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1.
Rationale
Noncontingent administration of amphetamine into the ventral striatum or systemic nicotine increases responses rewarded by inconsequential visual stimuli. When these drugs are contingently administered, rats learn to self-administer them. We recently found that rats self-administer the GABAB receptor agonist baclofen into the median (MR) or dorsal (DR) raphe nuclei. 相似文献2.
Andrés P. Varani Ester Aso Lirane Machado Moutinho Rafael Maldonado Graciela N. Balerio 《Psychopharmacology》2014,231(15):3031-3040
Rationale
Nicotine is a major active ingredient in tobacco and plays a major role in tobacco addiction. In rodents, repeated nicotine administration produces behavioral responses related to its addictive properties, such as reinforcing effects and physical dependence.Objectives
The aim of the present study was to evaluate the possible role of GABAB receptor in responses induced by repeated nicotine administration in Swiss Webster mice.Results
Nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.) administration induced rewarding properties in the conditioning place preference test. The GABAB receptor agonist, baclofen (3 mg/kg, i.p.) abolished the rewarding properties induced by nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.). In addition, naloxone-precipitated nicotine withdrawal induced somatic manifestations, anxiety-like effects in the elevated plus maze test and dysphoric manifestations in the conditioned place aversion paradigm. Baclofen (2 and 3 mg/kg, i.p.) prevented the somatic manifestations and the anxiety-like effects associated with naloxone-precipitated nicotine withdrawal but not the dysphoric manifestations.Conclusions
These results showed that nicotine rewarding properties and negative aspects of nicotine withdrawal, such as anxiety-like effects and somatic manifestations, can be modulated by the GABAB receptor activity. This study now reveals a novel possible application of baclofen to develop new therapeutic strategies to achieve smoking cessation. 相似文献3.
Sierra M. Webb Fiori R. Vollrath-Smith Rick Shin Thomas C. Jhou Shengping Xu Satoshi Ikemoto 《Psychopharmacology》2012,224(3):401-412
Rationale
The motivational process that regulates approach behavior toward salient distal stimuli (i.e., incentive motivation) plays a key role in voluntary behavior and motivational disorders such as addiction. This process may be mediated by many neurotransmitter systems and a network of many brain structures, including the median and dorsal raphe regions (MR and DR, respectively).Objective
We sought to examine whether the blockade of excitatory amino acid receptors in the MR and DR is rewarding, using intracranial self-administration, and whether the self-administration effect can be explained by drug??s effectiveness to enhance incentive motivation, using a visual sensation seeking procedure.Results
Rats learned to self-administer the AMPA receptor antagonist ZK 200775 into the vicinity of the MR, DR, or medial oral pontine reticular regions, but not the ventral tegmental area. The NMDA receptor antagonist AP5 was also self-administered into the MR, while it was not readily self-administered into other regions. When ZK 200775 was noncontingently administered into the MR, rats markedly increased approach responses rewarded by brief illumination of a light stimulus. In addition, contingent administration of ZK 200775 into the MR induced a conditioning effect on approach responses.Conclusions
Rats self-administer excitatory amino acid receptor antagonists into the MR and adjacent regions. Self-administration effect of AMPA receptor antagonists into the MR can be largely explained by the manipulation??s properties to invigorate ongoing approach behavior and induces conditioned approach. Glutamatergic afferents to the median raphe and adjacent regions appear to tonically suppress incentive-motivational processes. 相似文献4.
