Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D3 versus D2 dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01-0.1 mg/kg), the preferential D2 agonist, bromocriptine (1-10 mg/kg) and the selective D3 agonists, 7-OH-DPAT (0.003-0.1 mg/kg), PD 128907 (0.1-3 mg/kg), (+)3PPP (0.3-3 mg/kg), quinelorane (0.0001-0.003 mg/kg) and quinpirole (0.003-0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D3 but not D2 responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D2/D3 dopamine antagonists, haloperidol (0.1-0.4 mg/kg) and tiapride (10-60 mg/kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission.     

Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens

The opiate antagonist naltrexone suppresses ethanol-reinforced behavior in animals and decreases ethanol intake in humans. However, the mechanisms underlying these actions are not well understood. Experiments were designed to test the hypothesis that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine activity in the nucleus accumbens (NAcc). Simultaneous measures of the effects of naltrexone on dialysate dopamine levels in the NAcc and on operant responding for oral ethanol were used. Male Wistar rats were trained to self-administer ethanol (10-15%, w/v) in 0.2% (w/v) saccharin during daily 30 min sessions and were surgically prepared for intracranial microdialysis. Experiments began after reliable self-administration was established. Rats were injected with naltrexone (0.25 mg/kg, s.c.) or saline and 10 min later were placed inside the operant chamber for a 20 min waiting period with no ethanol available, followed by 30 min of access to ethanol. A transient rise in dialysate dopamine levels was observed during the waiting period, and this effect was not altered by naltrexone. Ethanol self-administration reliably increased dopamine levels in controls. Naltrexone significantly suppressed ethanol self-administration and prevented ethanol-induced increases in dialysate dopamine levels. Subsequent dose-effect analyses established that the latter effect was not merely a function of reduced ethanol intake but that naltrexone attenuated the efficacy of ethanol to elevate dialysate dopamine levels. These results suggest that suppression of ethanol self-administration by opiate antagonists is the result of interference with dopamine-dependent aspects of ethanol reinforcement, although possible additional effects via nondopaminergic mechanisms cannot be eliminated as a factor in opiate antagonist-induced reduction of ethanol intake.     

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Previous drug discrimination studies have elucidated the importance of gamma-aminobutyric acidA (GABAA), N-methyl-D-aspartate (NMDA) glutamate, and serotonin (5-HT) receptor systems in mediating the discriminative stimulus effects of ethanol. The present study used a three-choice operant drug discrimination procedure in an attempt to determine if salient GABAergic effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate pentobarbital (10.0 mg/kg; intragastrically (i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Stimulus substitution tests were conducted following the administration of allopregnanolone (1.0-17.0 mg/kg; intraperitoneally (i.p.)), diazepam (0.1-7.3 mg/kg; i.p.), midazolam (0.0056-17.0 mg/kg; i.p.), dizocilpine (0.01-0.56 mg/kg; i.p.), phencyclidine (1.0-5.6 mg/kg; i.p.), CGS 12066B (3-30 mg/kg; i.p.), RU 24969 (0.1-5.6 mg/kg; i.p.) and morphine (1 or 3.0 mg/kg; i.p.). Within the group, allopregnanolone and midazolam completely substituted (> 80%), and diazepam partly substituted (67%) for the discriminative stimulus effects of pentobarbital. Dizocilpine and phencyclidine partly substituted (58 and 57%, respectively) for ethanol without substantial pentobarbital-appropriate responding. RU 24969, CGS 12066B and morphine did not result in complete substitution for either ethanol or pentobarbital, although RU 24969 resulted in partial (68%) pentobarbital substitution. The ability to train the present three-choice discrimination in rats indicates that the discriminative stimulus effects of 10.0 mg/kg pentobarbital were separable from those of 2.0 g/kg ethanol. The results suggest that the pharmacological effects of ethanol, which can control behavior, may seemingly be modified by training conditions (two-versus three-choice discrimination procedures), to the extent that a receptor system prominently linked to the behavioral activity of ethanol (i.e. GABAA) appears no longer to be involved in the interoceptive effects of the drug.     

Fluvoxamine effects on concurrent ethanol- and food-maintained behaviors.

