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1.

Rationale and objectives  

Previous work has shown that wheel running reduced the maintenance of cocaine self-administration in rats. In the present study, the effect of wheel running on extinction and reinstatement of cocaine seeking was examined. Female rats were trained to run in a wheel during 6-h sessions, and they were then catheterized and placed in an operant conditioning chamber where they did not have access to the wheel but were allowed to self-administer iv cocaine. Subsequently, rats were divided into four groups and were tested on the extinction and reinstatement of cocaine seeking while they had varying access to a wheel in an adjoining compartment. The four groups were assigned to the following wheel access conditions: (1) wheel running during extinction and reinstatement (WER), (2) wheel running during extinction and a locked wheel during reinstatement (WE), (3) locked wheel during extinction and wheel running during reinstatement (WR), and (4) locked wheel during extinction and reinstatement (WL). WE and WR were retested later to examine the effect of one session of wheel access on cocaine-primed reinstatement.  相似文献   

2.

Rationale

Two pharmacological stressors commonly used in the study of stress-induced reinstatement of drug seeking are central injections of the stress peptide, corticotropin-releasing factor (CRF), and systemic administration of the ??2-adrenoceptor antagonist, yohimbine. Despite the widespread use of these stressors, the neurochemical systems mediating their ability to reinstate cocaine-seeking behaviour have not been fully characterized.

Objective

The present study was designed to characterize the role, specifically, of dopamine transmission in the reinstating effects of CRF and yohimbine on cocaine seeking.

Methods

Male Long-Evans rats were trained to self-administer cocaine (0.23?mg/kg/infusion) for 8?C10?days. Subsequently, responding for drug was extinguished, and tests for CRF- (0.5???g; i.c.v.) and yohimbine-induced (1.25?mg/kg; i.p.) reinstatement were conducted following pretreatment with the dopamine D1/5 receptor antagonists, SCH23390 (0.05, 0.1?mg/kg; i.p.) and/or SCH31966 (0.2?mg/kg; i.p.), and the D2/3 receptor antagonist, raclopride (0.25, 0.5?mg/kg; i.p.).

Results

Pretreatment with SCH23390, but not raclopride, blocked CRF-induced reinstatement of cocaine seeking. Pretreatment with SCH23390 and SCH31966, but not raclopride, blocked yohimbine-induced reinstatement of cocaine seeking.

Conclusions

These findings demonstrate that transmission at D1/5, but not D2/3, receptors mediates the reinstatement of cocaine seeking induced by CRF and yohimbine.  相似文献   

3.
Previous studies have indicated a role of serotonin (5-HT)2 receptors in modulation of the behavioral effects of cocaine. In the present study, the efficacy of SR 46349B (a 5-HT(2A) receptor antagonist) or SDZ SER-082 (a 5-HT(2C) receptor antagonist) in altering cocaine seeking behavior was examined in rats. Rats were trained to press a lever for cocaine (0.5 mg/kg/infusion, iv) paired with the cue (light + tone). After stabilization of self-administration response, the animals underwent daily extinction sessions during which responding had no consequences. The cocaine seeking behavior was reinstated by cocaine priming (10 mg/kg, ip) or by presentation of the cue. Neither SR 46349B (0.25-1 mg/kg) nor SDZ SER-082 (0.25-1 mg/kg) altered the maintenance of cocaine self-administration. SR 46349B (0.5-1 mg/kg) decreased responding to the cocaine priming dose and reduced cue-induced reinstatement, while SDZ SER-082 failed to alter both cue- and cocaine priming-induced reinstatement. These findings indicate that 5-HT(2A) and 5-HT(2C) receptors are not significant to cocaine rewarding effects. However, they show the importance of the 5-HT(2A) receptors (but not 5-HT(2C) receptors) in cocaine-priming- and cue-provoked reinstatement. Since drugs that reduce cocaine seeking also alleviate cocaine craving, 5-HT(2A) receptor antagonists may be considered to be of possible clinical application for the treatment of cocaine dependence.  相似文献   