Rationale and Objective
A stress-induced increase in excitability can result from a reduction in inhibitory neurotransmission. Modulation of gamma-aminobutyric acid (GABA)ergic transmission is an effective treatment for drug seeking and relapse. This study investigated whether baclofen, a GABAB receptor agonist, had an impact on morphine-induced conditioned place preference (CPP), extinction, and stress-induced relapse in chronically stressed mice.Methods
Chronic stress was induced by restraining mice for 2 h for seven consecutive days. We first investigated whether chronic stress influenced morphine-induced CPP, extinction, and stress-induced relapse in the stressed mice. Next, we investigated whether three different doses of baclofen influenced chronic stress as measured by the expression of morphine-induced CPP. We chose the most effective dose for subsequent extinction and reinstatement experiments. Reinstatement of morphine-induced CPP was induced by a 6-min forced swim stress. Locomotor activity was also measured for each test.Results
Chronic stress facilitated the expression of morphine-induced CPP and prolonged extinction time. Forced swim stress primed the reinstatement of morphine-induced CPP in mice. Baclofen treatment affected the impact of chronic stress on different phases of morphine-induced CPP.Conclusions
Our results showed that baclofen antagonized the effects of chronic stress on morphine-induced CPP. These findings suggest the potential clinical utility of GABAB receptor-positive modulators as an anti-addiction agent in people suffering from chronic stress. 相似文献5.
Rationale
With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-administration.Objectives
The study aimed to develop an operant model of oral alcoholic beer self-administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, on alcoholic beer self-administration.Methods
Mice were trained to self-administer, under a fixed ratio three schedule of reinforcement, 10?μl of beer containing increasing ethanol concentrations (0–18% v/v) in daily 30-min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25–5?mg/kg, intraperitoneal, i.p.) and BHF177 (3.75–30?mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-administration.Results
Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-administration increased (0.8–1.0?g/kg/session). Motor impairment was observed when more than 1.3?g/kg/session of ethanol was self-administered with beer and slight but consistent hyperlocomotion with more than 0.9–1.0?g/kg/session. BHF177 (15?mg/kg) preferentially reduced 9% alcoholic beer self-administration, while the higher dose (30?mg/kg)—like baclofen 5?mg/kg—also reduced near-beer self-administration.Conclusions
The operant model of oral alcoholic beer self-administration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction. 相似文献6.
Microinjection and lesion studies have implicated the midbrain dorsal (DR) and median raphe (MR) nuclei in behavioral arousal. This behavioral state is manifested as locomotor hyperactivity, hyperphagia, hyperdipsia and increases in plasma corticosteroid release. Intra-midbrain raphe injections of the GABAA agonist muscimol elicit this behavioral activation. We have demonstrated that similar infusions of tachykinins produce locomotor hyperactivity through activation of neurokinin-3 (NK-3) receptors located on serotonin cell bodies. The purpose of the present study was to determine the effects of intra-MR and DR infusions of senktide, an NK-3 agonist, on food and water consumption in nondeprived rats. Male Sprague-Dawley rats were implanted with indwelling intra-MR or intra-DR cannula. Infusions of muscimol (25 ng/0.5 microliters) into the MR increased water intake, while MR and DR infusions increased food consumption. In contrast, intra-MR injections of senktide decreased water intake and intra-MR and DR injections decreased food intake. The results suggest that the behavioral states induced by muscimol and neurokinin infusions into the raphe are distinct and that raphe/neurokinin pathways are involved in consummatory mechanisms. 相似文献
7.
Rationale
Pharmacological activation of GABAB receptors in the dorsal raphe nucleus (DRN) can escalate territorial aggression in male mice.Objectives
We characterized this escalated aggression in terms of its behavioral and environmental determinants.Methods
Aggressive behavior of resident male (CFW or ICR mouse) was assessed in confrontations with a group-housed intruder. Either baclofen (0.06 nmol/0.2 μl) or vehicle (saline) was microinjected into the DRN 10 min before the confrontation. We examined baclofen-heightened aggression in five situations: aggression in a neutral arena and after social instigation (experiment 1), aggression during the light phase of the cycle (experiment 2), aggression without prior fighting experience (experiment 3), aggression toward a female (experiment 4), and aggression after defeat experiences (experiment 5). In addition, we examined the body targets towards which bites are directed and the duration of aggressive bursts after baclofen treatment.Results
Regardless of the past social experience, baclofen escalated aggressive behaviors. Even in the neutral arena and after defeat experiences, where aggressive behaviors were inhibited, baclofen significantly increased aggression. Baclofen increased attack bites directed at vulnerable body areas of male intruders but not toward a female and only in the dark. Also, baclofen prolonged the duration of aggressive bursts.Conclusions
For baclofen to escalate aggression, specific stimulation (male intruder) and tonic level of serotonin (dark cycle) are required. Once aggressive behavior is triggered, intra-DRN baclofen escalates the level of aggression to abnormal levels and renders it difficult to terminate. Also, baclofen counteracts the effects of novelty or past experiences of defeat. 相似文献8.