In previous studies, the selective serotonin reuptake inhibitor fluvoxamine preferentially reduced responding for ethanol compared with responding for food under conditions in which each was available alone in separate groups or in the same subjects under a multiple schedule in which baseline response rates were matched. The impact of providing concurrent access to food on pharmacological effects on ethanol self-administration remains largely unexplored. In this study, acute doses of fluvoxamine (3.0-17.8 mg/kg) were administered 30 min before the experimental session to Lewis rats responding under a concurrent fixed-ratio, fixed-ratio schedule of ethanol and food presentation. Ratios for food were adjusted for each subject to provide matched rates of food and ethanol reinforcement across the 30-min session. Although the number of ethanol and food deliveries did not significantly differ under baseline conditions, response rates did differ. Following fluvoxamine administration, responding for food was decreased more than responding for ethanol. This differential effect did not appear to be related to response rate or fixed-ratio size. Thus, the selectivity of fluvoxamine on ethanol- versus food-maintained responding depends on the context in which the behavior occurs. Such results may help explain inconsistencies between preclinical results and those in humans, and could provide insight into the behavioral determinants of pharmacological effects on ethanol self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Human methadone self-administration: Effects of diazepam pretreatment.

The effect of diazepam on methadone self-administration was examined. Five methadone maintained patients with a history of benzodiazepine abuse were recruited, Patients were stabilized on 80 mg of methadone per day. After stabilization patients participated in methadone self-administration sessions. During each session, 128 presses (fixed ratio 128) of 1 button delivered 10 ml of 0.054 mg/ml methadone solution. The same number of button presses on a 2nd button delivered 10 ml of vehicle. Forty-five min prior to the self-administration session, 0 (placebo), 5, 10, or 20 mg per 70 kg body weight diazepam was administered. Ratings of drug liking, goodness, strength, and high were collected 5, 30, 60, 90, and 150 min after the end of the self-administration session. Diazepam pretreatment significantly decreased the amount of methadone consumed. The 10- and 20-mg diazepam doses significantly increased reports of good, like, strong, and high. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of gamma-aminobutyric acid agonists and N-methyl-D-aspartate antagonists on a multiple schedule of ethanol and saccharin self-administration in rats

Recently, it has been shown at both the cellular and behavioral levels that ethanol has effects on the N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)a receptor systems, leading to the possibility that the reinforcing effects of ethanol may be, at least partially, mediated via these receptor ionophores. In this study, a multiple schedule of ethanol and saccharin self-administration was used to study that possibility. Adult male Long-Evans rats were trained during 1-hr sessions to press on two different levers for 10% (w/v) ethanol and 0.1% (w/v) saccharin solutions, under an alternating 5-min, fixed-ratio-4 schedule of liquid availability. After training, tests were conducted with ethanol, NMDA antagonists and GABA agonists given before six consecutive sessions. Pretreatment with ethanol selectively decreased ethanol self-administration without altering saccharin self-administration. The competitive NMDA antagonist CPPene (D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid [SDZ EAA 494]) and the noncompetitive NMDA antagonist phencyclidine decreased both ethanol and saccharin self-administration. The GABA agonists pentobarbital and diazepam also failed to reduce ethanol self-administration, relative to saccharin. Although these results do not support the hypothesis that antagonism of the NMDA receptor system or activation of the GABA receptor system can selectively modify ethanol-reinforced responding, they identify important issues for designing the best strategies to be used to assess selective drug effects on ethanol self-administration.     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; i.p.), diazepam (0.3-10.0 mg/kg; i.p.) and pentobarbital (1.0-21.0 mg/kg; i.p.), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; i.p.), the 5-HT1 agonists TFMPP (0.3-5.6 mg/kg; i.p.) and RU 24969 (0.3-3.0 mg/kg; i.p.), and isopropanol (0.10-1.25 g/kg; i.p.). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT1-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.     

