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1.
Sunila G Nair Brittany M Navarre Carlo Cifani Charles L Pickens Jennifer M Bossert Yavin Shaham 《Neuropsychopharmacology》2011,36(2):497-510
In humans, relapse to maladaptive eating habits during dieting is often provoked by stress. In rats, the anxiogenic drug yohimbine, which causes stress-like responses in both humans and nonhumans, reinstates food seeking in a relapse model. In this study, we examined the role of medial prefrontal cortex (mPFC) dopamine D1-family receptors, previously implicated in stress-induced reinstatement of drug seeking, in yohimbine-induced reinstatement of food seeking. We trained food-restricted rats to lever press for 35% high-fat pellets every other day (9–15 sessions, 3 h each); pellet delivery was accompanied by a discrete tone-light cue. We then extinguished operant responding for 10–16 days by removing the pellets. Subsequently, we examined the effect of yohimbine (2 mg/kg, i.p.) on reinstatement of food seeking and Fos (a neuronal activity marker) induction in mPFC. We then examined the effect of systemic injections of the D1-family receptor antagonist (10 μg/kg, s.c.) on yohimbine-induced reinstatement and Fos induction, and that of mPFC SCH23390 (0.5 and 1.0 μg/side) injections on this reinstatement. Yohimbine-induced reinstatement was associated with strong Fos induction in the dorsal mPFC and with weaker Fos induction in the ventral mPFC. Systemic SCH23390 injections blocked both yohimbine-induced reinstatement and mPFC Fos induction. Dorsal, but not ventral, mPFC injections of SCH23390 decreased yohimbine-induced reinstatement of food seeking. In addition, dorsal mPFC SCH23390 injections decreased pellet-priming-induced reinstatement, but had no effect on ongoing high-fat pellet self-administration or discrete-cue-induced reinstatement. Results indicate a critical role of dorsal mPFC dopamine D1-family receptors in stress-induced relapse to palatable food seeking, as well as relapse induced by acute re-exposure to food taste, texture, and smell. SCH23390相似文献
2.
Rationale
In human and animal studies, adolescence marks a period of increased vulnerability to the initiation and subsequent abuse of drugs. Adolescents may be especially vulnerable to relapse, and a critical aspect of drug abuse is that it is a chronically relapsing disorder. However, little is known of how vulnerability factors such as adolescence are related to conditions that induce relapse, triggered by the drug itself, drug-associated cues, or stress.Objective
The purpose of this study was to compare adolescent and adult rats on drug-, cue-, and stress-induced reinstatement of cocaine-seeking behavior.Methods
On postnatal days 23 (adolescents) and 90 (adults), rats were implanted with intravenous catheters and trained to lever press for i.v. infusions of cocaine (0.4 mg/kg) during two daily 2-h sessions. The rats then self-administered i.v. cocaine for ten additional sessions. Subsequently, visual and auditory stimuli that signaled drug delivery were unplugged, and rats were allowed to extinguish lever pressing for 20 sessions. Rats were then tested on cocaine-, cue-, and yohimbine (stress)-induced cocaine seeking using a within-subject multicomponent reinstatement procedure.Results
Results indicated that adolescents had heightened cocaine seeking during maintenance and extinction compared to adults. During reinstatement, adolescents (vs adults) responded more following cocaine- and yohimbine injections, while adults (vs adolescents) showed greater responding following presentations of drug-associated cues.Conclusion
These results demonstrated that adolescents and adults differed across several measures of drug-seeking behavior, and adolescents may be especially vulnerable to relapse precipitated by drugs and stress. 相似文献3.
Casey E. O’Neill Benjamin D. Hobson Sophia C. Levis Ryan K. Bachtell 《Psychopharmacology》2014,231(16):3179-3188
Rationale
Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors.Objectives
These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking.Methods
Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks. Following a 1-week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA, 0.03 and 0.1 mg/kg), the adenosine A2A agonist, CGS 21680 (0.03 and 0.1 mg/kg), the presynaptic adenosine A2A receptor antagonist, SCH 442416 (0.3, 1, and 3 mg/kg), or vehicle prior to each of six daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D2 receptor agonist, quinpirole.Results
All doses of CPA and CGS 21680 impaired initial extinction responding; however, only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking.Conclusions
These findings demonstrate that adenosine A1 or A2A receptor stimulation directly impair extinction responding. Interestingly, adenosine A1 receptor stimulation or presynaptic adenosine A2A receptor blockade during extinction produces lasting changes in relapse susceptibility. 相似文献4.