Yang B Wang BF Lai MJ Zhang FQ Yang XW Zhou WH Lian QQ 《Acta pharmacologica Sinica》2011,32(12):1460-1465
Aim:
Propofol has shown abuse potential. The aim of the present study is to investigate the effects of GABAA antagonist and GABAB agonist on propofol reinforcement.Methods:
Sprague-Dawley rats were trained to self-administer propofol at a dose of 1.7 mg/kg per infusion under a fixed ratio (FR1) schedule of reinforcement for 14 d. In a separate set of experiments, food-maintained self-administration under a fixed ratio (FR5) schedule and locomotor activities of Sprague-Dawley rats were examined.Results:
GABAA receptor antagonist bicuculline (0.25 mg/kg, ip) significantly increased the number of injections and active responses. Pretreatment with GABAB receptor agonist baclofen (3 mg/kg, ip) significantly decreased the number of active responses and total infusions of propofol during the training session. Moreover, microinjection of baclofen (50 and 100 ng/side) into the ventral tegmental area (VTA) significantly decreased the number of active responses and total infusions of propofol. Neither baclofen (1-3 mg/kg, ip) nor bicuculline (0.25-1 mg/kg, ip) affected food-maintained responses or motor activities.Conclusion:
Propofol maintains its reward properties partially through GABAA receptor activation. Stimulation of GABAB receptors in VTA may counteract the reinforcing properties of propofol. 相似文献9.
Rationale Recent reports have demonstrated that gamma-aminobutyric acid (GABA)-ergic compounds attenuate the reinforcing effects of cocaine in rats. Baclofen, a GABAB receptor agonist, appears to be particularly effective in this respect, suggesting that GABAB receptor activation is critically involved in mediating anti-cocaine effects. Amphetamine, like cocaine, is a psychomotor stimulant with high abuse potential in humans.Objectives The purpose of the present investigation was to determine whether baclofen may attenuate the reinforcing effects of d-amphetamine (dAMPH) in rats. Dose–response curves were generated to examine the effect of three doses of baclofen (1.8, 3.2 or 5.6 mg/kg, IP) on dAMPH intravenous self-administration (IVSA). Separate groups were trained to self-administer two doses of dAMPH (0.1 mg/kg or 0.2 mg/kg per injection) under either a fixed-ratio (FR) or progressive ratio (PR) schedule of reinforcement. Microdialysis was performed in an additional group of rats to examine the effect of baclofen on dAMPH-induced increases in dopamine (DA) efflux in the nucleus accumbens (NAc).Results Pretreatment with baclofen produced dose-dependent reductions in responding for dAMPH under both the FR and PR schedules, and attenuated dAMPH-induced increases in DA levels in the NAc.Conclusion These results add to previous findings showing that baclofen attenuates the reinforcing effects of psychostimulant drugs, and suggest that further investigation into the effects of GABAB receptor agonists on drug self-administration is warranted. 相似文献
10.
11.
