, we characterized the effects of social defeat (a naturalistic stressor) or a cue associated with the defeat experience on reinstatement of alcohol seeking. We also examined the effect of unconditioned and conditioned social defeat on alcohol self-administration.Methods Rats were trained to self-administer alcohol (12% w/v, 1 h day⁻¹), and after stable responding, one group of animals received five exposures to social defeat paired with peppermint odor prior to daily self-administration sessions. After three more self-administration sessions, these rats were tested for the effects of the peppermint odor cue on self-administration. In another group of rats, the effects of three daily exposures to social defeat paired with peppermint odor on extinction of responding were examined. After further extinction sessions, the effect of the odor cue on reinstatement was tested in these animals. The acute effect of social defeat on reinstatement was examined in another group of animals.Results Acute exposure to social defeat decreased alcohol self-administration, reduced rates of responding during extinction, and did not reinstate alcohol seeking. Exposure to a discrete odor cue previously paired with social defeat decreased alcohol self-administration but induced modest reinstatement of alcohol seeking.Conclusions Results provide the first demonstration of reinstatement of alcohol seeking by a cue paired with social defeat and are also in agreement with previous findings on the suppressive effect of social defeat stress on alcohol self-administration.     

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.     

Alprazolam and oxazepam block the cue-induced reinstatement of extinguished cocaine seeking in rats

Rationale  We have previously reported that pretreatment with benzodiazepines reduces intravenous cocaine self-administration in rats. Objective  This experiment was designed to investigate whether or not benzodiazepines would also inhibit the reinstatement of cocaine seeking induced by the presentation of a conditioned reinforcer. Materials and methods  Adult male rats were implanted with jugular catheters and trained to self-administer cocaine (0.25 mg/kg/infusion) during daily 2-h sessions. During training, cocaine delivery was paired with the presentation of a tone and the illumination of a houselight. Once a stable baseline of cocaine self-administration was observed, lever pressing was extinguished to less than 20% of baseline rates. During reinstatement testing, responding resulted in the presentation of the conditioned reinforcer (i.e., the houselight and tone previously paired with self-administered cocaine). Results  The response-contingent presentation of the conditioned reinforcer reliably reinstated cocaine seeking. Pretreatment with alprazolam (2 or 4 mg/kg, ip) or oxazepam (20 or 40 mg/kg, ip) reversed the conditioned reinforcer-induced reinstatement of extinguished cocaine-seeking behavior at doses that did not reliably affect the conditioned reinforcer-induced reinstatement of extinguished food seeking, suggesting that benzodiazepines may not have reduced reinstatement responding due to non-specific reductions in behavior. Conclusions  These data suggest that benzodiazepines may be useful in blocking the ability of environmental cues to stimulate cocaine seeking. This work was supported in part by USPHS grant DA06013 from the National Institute on Drug Abuse.     

Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP

Relapse to alcohol use after periods of abstinence is a hallmark behavioral pathology of alcoholism and a major clinical problem. Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate relapse to alcohol-seeking behavior but the molecular mechanisms of this potential therapeutic effect remain unexplored. The extracellular signal-regulated kinase (ERK(1/2)) pathway is downstream of mGluR5 and has been implicated in addiction. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior, and its reduction by an mGluR5 antagonist, is associated with changes in ERK(1/2) activation in reward-related limbic brain regions. Selectively-bred alcohol-preferring (P) rats were trained to lever press on a concurrent schedule of alcohol (15% v/v) vs. water reinforcement. Following 9 days of extinction, rats were given an additional extinction trial or injected with the mGluR5 antagonist MPEP (0, 1, 3, or 10mg/kg) and tested for cue-induced reinstatement. Brains were removed 90-min later from the rats in the extinction and MPEP (0 or 10mg/kg) conditions for analysis of p-ERK(1/2), total ERK(1/2), and p-ERK(5) immunoreactivity (IR). Cue-induced reinstatement of alcohol-seeking behavior was associated with a three to five-fold increase in p-ERK(1/2) IR in the basolateral amygdala and nucleus accumbens shell. MPEP administration blocked both the relapse-like behavior and increase in p-ERK(1/2) IR. p-ERK(1/2) IR in the central amygdala and NAcb core was dissociated with the relapse-like behavior and the pharmacological effect of mGluR5 blockade. No changes in total ERK or p-ERK(5) were observed. These results suggest that exposure to cues previously associated with alcohol self-administration is sufficient to produce concomitant increases in relapse-like behavior and ERK(1/2) activation in specific limbic brain regions. Pharmacological compounds, such as mGluR5 antagonists, that reduce cue-induced ERK(1/2) activation may be useful for treatment of relapse in alcoholics that is triggered by exposure to environmental events.     