4.
Rationale and objectives  Although onset of drug use during adolescence appears to increase long-term vulnerability to drug dependence in humans, relatively little is known about extinction and reinstatement of drug seeking after periadolescent onset of drug self-administration in laboratory animals. Furthermore, although cue-induced reinstatement of cocaine seeking increases progressively during abstinence from cocaine self-administration in adult subjects, this “incubation of cocaine craving” remains unexplored after adolescent drug intake in animal models. Materials and methods  We allowed periadolescent (postnatal day (PND) 35 at start) and adult (PND 83–95 at start) male Wistar rats to self-administer cocaine (0.36 mg/kg/infusion) in 2-h daily sessions on a fixed ratio 1 schedule of reinforcement over 14 days. Then, we compared extinction and cue-induced or cocaine priming-induced reinstatement (10 mg/kg cocaine, intraperitoneal) of cocaine seeking in both age groups after 30 days of abstinence in home cages. In separate cohorts, we tested for time-dependent increases in cue-induced reinstatement over approximately 1, 14, 30, or 60 days of abstinence in both age groups. Results  Adolescent and adult rats self-administered similar amounts of cocaine. Subsequent cue-induced reinstatement was lower in the adolescent-onset group after a 30-day abstinence period, but cocaine priming-induced reinstatement did not differ across ages. Also, extinction responding and time-dependent increases in cue-induced reinstatement (incubation) were less pronounced in rats that took cocaine as adolescents compared with adults. Conclusions  Surprisingly, these results may reflect resistance among adolescent subjects to some enduring effects of drug self-administration, such as reward learning.  相似文献   

5.
RATIONALE: Acute serotonin (5-HT) depletion by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, attenuates cocaine seeking in rats. OBJECTIVE: The present study examined the effects of chronic 5-HT depletion on cocaine- and sucrose seeking using the 5-HT-selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). METHODS: Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for sucrose pellets (45 mg Noyes) on a fixed ratio (FR) 1 schedule of reinforcement during daily 2-h sessions. Subsequently, animals received i.c.v. infusions of either vehicle or 5,7-DHT (150 microg/6 microl or 200 microg/20 microl). After a minimum of 10 days post-lesion, cocaine- and sucrose seeking were measured as lever presses in the absence of reinforcement (extinction). Some cocaine-trained animals were also assessed for the re-establishment of self-administration and reinstatement of extinguished cocaine seeking by i.v. cocaine priming injections and response-contingent presentations of cocaine-paired stimuli. RESULTS: 5-HT depletion by the 150 microg/6 microl dose of 5,7-DHT failed to alter cocaine- and sucrose seeking despite producing a 42-77% depletion of 5-HT in limbic terminal regions. The 200 microg/20 microl dose of 5,7-DHT attenuated cocaine seeking but enhanced sucrose seeking during extinction and produced a 55-85% depletion of 5-HT. In addition, cocaine-paired cues and cocaine priming reinstated cocaine-seeking behavior, and responding was enhanced in 5,7-DHT-treated animals relative to vehicle-treated controls at the 1 mg/kg/0.1 ml priming dose. However, re-establishment of cocaine self-administration was not altered by 5,7-DHT. CONCLUSION: The results suggest that 5-HT depletion may attenuate cocaine seeking but may enhance sucrose seeking when animals are tested during extinction. Furthermore, 5-HT depletion may enhance cocaine seeking produced by cocaine itself. Together these findings suggest that 5-HT depletion may have opposite effects on incentive motivation for cocaine during abstinence versus relapse.  相似文献   