Vikram K. Reddy K. Girish Pandit Lakshmi R. Vijendra Ajay Kumar R. Harsha 《Indian journal of pharmacology》2014,46(4):372-377
Objectives:
Benzodiazepines (BZDs) are the first-line drugs in alcohol-withdrawal syndrome (AWS). Baclofen, a gamma-aminobutyric acidB (GABAB) agonist, controls withdrawal symptoms without causing significant adverse effects. The objective of this study was to compare the cost-effectiveness of baclofen and chlordiazepoxide in the management of uncomplicated AWS.Materials and Methods:
This was a randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis (CEA) of baclofen and chlordiazepoxide in 60 participants with uncomplicated AWS. Clinical efficacy was measured by the Clinical Institute Withdrawal Assessment for alcohol (CIWA-Ar) scores. Lorazepam was used as supplement medication if withdrawal symptoms could not be controlled effectively by the study drugs alone. Both direct and indirect medical costs were considered and the CEA was analyzed in both patient''s perspective and third-party perspective.Results:
The average cost-effectiveness ratio (ACER) in patient''s perspective of baclofen and chlordiazepoxide was Rs. 5,308.61 and Rs. 2,951.95 per symptom-free day, respectively. The ACER in third-party perspective of baclofen and chlordiazepoxide was Rs. 895.01 and Rs. 476.29 per symptom-free day, respectively. Participants on chlordiazepoxide had more number of symptom-free days when compared with the baclofen group on analysis by Mann-Whitney test (U = 253.50, P = 0.03).Conclusion:
Both study drugs provided relief of withdrawal symptoms. Chlordiazepoxide was more cost-effective than baclofen. Baclofen was relatively less effective and more expensive than chlordiazepoxide.KEY WORDS: Alcohol-withdrawal syndrome, baclofen, chlordiazepoxide, clinical institute withdrawal assessment for alcohol, cost-effectiveness analysis 相似文献12.
Rationale
The striatopallidal medium spiny neurons have been viewed as a final common path for drug reward, and the ventral pallidum (VP) as a convergent point for hedonic and motivational signaling. The medium spiny neurons are GABAergic, but they colocalize enkephalin.Objective
The present study investigated the role of the GABAergic mechanisms of the VP in ethanol consumption.Methods
The effects of bilateral microinjections of GABAA and GABAB receptor agonists and antagonists into the VP on voluntary ethanol consumption were monitored in alcohol-preferring Alko alcohol rats given 90 min limited access to ethanol in their home cages every other day. The influences of coadministration of GABA and opioid receptor modulators were also studied.Results
The GABAA receptor agonist muscimol (1–10 ng/site) decreased ethanol intake dose-dependently, while administration of the GABAA receptor antagonist bicuculline (10–100 ng) had an opposite effect. The GABAB receptor agonist baclofen (3–30 ng) also suppressed ethanol intake, but the GABAB receptor antagonist saclofen (0.3–3 μg) failed to modify it. Animals coadministered with bicuculline (30 ng) and baclofen (30 ng) consumed ethanol significantly less than those treated with bicuculline alone. Coadministration of the μ-receptor agonist D-Ala2,N-Me-Phe4,Glyol5-enkephalin (DAMGO, 0.1 μg) with bicuculline counteracted, whereas the μ-receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 1 μg) enhanced the bicuculline-induced increase of ethanol intake. When given alone, DAMGO decreased while CTOP increased ethanol intake.Conclusions
The study provides evidence for the ventral pallidal GABAergic mechanisms participating in the regulation of ethanol consumption and supports earlier work suggesting a role for pallidal opioidergic transmission in ethanol reward. 相似文献13.
Rationale Previous work has indicated a potential role for -aminobutyric acid-B (GABAB) receptor agonists in treating drug addiction in humans. Specifically, GABAB receptor agonists decreased cocaine, heroin and nicotine self-administration in rats.Objectives The purpose of the present studies was to extend previous findings by assessing the effects of additional GABAB receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats.Methods Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABAB receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules.Results Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function (r=0.61). Both CGP44532 and (–)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule.Conclusion The present data demonstrate that administration of GABAB receptor agonists decreased intravenous nicotine self-administration under both fixed and progressive ratio schedules of reinforcement, possibly reflecting reduced rewarding effects of nicotine. Both baclofen and CGP44532 exhibited specificity for nicotine- versus food-maintained responding on the fixed ratio schedules but not on the progressive ratio schedule (CGP44532 tested only), indicating the potential usefulness of GABAB receptor agonists as therapeutics for smoking cessation. 相似文献
14.