Neurobehavioral effects of alcohol in AMPA receptor subunit (GluR1) deficient mice

Of the ionotropic glutamatergic receptors, the NMDA receptor is clearly implicated in the acute and chronic effects of ethanol; however, the role of the AMPA receptor in mediating the effects of ethanol in vivo is as yet unclear. Using mice deficient in the AMPA receptor subunit GluR1 (GluR1-/- mice), we investigated whether the AMPA receptor had a significant role in mediating the effects of ethanol. GluR1-/- mice showed greater locomotor activity in a novel environment, but by the fifth day of repeated testing their activity was the same as that of wild-type mice. In contrast to their enhanced locomotor activity, on an accelerating rotarod GluR1-/- mice performed consistently worse than wild-types. With regard to the effects of ethanol on motor responses, GluR1-/- mice did not differ significantly from wild-type mice in ethanol's sedative or incoordinating effects. However, the GluR1-/- mice were insensitive to the hypothermic effects of a hypnotic dose of ethanol in contrast to wild-types; this effect was dissociable from the hypnotic effects of ethanol. Further, tolerance to ethanol developed equally for GluR1-/- mice versus wild-type mice. In terms of alcohol drinking behavior, compared to wild-types, GluR1-/- mice differed neither in the acquisition of voluntary ethanol consumption nor in stress-induced ethanol drinking, nor in the expression of an alcohol deprivation effect (ADE) which is used as a model of relapse-like drinking behavior. In summary, although the loss of a hypothermic effect of ethanol in GluR1-/- mice indicates a critical role for the AMPA receptors in this effect, the GluR1 subunit of the AMPA receptor does not seem to play a critical role in the etiology of alcohol dependence. However, changes observed in activity patterns may be related to the putative role of AMPA receptors in attention deficit hyperactivity disorder.     

Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats

Rationale It has been suggested that endocannabinoid mechanisms are involved in the control of ethanol consumption. Objectives The aims of the present study were (1) to evaluate the role of the endocannabinoid system in the control of operant ethanol self-administration and in the reinstatement of ethanol seeking, when induced by stress or conditioned stimuli and (2) to offer new insights on the specificity of such a role. Methods Rats were administered intraperitoneally with the selective cannabinoid CB₁ receptor antagonist, SR-141716A, 30 min before operant self-administration or reinstatement sessions. Two schedules of reinforcement, the fixed-ratio 1 (FR1) and the progressive ratio (PR), were used to study 10% (w/v) alcohol and 5.0% sucrose self-administration. NaCl (2% w/v) intake in sodium-depleted rats was studied only under the FR1 program. Results Treatment with SR-141716A (0.3–3.0 mg/kg) significantly attenuated FR1 alcohol self-administration and lowered the break point for ethanol under PR. SR-141716A also markedly inhibited the reinstatement of alcohol seeking elicited by presentation of cues predictive of drug availability. Conversely, the cannabinoid antagonist did not prevent the reinstatement of alcohol seeking induced by foot-shock stress. Lever pressing for sucrose under FR1 and PR schedules was also significantly decreased by SR-141716A treatment, whereas the drug modestly and only at the highest dose decreased 2% NaCl self-administration. Conclusions Results emphasize that endocannabinoid mechanisms play a major role in the control of ethanol self-administration and in the reinstatement of conditioned ethanol seeking. However, these effects extend to the control of operant behaviours motivated by natural rewards (i.e. sucrose). On the other hand, SR-141716A only weakly reduces NaCl self-administration in sodium-depleted rats, in which salt intake is largely controlled by homeostatic mechanisms. Overall, these observations demonstrate that the inhibition of operant behaviour following blockade of CB₁ receptors by SR-141716A is linked to a reduction of reward-related responding and is not related to drug-induced motor deficits.     

mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior

Pharmacological blockade of the type 5 metabotropic glutamate receptor (mGluR5) attenuates cue-induced reinstatement of ethanol-seeking behavior, yet the brain regions involved in these effects are not yet known. The purpose of the present study was to determine if local blockade of mGluR5 receptors in the basolateral amygdala (BLA) and/or the nucleus accumbens (NAc), two brain regions known to be involved in stimulus-reward associations, attenuate the reinstatement of ethanol-seeking behavior induced by ethanol-paired cues. As a control for possible non-specific effects, the effects of mGluR5 blockade in these regions on cue-induced reinstatement of sucrose-seeking were also assessed. Male Wistar rats were implanted with bilateral microinjection cannulae aimed at the BLA or NAc. Following recovery, animals were trained to self-administer ethanol (10% w/v) or 45 mg sucrose pellets on an FR1 schedule of reinforcement in 30 min daily sessions using a sucrose fading procedure. Following stabilization of responding, animals underwent extinction training. Next, animals received infusions of vehicle or the selective mGluR5 antagonist MTEP (3 μg/μl) into the BLA or NAc prior to cue-induced reinstatement testing sessions. mGluR5 blockade eliminated cue-induced reinstatement of alcohol — but not sucrose-seeking behavior. Results from this study indicate that mGluR5 receptors in the BLA and NAc mediate cue-induced reinstatement of ethanol-seeking behavior, and provide two potential neuroanatomical sites of action where systemically administered mGluR5 antagonists attenuate cue-induced reinstatement. These data are consistent with previous findings that cue-induced reinstatement of ethanol-seeking increases neuronal activity and glutamatergic transmission in these two regions.     

The CRF<Subscript>1</Subscript> receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats

Rationale and objectives Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF₁) receptor antagonist antalarmin. Materials and methods In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin’s effect on yohimbine-induced reinstatement of alcohol seeking. Results Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats. Conclusions These results suggest that extrahypothalamic CRF₁ receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF₁ receptor antagonists should be considered in alcohol addiction treatment.     

l-Cysteine reduces oral ethanol self-administration and reinstatement of ethanol-drinking behavior in rats

Our previous findings have shown that l-cysteine, a non essential amino acid, prevented ethanol (EtOH) induced conditioned place preference. The aim of the present study was to examine the effect of l-cysteine on the acquisition and maintenance of oral EtOH self-administration and on the reinstatement of EtOH-drinking behavior in Wistar rats. Rats were pretreated intraperitoneally with saline or l-cysteine (20 and 40 mg/kg) 30 min before each acquisition trial, in an operant nose-poking paradigm where they were given the opportunity to orally self-administer tap water or EtOH (5-10% v/v). Further, to evaluate if l-cysteine reduces the acquired oral EtOH self-administration, we carried out an independent experiment in which rats were trained to self-administer EtOH (10%); after all groups of rats developed similarly stable oral EtOH self-administration, the effect of l-cysteine (0, 40, 60, 80 and 100 mg/kg) was tested. An additional group of rats was pretreated with saline or l-cysteine (80 mg/kg) and tested on reinstatement after EtOH extinction and, at the end of last reinstatement session, were utilized to measure blood and brain EtOH levels. The animals that had access to EtOH solution discriminated between the active and inactive nose-pokes and showed rates of active nose-pokes significantly higher than the tap water group. Furthermore, rats self-administering EtOH (10%) also demonstrated extinction behavior and gradually reinstated active nose-poke responding when EtOH was reintroduced. l-cysteine reduced both the acquisition and maintenance of oral EtOH self-administration. The reduced reinstatement of EtOH-drinking behavior was paralleled by a significant reduction of EtOH intake and correlated with blood and brain EtOH levels. The efficacy of l-cysteine on the various phases of alcohol drinking in rats, could represent an interesting pharmacological approach and could open a new line of research for the development of therapies to reduce EtOH intake in alcoholic patients.     

Cadmium-induced changes in Per 1 and Per 2 gene expression in rat hypothalamus and anterior pituitary: effect of melatonin

Chronic cadmium (Cd) administration affects the circadian release of pituitary hormones in rats. To assess whether Cd modifies expression of two major clock genes, period (Per) 1 and Per 2, in the hypothalamic-pituitary unit and to what extent the changes could be prevented by melatonin, rats were exposed to CdCl(2) (5ppm in drinking water) with or without melatonin (3 microg/mL drinking water) for 1 month and were killed at two time intervals, i.e. a the beginning of the rest span (09:00h) and at the middle of the activity span (01:00h). Hypothalamic and pituitary mRNA levels encoding Per 1 and Per 2 were measured by real-time PCR analysis. Cd treatment decreased expression of hypothalamic Per 1 gene at both time intervals, of hypothalamic Per 2 gene at 01:00h, and of adenohypophysial Per 1 and Per 2 genes at 09:00h. Melatonin administration counteracted most of the effects of Cd and augmented hypothalamic Per 2, and adenohypophysial Per 1 and Per 2 gene expression. The results indicate that Cd administered chronically in the drinking water to rats affected expression of clock genes in the hypothalamic-pituitary unit, an effect prevented by melatonin.     