Intravenous self-administration of ethanol in beta-endorphin-deficient mice

Extensive research on both human alcoholics and in animal models of alcoholism has implicated the release of endogenous opioids in the consumption of ethanol. Various experiments using opioid antagonists have indicated that these drugs cause both humans and animals to decrease their consumption of ethanol. However, it remains unclear exactly which of the endogenous opioids mediates the rewarding effects of ethanol. The present experiment used intravenous self-administration of ethanol to determine whether beta-endorphin (BE)-deficient mice differed from wild-type (WT) mice in ethanol self-administration. The BE-deficient mice completely lack BE, but are otherwise similar to the WT mice. By using intravenous self-administration, we were able to rule out any ability of BE to mediate differences in ethanol consumption via palatability factors alone. Both types of mice were 7 generations backcrossed onto a C57BL/6J inbred strain background. During nine daily, 2-hr free-operant sessions, 14 BE-deficient and 17 WT mice could nosepoke for 75 mg/kg ethanol infusions delivered intravenously on an fixed-ratio 3 schedule with a 2-sec time-out after each reinforcer delivery. Reinforcer delivery occurred following nosepokes in only one of two holes. Contrary to what was expected, BE-deficient mice acquired selective operant responding for ethanol, whereas WT mice did not. Although the two genotypes did not differ in either operant or locomotor behavior during the first session, by the end of the nine sessions, BE deficient mice were reliably nosepoking for ethanol, whereas WT mice were not. These findings may indicate that BE is not essential for the postingestive reinforcing effects of ethanol in these animals.     

Blockade of the serotonin 5-ht2a receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model.

The serotonin 5-HT2A receptor (5-HT2AR) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT2AR antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in na?ve, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT2AR antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001–0.8 mg/kg ip) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (high extinction responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT2AR attenuates the incentive-motivational effects of cocaine-paired cues, particularly in high extinction responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuronal spike activity in the nucleus accumbens of behaving rats during ethanol self-administration

Many lines of evidence support the importance of the nucleus accumbens (NAC) for ethanol-reinforced behavior. The nature of the neuronal activity that occurs in this region during ethanol self-administration is not known. We recorded from ensembles of single-units primarily located within the shell of the NAC during operant responding for oral ethanol solutions by well-trained rats. Of 90 units recorded from seven sessions from seven rats, 41 (46%) did not exhibit significant changes in relation to the experimental events. Of the 49 units (54%) that did exhibit significant phasic changes, alterations in firing rate occurred in relation to the following experimental events: operant response (63%), tone stimulus (20%), and ethanol delivery (63%). In addition, changes in spike activity during the intervals between the three experimental events were noted in 33% of the units. Most units (55% of responsive units) responded to multiple experimental events. Thus different but overlapping populations of neurons in the NAC represent each event that occurs along the temporal dimension of a single trial performed to obtain ethanol reward. The data suggest that the NAC plays a crucial role in linking together conditioned and unconditioned internal and external stimuli with motor plans to allow for ethanol-seeking behavior to occur.     

AMPA receptors and motivation for drug: effect of the selective antagonist NBQX on behavioural sensitization and on self-administration in mice

A series of experiments was carried out in which the potency of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smallest dose of NBQX significantly reducing spontaneous or cocaine-induced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomotor response to a challenge dose of cocaine (16 mg/kg). NBQX reversed the sensitized response at 30 and 100 mg/kg. The pattern of results obtained leaves open the role that AMPA-receptors may have in the expression of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 micrograms per reinforcer) via intravenous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 micrograms) or halved (to 15 micrograms) the mice adapted lever pressing rates to maintain some constancy of self-dosing (but not at 7.5 micrograms per reinforcer) and when saline was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-administration of 30 micrograms reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifically antagonized the reinforcing effect of cocaine, as responding was similarly reduced on both the reinforced and the non-reinforced lever, nor did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor experiments and the self-administration experiments are discussed together, in terms of current hypotheses about glutamatergic mechanisms involved in motivation for drug.     

The opioid receptor antagonist nalmefene reduces responding maintained by ethanol presentation: preclinical studies in ethanol-preferring and outbred Wistar rats

Nalmefene, the 6-methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two-lever, fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin-maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose-dependent suppression of EtOH-maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose-dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10-min period, with little additional suppression occurring across the remainder of the 60-min period. Subcutaneous nalmefene was 3200- to 6400-fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH-motivated behavior and prevent relapse.     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

An investigation into the effects of 5-HT agonists and receptor antagonists on ethanol self-administration in the rat