Ada Ledonne Luca Sebastianelli Mauro Federici Giorgio Bernardi Nicola Biagio Mercuri 《British journal of pharmacology》2009,156(6):962-969
Background and purpose
Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells.Experimental approach
Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABAA and GABAB receptors.Key results
Fenfluramine and sibutramine reduced, concentration-dependently, the GABAB IPSPs, without affecting the GABAA-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABAB receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT1B) receptor antagonist, SB216641, blocked the reduction of GABAB IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT1B.Conclusions and implications
Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT1B receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. 相似文献15.
Lara S. Hwa Mikhail Kalinichev Hasnaà Haddouk Sonia Poli Klaus A. Miczek 《Psychopharmacology》2014,231(2):333-343
Rationale
A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents.Objective
The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA).Methods
Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.o.) before the fourth test day of repeated DID access to 20 % ethanol. Another group of mice had a history of 4 weeks of IA before ADX71441 (3, 10, 17 mg/kg, p.o.) treatment. The opioid antagonist, naltrexone (0.1, 1, 10 mg/kg, i.p.), was administered to different groups of mice in both protocols as a positive control.Results
In both DID and IA protocols, ADX71441 showed a selective and potent reduction of ethanol drinking, but not water drinking, while naltrexone had a more modest and transient effect on reducing ethanol drinking. The long-lasting effect of ADX71441 agrees with its plasma pharmacokinetics in showing peak concentrations at 2 h followed by a slow decay lasting well beyond 8 h.Conclusions
These findings support previous studies demonstrating that GABAB R PAMs decrease voluntary ethanol intake without altering water intake. ADX71441 may be a worthwhile candidate for developing a treatment of alcoholism, yet its site of action in the brain and long-term pharmacological effects require further exploration. 相似文献16.
The actions of γ-aminobutyric acid (GABA) and its analogues, 3-amino-1-propanesulphonic acid (3APS) and baclofen, have been investigated using isolated segments of the guinea-pig ileum and distal colon. GABA and 3APS, but not baclofen, induced GABAA-receptor mediated effects; prompt, dose-dependent contractions of the ileum which were antagonised by bicuculline, picrotoxinin, piretanide, tetramethylenedisulphotetramine, atropine and tetrodotoxin. Baclofen and GABA, but not 3APS, induced a dose-dependent GABAB-receptor mediated depression of electrically elicited twitch contractions of the ileum, unaffected by the GABAA-receptor antagonists or by antagonism of adenosine, adrenergic, opiate or nicotinic receptors. In the distal colon, baclofen and GABA caused a bicuculline- and picrotoxinin-intensitive depression of spontaneous cholinergic contractions. Desensitization to GABA and baclofen, and cross-desensitization to both agonists was observed. Combined antagonism of GABAA-receptors and desensitization to baclofen slowed pellet expulsion to the same extent as GABA desensitization alone, indicating that both GABAA- and GABAB-receptor sites are involved in this modification of peristalsis by GABA. 相似文献
17.
Sahraei H Etemadi L Rostami P Pourmotabbed A Zarrindast MR Shams J Ghoshooni H Noroozzadeh A Esfandiari B Salimi SH 《Pharmacology, biochemistry, and behavior》2009,91(3):409-416
The influence of intra-ventral tegmental area administration of gamma-amino-butyric-acid-B (GABAB) receptor agonist and antagonist on the expression and acquisition of morphine-induced conditioned place preference (CPP) in morphine-sensitized female rats was examined. Our pilot experiment showed that subcutaneous administration of morphine-(2.5, 5 and 7.5 mg/kg) induced CPP. Administration of one dose daily morphine (5 mg/kg) for 3 days followed by 5 days rest, enhanced the conditioning induced by ineffective doses of morphine (0.25, 0.5 and 1 mg/kg). Injections of GABAB receptor agonist, baclofen, (1.5 and 12 µg/rat) reduced the expression of morphine CPP whereas the dose of 6 µg/rat of the drug increased it. Baclofen also significantly reduced the acquisition of morphine CPP in morphine-sensitized animals. Administration of GABAB receptor antagonist, CGP 35348, significantly reduced the expression (12 µg/rat) and acquisition (1.5, 6 and 12 µg/rat) of morphine CPP in morphine-sensitized animals.In conclusion, results confirmed the importance of GABAB receptors within the ventral tegmental area of morphine CPP in morphine-sensitized female rats. 相似文献
18.