Effects of triazolam on drinking in baboons with and without an oral self-administration history: a reinstatement phenomenon

In a test of the reinforcing efficacy of triazolam under an oral drug self-administration procedure, three baboons consumed higher volumes of triazolam than of vehicle. Although these results suggested that triazolam was serving as a reinforcer, the unconditioned effect of triazolam itself on drinking remained unclear. Therefore, the effect of pretreatment with triazolam on consumption of a nondrug fluid was assessed in sessions that were otherwise identical to oral drug self-administration sessions. Following oral pretreatment with triazolam (0.6–19.2 mg total dose), there was a dose-dependent increase in drinking, suggesting that triazolam increased fluid consumption per se. However, subsequent manipulations showed that following pretreatment with triazolam, there was no systematic change in tap water consumption from the regular drinking spout and that the dipsogenic effect of pretreatment with triazolam was not specific to a particular fluid; however, the effect was specific to prior experience with the oral self-administration procedure. Thus, the dose-related increase in consumption from the drinkometer spout following triazolam pretreatment most likely is explained as the priming or reinstatement of an operant that previously had produced drug reinforcement, even though extinction (i.e., substitution of the drug vehicle) was in effect.This research was supported, in part, by National Institute on Drug Abuse Contract 271-92-7204 and Grant DA-04133. Portions of these data were presented at the meetings of the College on Problems of Drug Dependence, Palm Beach, Fla., 1994.     

Differential ability of D1 and D2 dopamine receptor agonists to induce and modulate expression and reinstatement of cocaine place preference in rats

Rationale D1-Like agonists are self-administered by drug-naive animals, whereas D2-like agonists reinstate cocaine-seeking behavior, but the rewarding and reinstating effects of D1- and D2-like agonists in pavlovian-based conditioned place preference are equivocal. Objective To compare the ability of D1 and D2 agonists to produce conditioned place preference with their modulation of expression and reinstatement of an established cocaine place preference. Methods Using an unbiased procedure, we measured the place preference induced by the D1 receptor agonist SKF 81297 and the D2/D3 receptor agonist quinpirole in drug-naive or cocaine-exposed rats. The rewarding effects of the D1 agonists SKF 82958, ABT-431, A-77636, and the D2/D3 receptor agonist 7-OH-DPAT were also tested. Additionally, we tested the ability of SKF 81297 and quinpirole to modulate expression and reinstatement of an established cocaine place preference. Results The D1 receptor agonists SKF 81297, SKF 82958, and ABT-431 produced dose-dependent conditioned place preferences, whereas A-77636 produced only place aversion, and the D2/D3 agonists quinpirole and 7-OH-DPAT were without effect in drug naive rats. In cocaine-treated rats, SKF-81297-induced place preference was reduced, whereas quinpirole-induced place preference was revealed. Pretreatment using either D1 or D2/D3 agonists blocked expression of an established cocaine place preference, but only the D1 agonist SKF 81297 and cocaine dose-dependently reinstated an extinguished cocaine place preference, whereas the D2/D3 agonist quinpirole induced place aversion but failed to alter cocaine-induced reinstatement. Conclusions D1, but not D2/D3, agonists mediate rewarding effects and reinstatement of cocaine place preference, but the reinstating effects differ markedly from self-administration paradigms.     

Pharmacologically targeting the P2rx4 gene on maintenance and reinstatement of alcohol self-administration in rats

Genetic studies indicate that alcohol consumption associates with expression of the P2rx4 gene, a gene that codes for the P2X₄ receptor. This receptor is a subtype in the purinergic system of ligand-gated ion channels that when activated exerts excitatory effects in CNS. P2X₄ function is inhibited by alcohol and P2X₄ receptors are modulated positively by the antiparasitic agent, ivermectin. Two experiments were performed to test the ability of ivermectin to alter the behavioral effects of alcohol in rats. After alcohol exposure was achieved via the “drinking in the dark” procedure, separate groups of Sprague-Dawley rats were trained to lever press for either alcohol (10% ethanol/2% sucrose) or sucrose (3%) solutions in operant chambers. Rats were tested for maintenance of operant self-administration under a progressive ratio condition (Experiment 1) and for reinstatement of extinguished responding induced by solution presentation (Experiment 2) after ivermectin (0; 1-10 mg/kg; IP) administration. Ivermectin decreased the amount of work that the animal performed to obtain reinforcers in the maintenance study, particularly in the group reinforced with alcohol, and tended to decrease reinstated lever press responding. Conditioned approach behavior (head entries) was significantly reduced by ivermectin in both experiments. Reduction in motor activity was seen during the longer maintenance sessions but not in the shorter reinstatement sessions. Results suggest some support for ivermectin-like drugs as potential treatment agents for alcohol dependence. Caution is warranted due to modest specificity on behavior reinforced by alcohol, some reduction in general activity levels, and the lack of dose-response effects.     