Pharmacological manipulation leading to altered 5-HT function has been widely demonstrated to reduce ethanol intake in free choice tests. The aim of the present study was to examine the effects of a range of compounds known to influence 5-HT neurotransmission, including selective 5-HT receptor agonists and antagonists, on ethanol ingestion and maintained behaviour in an operant self-administration paradigm. Female Sprague-Dawley rats were trained to respond for 8% ethanol (v/v) in a 60-min test by a previously described technique. The number of responses and ethanol reinforcers (dipper deliveries), ethanol consumption (g/kg of body weight), and locomotor activity (LMA) were measured following administration of 5-HT agonists (5-HT, d-fenfluramine, fluoxetine, buspirone, TFMPP, and DOI) and antagonists (metergoline, ritanserin, and ondansetron) 30 min prior to testing. d-Fenfluramine, fluoxetine, buspirone, TFMPP, and DOI all produced a reduction in ethanol ingestion and maintained behaviour at doses that failed to reduce LMA. Conversely, metergoline and ritanserin only reduced ethanol self-administration at doses that concomitantly reduced LMA. 5-HT and ondansetron were without effect on any measure. These results demonstrate that, under the present experimental conditions, activation of central 5-HT1A, 5-HT1B, and 5-HT2 receptors reduced ethanol intake and reinforced behaviour in an operant paradigm.     

Stimulus compounding enhances conditioned suppression produced by cocaine-paired stimuli.

When 2 stimuli that occasion cocaine self-administration are presented in compound, their ability to increase cocaine-reinforced operant responding is substantially enhanced. The goal of the present experiment was to determine whether stimulus compounding could produce analogous enhancements of a classically conditioned drug effect. Food-maintained responding in rats was suppressed by a tone and a light that were individually paired with response independent cocaine (3 mg/kg iv). This conditioned suppression was significantly enhanced when the stimuli were presented together in a stimulus-compounding test. The magnitude of this enhancement was similar to that in previous studies in which responding was suppressed by shock-paired stimuli. These results demonstrate that multiple drug-related cues interact in a predictable manner to influence both operant and classically conditioned behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in oral ethanol self-administration patterns resulting from ethanol concentration manipulations

A variety of initiation procedures have been used to develop oral ethanol consumption. Using the sucrose-substitution procedure, oral self-administration of ethanol-water solutions with ethanol concentrations as high as 40% can be initiated in food- and fluid-sated rats. An important question for these models is the relationship between ethanol concentration and self-administration patterns after initiation. This study examined the differential patterns of ethanol self-administration maintained by a range of ethanol solutions (10 to 30%) over a 5-week period, compared with rats maintained on 10% ethanol for 5 weeks. In 43 male Long Evans rats, the sucrose-substitution procedure was used to initiate responding maintained by 10% ethanol on a Fixed Ratio 4 schedule of reinforcement. The ethanol concentration presented was then increased to 30% in stepwise fashion and then returned to 10% [Ethanol Concentration Manipulation (ECM) group, n = 32], or 10% ethanol was maintained as the reinforcer for 5 weeks [Control (Con) group, n = 11]. Significant increases in ethanol intake and decreases in responding were associated with increased ethanol concentration. Although no overall differences in total session responding were observed in either group between week 1 and week 5 (10E vs. 10E), examination of changes in initial low responders of the ECM group revealed significant increases in responding that were not observed in the initial low responders of the Con group. Significant increases in momentary response rates were observed on both the ECM and Con groups, independent of the ethanol concentration presented. Increases in response rate in the ECM group were the result of increases in initial low rate and high rate responders; however, the increased response rates in the Con group were the result of increases only in the initial low rate responders. These data suggest that the ECM procedure can aid in the initiation of ethanol self-administration and may be particularly useful in rats of heterogeneous stock.     

The discriminative stimulus effects of clomethiazole in the rat

Rats were trained in a two-lever drug discrimination procedure using saline or clomethiazole (8 mg/kg, s.c. 15 min) as the training stimuli. A criterion of 9/10 days correct lever choice was adopted to select rats for substitution tests. The clomethiazole (CMZ) cue was not especially strong, and stable performance at this level was not achieved consistently. Nevertheless, in a series of substitution tests carried out in extinction, diazepam (3 mg/kg), chlordiazepoxide (10 mg/kg), phenobarbital (60 mg/kg), dizocilpine (0.1 mg/kg) and mianserin (3.0 mg/kg) were found to substitute for the training dose of CMZ. The first two of these produced a percentage choice of the drug lever equal to that produced by the training dose of CMZ (full generalization) whereas the latter three produced only partial generalization. Ethanol, muscimol, allopregnanolone, chlorpromazine and amitriptyline did not generalize to CMZ. CMZ is known to potentiate gamma-aminobutyric acid (GABAA) receptor function, a finding supported by the generalization to CMZ of the two benzodiazepines and phenobarbital. However, not all drugs acting at GABAA receptors generalized to CMZ. Although CMZ has no affinity for the N-methyl-D-aspartate (NMDA) receptor, it antagonizes a number of pharmacological responses mediated by NMDA receptors. The generalization in the drug discrimination procedure reported here support the suggestion that altering GABA activity can modulate NMDA-mediated responses. The lack of generalization after treatment with ethanol, chlorpromazine and amitriptyline suggests that the interoceptive cues are not mediated by a generalized sedation or drug-induced motor impairment.     