Felice Nava Giovanna Carta Marco Bortolato Gian Luigi Gessa 《European journal of pharmacology》2001,430(2-3)
The effect of γ-hydroxybutyric acid (GHB) and baclofen, a GABAB receptor agonist, on extracellular hippocampal acetylcholine levels was studied in freely moving rats by microdialysis. GHB (200 and 500 mg/kg, i.p.) reduced in a dose-dependent manner, extracellular hippocampal acetylcholine concentrations and this effect was prevented by the GABAB receptor antagonist (2S)(+)-5,5-Dimethyl-2-morpholineacetic acid (SCH 50911), at the dose of 20 mg/kg (i.p.), while the putative GHB receptor antagonist 6,7,8,9-Tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS 382) was ineffective. Similar to GHB, the GABAB agonist baclofen (10 and 20 mg/kg, i.p.) produced a dose-related reduction in extracellular acetylcholine concentrations which was prevented by SCH 50911. These findings indicate that GHB-induced reduction of hippocampal acetylcholine release is mediated by GABAB receptors and support a possible involvement of hippocampal GABAB receptors in the control of cognitive processes and in the claimed amnesic effect of GHB intoxication. 相似文献
19.
Rationale: Recent studies suggest that the GABAB receptor agonist, baclofen, may be a useful pharmacotherapy for cocaine abuse. Objectives: To investigate further the effects of baclofen on maintenance and reinstatement of cocaine-reinforced behavior in rats. Methods: Two groups of rats were trained to self-administer IV cocaine (0.2 or 0.4 mg/kg per infusion) during daily 7-h sessions under
a fixed-ratio 1 schedule. Rats were pretreated with baclofen (1.25, 2.5 or 5 mg/kg IP) or saline before the session for 5
consecutive days. An additional group of rats was trained to self-administer IV cocaine (0.4 mg/kg per infusion) during the
first 2 h of daily 7-h sessions. Cocaine was replaced by saline for the remaining 5 h of the session. Once behavior had stabilized
over the 7-h period, priming injections of saline (IV), cocaine (3.2 mg/kg IV) or baclofen (1.25 or 2.5 mg/kg IP) were administered
prior to hour 4. Injections of baclofen (1.25 or 2.5 mg/kg IP) or saline were also given before priming injections of cocaine.
Results: Pretreatment with the two higher doses of baclofen (2.5 and 5 mg/kg) decreased the number of cocaine infusions in both maintenance
groups (0.2 and 0.4 mg/kg) over the 5-day treatment period. Baclofen had a greater suppressant effect on responding maintained
by the lower dose of cocaine. Priming injections of baclofen (1.25 and 2.5 mg/kg) or saline did not reinstate responding.
However, these same doses of baclofen dose-dependently reduced the reinstatement of responding produced by priming injections
of cocaine. Conclusions: 1) The magnitude of the suppressant effects of baclofen on maintenance of cocaine self-administration depends upon the maintenance
dose, 2) baclofen may be useful in preventing reinstatement of cocaine-seeking behavior, and 3) compared to maintenance, reinstatement
of responding is more sensitive to the suppressant effects of baclofen.
Received: 10 August 1998 / Final version: 31 October 1998 相似文献
20.
Rationale A growing number of studies suggest that -aminobutyric acid type-B (GABAB) receptor agonists reduce alcohol use and craving.Objectives This study was designed to further clarify behavioral mechanism(s) by which GABAB agonists may decrease alcohol reinforcement.Methods Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABAB agonist baclofen (0–17 mg/kg, IP) or SKF 97541 (0–1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABAB agonists was examined in ethanol naive and self-administering mice.Results Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABAB agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABAB agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABAB agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.Conclusions GABAB agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABAB agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABAB positive modulation. These data question the safety of prescribing GABAB agonists to alcoholics since these drugs may potentiate ethanols sedative/hypnotic effects during relapse. 相似文献