6.
Environmental stimuli can exert a powerful influence over drug seeking and taking. For example, previous experiments found that combining multiple drug-related stimuli tripled drug seeking and doubled drug intake (L. V. Panlilio, S. J. Weiss, & C. W. Schindler, 1996, 2000), whereas a signal for the absence of cocaine (i.e., a drug-related inhibitor) dramatically reduced cocaine seeking in rats by over 90% (D. N. Kearns, S. J. Weiss, C. W. Schindler, & L. V. Panlilio, 2005). In the present experiment, a signal for the absence of food created through the A+/AB- conditioned inhibition paradigm also suppressed responding for cocaine by approximately 90%. Symmetrically, a signal for the absence of cocaine (i.e., a cocaine-based inhibitor) suppressed food seeking to a similar degree. These findings, consistent with the appetitive-aversive interaction theory of motivation, suggest that using inhibitors based on nondrug appetitive reinforcers might be a practical method of reducing drug seeking in human drug abusers and should be seriously considered for clinical test and application.  相似文献   

7.
The orexin/hypocretin system has been implicated in multiple phases of drug addiction. Acute orexin receptor blockade with the orexin-1 receptor (OX1R) antagonist, SB-334867, has been found to reduce cocaine seeking after cocaine self-administration. As repeated drug dosing can have differential effects and is more clinically relevant than acute dosing, in the current study we examined the effects of repeated SB-334867 on cocaine self-administration, extinction, and reinstatement to cocaine seeking in Sprague–Dawley rats. We found that repeated SB-334867 (10 mg/kg/day) had no effect on established cocaine self-administration. Repeated SB-334867 (both 10 and 20 mg/kg) attenuated cocaine seeking during extinction; however, this effect was only observed when animals had no prior experience with SB-334867 and when SB-334867 was administered prior to, but not after, daily extinction sessions. Notably, daily treatment with SB-334867 (10 mg/kg) during extinction increased subsequent cue-induced reinstatement, whereas repeated SB-334867 (20 mg/kg) administration during extinction enabled acute SB-334867 to reduce cue-induced reinstatement. Repeated SB-334867 treatment (10 or 20 mg/kg) failed to affect reinstatement induced by priming injections of cocaine (10 mg/kg). These results show that repeated inhibition of OX1R-mediated signaling exerts a lasting and specific role in mediating environmentally activated cocaine seeking.  相似文献   

8.
9.
10.
Acute exposure to the pharmacological stressor yohimbine (YOH) reinstates drug seeking in rats. The present experiments investigated whether repeated exposure to YOH during extinction training affects the time-course of extinction and the magnitude of subsequent YOH- or footshock-induced reinstatement of cocaine seeking. Rats trained to self-administer cocaine were given five days of extinction training, during which they were injected with YOH (1.25 mg/kg, i.p.) either before or after daily extinction sessions. Following additional extinction training in the absence of YOH, animals were tested for reinstatement to a YOH (1.25 mg/kg, i.p.) or footshock (20 min, intermittent, 0.9 mA per 0.5 s shock) challenge. Animals injected with YOH before daily extinction sessions showed an attenuated rate of extinction, relative to control animals. Following additional extinction training in the absence of YOH treatment, these same animals showed a marked attenuation of YOH-induced reinstatement of cocaine seeking. YOH treatment during extinction did not, however, affect the magnitude of reinstatement induced by footshock. These findings demonstrate that repeated exposure to a stressor during extinction training can modulate the processes governing extinction learning and the subsequent reinstatement of drug seeking induced by that stressor.  相似文献   