Ethanol elimination rates in mice: Effects of gender,nutrition, and chronic ethanol treatment

Twenty male and 20 female mice of a heterogeneous stock were assigned to each of three groups. One group was administered ethanol in a liquid diet for 9 days, a second group was fed an isocalorically controlled diet containing no ethanol for the same length of time, and the third group was fed standard lab chow. Each animal was injected with a dose of ethanol equal to 3.5 g/kg body weight at the time corresponding to 6 hr post-withdrawal for the ethanol-treated group. Blood ethanol elimination rates were determined at 1, 2, and 3 hr post-injection. Neither gender, nutritional state, nor chronic ethanol treatment was found to affect ethanol elimination rates.     

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 μg, 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.     

CB1 receptors regulate alcohol-seeking behavior and alcohol self-administration of alcohol-preferring (P) rats

Rationale

The endogenous cannabinoid (CB) system mediates a number of behaviors associated with drug-seeking and drug self-administration. In this study the effects of CB1 receptor manipulations on operant ethanol (EtOH) responding during EtOH-seeking, EtOH-relapse as well as on-going EtOH self-administration were determined.

Methods

Alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages without access to EtOH or operant chambers. Rats were then returned to the operant chambers for testing of EtOH-seeking behavior (no EtOH present) for 4 sessions. After a week in their home cages following the EtOH-seeking test, rats were returned to the operant chambers with access to EtOH and water (relapse). Rats were then maintained in the operant chambers for daily 1-h sessions with access to 15% EtOH and water for several weeks.

Results

The CB1 receptor antagonist (SR141716A), at doses of 1 and 2 mg/kg, i.p. reduced EtOH-seeking and transiently reduced EtOH self-administration during relapse and maintenance. Conversely, treatment with the CB1 receptor agonist CP 55, 940, at doses of 1 and 10 μg/kg i.p., increased EtOH-seeking and EtOH self-administration during relapse.

Conclusions

The results of this study demonstrate that activation of CB1 receptors are involved in regulating EtOH-seeking as well as the reinforcing effects of EtOH under relapse and on-going self-administration conditions.     

Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans

Rationale: Data in laboratory animals suggest that D₁ receptor agonists may have potential utility for the treatment of cocaine abuse. Objective: The effects of ABT-431, a selective agonist at the dopamine D₁ receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. Method: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4 mg IV) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus $5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. Results: ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of “High,”“Stimulated,” dose liking, estimates of dose value, “Quality,” and “Potency.” Furthermore, there was a trend for ABT-431 (4 mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. Conclusions: These data suggest that D₁ agonists may have potential utility for the treatment of cocaine abuse. Received: 18 August 1998/Final version: 16 October 1998     

Cannabinoid CB1 receptors mediate the effects of corticotropin-releasing factor on the reinstatement of cocaine seeking and expression of cocaine-induced behavioural sensitization

BACKGROUND AND PURPOSE

The endocannabinoid and corticotropin-releasing factor (CRF) systems have been implicated in several long-lasting behavioural effects of prior cocaine experience. The present experiments were designed to probe functional interactions between endocannabinoids and CRF by testing the role of cannabinoid CB₁ receptors in cocaine-related behaviours induced or mediated by CRF.

EXPERIMENTAL APPROACH

In Experiment 1, rats trained to self-administer cocaine were pretreated with the CB₁ receptor antagonist, AM251 (0, 10, 100 or 200 µg, i.c.v.), before tests for reinstatement in response to CRF (0, 0.5 µg, i.c.v.), intermittent footshock stress (0, 0.9 mA) or cocaine (0, 10 mg·kg⁻¹, i.p.). In Experiment 2, rats pre-exposed to cocaine (15–30 mg·kg⁻¹, i.p.) or saline for 7 days were pretreated with AM251 (0, 10 or 100 µg, i.c.v.) before tests for locomotion in response to CRF (0.5 µg, i.c.v.), cocaine (15 mg·kg⁻¹, i.p.) or saline (i.c.v.).

KEY RESULTS

Pretreatment with AM251 selectively interfered with CRF-, but not footshock- or cocaine-induced reinstatement. AM251 blocked the expression of behavioural sensitization induced by challenge injections of both CRF and cocaine.

CONCLUSIONS AND IMPLICATIONS

These findings reveal a mediating role for CB₁ receptor transmission in the effects of CRF on cocaine-related behaviours.