Comparison of the effects of methamphetamine, bupropion, and methylphenidate on the self-administration of methamphetamine by rhesus monkeys.

The effectiveness of methadone as a treatment for opioid abuse and nicotine preparations as treatments for tobacco smoking has led to an interest in developing a similar strategy for treating psychostimulant abuse. The current study investigated the effects of three such potential therapies on intravenous methamphetamine self-administration (1 – 30 μg/kg/injection) in rhesus monkeys. When given as a presession intramuscular injection, a high dose of methamphetamine (1.0 mg/kg) decreased intravenous methamphetamine self-administration but did not affect responding for a food reinforcer during the same sessions. However, the dose of intramuscular methamphetamine required to reduce intravenous methamphetamine self-administration exceeded the cumulative amount taken during a typical self-administration session, and pretreatment with a low dose of methamphetamine (0.3 mg/kg) actually increased self-administration in some monkeys at the lower self-administration dose. Like pretreatment with methamphetamine, pretreatment with bupropion (3.2 mg/kg) decreased methamphetamine self-administration but did not affect responding for food. Pretreatment with methylphenidate (0.56 mg/kg) did not significantly alter methamphetamine self-administration. These results suggest that some agonist-like agents can decrease methamphetamine self-administration. Although the most robust effects occurred with a high dose of methamphetamine, safety and abuse liability considerations suggest that bupropion should also be considered for further evaluation as a methamphetamine addiction treatment. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Extracellular serotonin is enhanced in the striatum, but not in the dorsal hippocampus or prefrontal cortex, in rats subjected to an operant conflict procedure.

In rats trained in an operant fixed-interval-30-s schedule of food reward (FI-30s), acute exposure to contingent footshock resulted in a response suppression that was released by diazepam (DZP; 4 mg/kg ip) but not by buspirone (0.25 or 0.50 mg/kg ip). Compared with baseline, hippocampal and cortical extracellular levels of serotonin (5-HText) did not change, regardless of operant period (punished or nonpunished) and drug. In contrast, in the striatum, an increase of 5-HText levels (535%) occurred during the punished period, counteracted by DZP. This effect was observed only in rats that were low responders during both nonpunished and punished periods, that is, those that exerted an efficacious control over responding. Uncontrollable shocks or exposure to an unfamiliar open field did not modify striatal 5-HText. Together, these results suggest that an acute activation of 5-HT neurons afferent to the striatum allows the rats to efficiently block responses that are negatively reinforced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of nicotine and mecamylamine microinjections into the nucleus accumbens on ethanol and sucrose self-administration

Nicotine (NIC) and ethanol (ETOH) are both drugs of abuse that can affect similar pathways in the central nervous system. However, the role of nicotinic processes in ETOH's reinforcing actions is unclear. Although the mesolimbic dopamine systems are known to be involved in the reinforcing effects of ETOH, the role of nicotinic receptors within the nucleus accumbens (NAc) in ETOH reinforcement has not been studied. To address this issue, adult male Long-Evans rats were initiated to self-administer ETOH (10% v/v, n = 14) using the sucrose-substitution procedure or sucrose (5% w/v, n = 8) in a 30-min operant session. They were then surgically implanted with bilateral stainless-steel guide cannulae to allow for microinjection into the core of the NAc. After recovery from surgery, presession microinjections of NIC (0.3, 3.3, 10, 30, and 60 microg/1 microl/brain) or the antagonist mecamylamine (MEC) (1, 3, 10, 30, and 60 microg/1 microl/brain) were performed prior to an ETOH or sucrose self-administration session. NIC (3.3 and 60 microg/microl) and MEC (30 microg/microl) both reduced ETOH self-administration behavior, without affecting sucrose-reinforced behavior. A reduction in the total duration of ETOH responding (termination) was also observed after either 60 microg/microl of NIC and 30 microg/microl of MEC. The lack of a clear dose-response relationship for the agonist and the antagonist indicates that the interaction between the NAc nicotinic system and ETOH self-administration is complex.