11.
Molecular cloning of adenosine A1 and A2 receptors   总被引:1,自引:0,他引:1  
  相似文献   

12.
The overactivation of glutamate receptors is a major cause of Ca(2+) overload in cells, potentially leading to cell damage and death. There is an abundance of agents and mechanisms by which glutamate receptor activation can be prevented or modulated in order to control these effects. They include the well-established, competitive and non-competitive antagonists at the N-methyl-D-aspartate (NMDA) receptors and modulators of desensitisation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. More recently, it has emerged that some compounds can act selectively at different subunits of glutamate receptors, allowing a differential blockade of subtypes. It is also becoming clear that a number of endogenous compounds, including purines, can modify glutamate receptor sensitivity. The kynurenine pathway is an alternative but distinct pathway to the generation of glutamate receptor ligands. The products of tryptophan metabolism via the kynurenine pathway include both quinolinic acid, a selective agonist at NMDA receptors, and kynurenic acid, an antagonist at several glutamate receptor subtypes. The levels of these metabolites change as a result of the activation of inflammatory processes and immune-competent cells, and may have a significant impact on Ca(2+) fluxes and neuronal damage. Drugs which target some of these various sites and processes, or which change the balance between the excitotoxin quinolinic acid and the neuroprotective kynurenic acid, could also have potential as neuroprotective drugs.  相似文献   

13.
Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking.  相似文献   

14.
Adenosine is an endogenous purine nucleoside, which acts as a neuromodulator in the central nervous system. A2A adenosine and D2 dopamine receptors are colocalized in the same neurons in discrete brain areas, and the dopaminergic transmission plays a crucial role in the addictive properties of drugs of abuse, such as cocaine. In the present study, we have investigated the specific role of A2A adenosine receptors in cocaine-induced behavioral responses related to its addictive properties. For this purpose, we have evaluated the acute locomotor effects produced by cocaine and the development of locomotor sensitization by repeated cocaine administration. In addition, we have also examined cocaine acute rewarding properties using the conditioned place preference. Finally, we used the intravenous drug self-administration paradigm to investigate the acquisition of an operant response maintained by cocaine self-administration and the reinforcing efficacy of the drug in these knockout animals. Acute cocaine induced a similar increase of locomotor activity in mice lacking A2A adenosine receptors and wild-type littermates. Cocaine-induced locomotor sensitization and conditioned place preference were also maintained in A2A knockout mice. Nevertheless, these knockout mice showed a lower rate of cocaine self-administration than wild-type mice in both fixed ratio 1 and 3 schedules of reinforcement. Moreover, a reduction in the maximal effort to obtain a cocaine infusion was found in A2A knockout mice under a progressive ratio schedule. In addition, a vertical shift of the cocaine dose-response curve was observed in mice lacking A2A adenosine receptors in comparison with wild-type littermates. Our study demonstrates that A2A adenosine receptors play an important role in cocaine addictive properties, and these receptors seem to be required to develop the addictive effects of this drug.  相似文献   

15.
16.

Rationale

Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity.

Objectives

We investigated the necessity of NMDArs for extinction of cocaine seeking and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci.

Methods

Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal.

Results

Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, administration of the NMDAr coagonist D-serine after four brief extinction sessions attenuated lever pressing during subsequent extinction, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction.

Conclusions

Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse.  相似文献   

17.

Rationale

Several compounds that potentiate GABA-induced inhibitory currents also decrease stress, anxiety and addiction-related behaviors. Because of the well-established connection between stress and addiction, compounds that reduce stress-induced responses might be efficacious in treating addiction. Since endogenous neurosteroids such as allopregnanolone may function in a manner similar to benzodiazepines to reduce HPA axis activation and anxiety following stressful stimuli, we hypothesized that exogenously applied neurosteroids would reduce cocaine reinforcement in two animal models.

Methods

Male Wistar rats were trained to self-administer cocaine and food under a concurrent alternating operant schedule of reinforcement. Two separate groups of rats were trained to self-administer cocaine or food pellets and were then exposed to similar cue-induced reinstatement paradigms. Both groups of rats were pretreated with various doses of neurosteroids.

Results

Allopregnanolone and 3α-hydroxy-3β-methyl-17β-nitro-5α-androstane (R6305-7, a synthetic neurosteroid) were ineffective in selectively decreasing cocaine relative to food self-administration. On the other hand, both allopregnanolone and R6305-7 significantly decreased the cue-induced reinstatement of extinguished cocaine seeking, confirmed by one-way ANOVA.

Conclusions

These results suggest that neurosteroids may be effective in reducing the relapse to cocaine use without affecting ongoing cocaine self-administration.  相似文献   

18.
Detailed amino acid sequence analyses of A1 and A2a adenosine receptors were assembled by analogy to other G-protein-coupled receptors and correlated with pharmacological observations. Sites for phosphorylation, palmitoylation, and sodium binding have been proposed. Striatal A2a receptors from human and other species were photoaffinity-labeled using the selective, radioiodinated agonist PAPA-APEC. Selective chemical affinity labels for A1 and A2a receptors have been introduced. For example, an isothiocyanate, ρ-DITC-APEC (100 nM), irreversibly diminished the Bmax for [3H]CGS 21680 (2-[4-[(2-carboxyethyl) phenyl] ethylamino]-5′-N-ethylcarboxamido-adenosine) binding in rabbit striatal membranes by 71% (Kd unaffected), suggesting a direct modification of the ligand binding site. Novel trifunctional affinity labels have been designed. Rabbit and human A2a receptors were characterized using [3H]XAC binding in the presence of 50 or 25 nM CPX (8-cyclopentyl-1,3-dipropylxanthine), respectively. The inhibition of A2 radioligand binding by the histidyl-modifying reagent diethylpyrocarbonate suggested the involvement of His residues in interactions with adenosine agonists and antagonists. Properties of transiently expressed mutants of bovine A1 receptors in which either His251 or His278 residues have been substituted with Leu suggest that both histidines are important in binding. © 1993 Wiley-Liss, Inc.  相似文献   

19.
The effects of enprofylline were studied on A1 adenosine receptors of rat fat cells and on A2 adenosine receptors of human platelets and of guinea-pig lung. Enprofylline antagonized the 5′-N-ethylcarboxamidoadenosine (NECA)-induced stimulation of platelet adenylate cyclase activity with a KB of 130 μM. In human platelets, enprofylline did not antagonize but potentiated the NECA-induced inhibition of aggregation. This potentiation was abolished in the presence of the phosphodiesterase inhibitor papaverine. An adenosine antagonistic effect of enprofylline could not be evaluated on A2 receptors of guinea-pig lung because the xanthine enhanced basal and NECA-stimulated cyclic AMP accumulation. Enprofylline antagonized the N6-R-(−)-phenylisopropyladenosine (R-PIA)-induced inhibition of rat fat cell adenylate cyclase with a KB of 32 μM. The Ki value for inhibition of [3H]PIA binding to fat cell membranes was 45 μM. Enprofylline inhibited cyclic AMP phosphodiesterase activity of human platelets, guinea-pig lung and rat fat cells with Ki values of 15, 130 and 110 μM, respectively. The results show that enprofylline was nearly equipotent as antagonist at A1 and A2 adenosine receptors. Mechanisms other than adenosine antagonism or phosphodiesterase inhibition may be involved in the pharmacological effects of enprofylline.  相似文献   

20.
The essential role of corticotropin releasing factor (CRF) and its type-1 receptor (CRF1) in stress-induced relapse to drug seeking has been demonstrated. The bed nucleus of the stria terminalis is the major anatomical substrate for this CRF/CRF1 receptor action. More recently, the role of type-2 CRF (CRF2) receptors in stress-induced relapse to cocaine seeking has also has been documented. The ventral tegmental area is the anatomical substrate for this CRF/CRF2 receptor action. The new information involving CRF2 receptors in stress-induced relapse to cocaine seeking has generated a need for a reappraisal of the existing anatomical and pharmacological evidence that have been used to support the critical role of CRF1 receptors. The role of CRF2 receptors in stress-induced relapse to drug seeking also opens the question of the putative role of the other peptides of the CRH family (urocotin-1, urocortin-2 and urocortin-3) that have high affinity for CRF2 receptors. In this commentary, the available evidence supporting the role of both CRF1 and CRF2 receptors in stress-induced relapse to drug seeking is reviewed.  相似文献   

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