Jayme R. McReynolds Oliver Vranjkovic Malia Thao David A. Baker Khadijah Makky Yiwei Lim John R. Mantsch 《Psychopharmacology》2014,231(20):3953-3963
Rationale
Understanding the mechanisms responsible for stress-induced relapse is important for guiding treatment strategies aimed at minimizing the contribution of stress to addiction. Evidence suggests that these mechanisms involve interactions between noradrenergic systems and the neuropeptide corticotropin-releasing factor (CRF).Objectives
The interaction between β-adrenergic receptors (ARs) and CRF as it relates to the reinstatement of cocaine-conditioned reward in response to a stressor was examined in mice. We hypothesized that β2-ARs are required for stress-induced activation of CRF pathways responsible for reinstatement.Methods
Stress-induced relapse was examined based on the re-establishment of cocaine-induced conditioned place preference (CPP; 4?×?15 mg/kg cocaine, i.p.) after extinction using forced swim (6 min at 22 °C) or an injection of the β2-AR agonist, clenbuterol (4 mg/kg, i.p.). The CRF-R1 antagonist antalarmin (10 mg/kg, i.p.) or the β2-AR antagonist ICI-118,551 (1 mg/kg, i.p.) were given 30 min prior to reinstating stimuli. Quantitative PCR was conducted in dissected bed nucleus of the stria terminalis (BNST) and amygdala, putative sources of CRF that contribute to reinstatement, to examine the effects of ICI-118,551 on swim-induced increases in CRF messenger RNA (mRNA) in mice with a cocaine history.Results
Pretreatment with ICI-118,551 or antalarmin blocked swim-induced reinstatement of CPP. Reinstatement by clenbuterol was also blocked by antalarmin. ICI-118,551 pretreatment prevented swim-induced increases in CRF mRNA in the BNST. Effects in the amygdala were not observed.Conclusions
These findings indicate that, during stress, norepinephrine, via β2-ARs, either directly or indirectly activates CRF-releasing neurons in the BNST that interface with motivational neurocircuitry to induce reinstatement of cocaine-conditioned reward. 相似文献5.
Rationale
Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.Objectives
The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.Methods
Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.Results
Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.Conclusions
These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse. 相似文献6.
Rationale
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a widely abused drug, particularly in adolescent and young adult populations. Although it was shown that MDMA-associated cues reinstate extinguished MDMA seeking in an animal relapse model, there is little information regarding the neural mechanisms underlying this behavior.Objectives
Because the medial prefrontal cortex (mPFC) plays an important role in relapse to cocaine and methamphetamine seeking, we tested the effects of lidocaine inactivation of prelimbic (PL) and infralimbic (IL) subregions of mPFC on cue-induced relapse to MDMA seeking.Methods
Rats were trained to respond for MDMA infusions (0.50?mg/kg/infusion, i.v.) paired with a discrete cue in daily 2-h sessions. Responding was reinforced contingent on a modified fixed ratio 5 schedule of reinforcement. Cue-induced reinstatement tests were conducted after responding was extinguished in the absence of MDMA and the conditioned cues. Prior to reinstatement tests, rats received bilateral microinjections of either lidocaine (100???g/0.5???l/side) or physiological saline (0.5???l/side) delivered to either PL or IL mPFC.Results
Microinjections of lidocaine into PL completely blocked reinstatement of MDMA-seeking behavior compared with saline microinjections into the same region. Lidocaine microinjections did not, however, have an effect on food-maintained responding, ruling out a nonspecific disruption of motor performance. Conversely, lidocaine inactivation of IL had no effect on reinstatement of MDMA seeking or food-maintained responding.Conclusions
Our results provide direct support for PL activation in reinstatement of MDMA-seeking behavior. Moreover, akin to cocaine seeking, there appears to be differential involvement of PL and IL subregions in this behavior. 相似文献7.
Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. 总被引:6,自引:0,他引:6
Buyean Lee Stefan Tiefenbacher Donna M Platt Roger D Spealman 《Neuropsychopharmacology》2004,29(4):686-693
Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an alpha(2)-adrenoceptor antagonist, is known to be anxiogenic and induce stress-related responses in humans and animals. Here, we tested the ability of yohimbine to reinstate cocaine-seeking behavior and induce behavioral and physiological signs characteristic of stress in squirrel monkeys. Monkeys were trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Drug seeking subsequently was extinguished by substituting saline for cocaine injections and omitting the cocaine-paired stimulus. The ability of yohimbine and the structurally distinct alpha(2)-adrenoceptor antagonist RS-79948 to reinstate cocaine-seeking behavior was assessed by administering priming injections immediately before test sessions in which the cocaine-paired stimulus was either present or absent. Priming injections of yohimbine (0.1-0.56 mg/kg, i.m.) or RS-79948 (0.01-0.1 mg/kg, i.m.) induced dose-related reinstatement of cocaine-seeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocaine-paired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and self-grooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the alpha(2)-adrenoceptor agonist clonidine (0.1-0.3 mg/kg, i.m.) dose-dependently inhibited yohimbine-induced reinstatement of cocaine seeking. In contrast, pretreatment with the dopamine receptor antagonist flupenthixol failed to inhibit yohimbine-induced reinstatement of cocaine seeking. The results show that pharmacological blockade of alpha(2)-adrenoceptors can induce reinstatement of cocaine-seeking behavior and characteristic stress responses in squirrel monkeys, providing a potentially useful model of stress-induced relapse to drug seeking. 相似文献
8.
Rationale
Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.Objective
To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.Methods
Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).Results
Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.Conclusions
Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure. 相似文献9.
Rationale
Stress, a powerful precipitant of drug seeking during abstinence, may also accelerate the return to pathological patterns of intake after initial instances of drug reuse.Objective
To explore the effect of stress on a learning process underlying relapse, this study assessed the effect of yohimbine on reacquisition of oxycodone seeking.Methods
One hundred thirty-two male Sprague?CDawley rats underwent place conditioning with oxycodone (2?mg/kg, SC; ×6?days), extinction (vehicle?×?6?days), and reconditioning with 0, 0.25, 2, or 5?mg/kg oxycodone (2?days). Yohimbine (0, 2.5, or 5?mg/kg, IP) was administered 30?min prior to reconditioning.Results
Pretreatment with 2.5?mg/kg yohimbine increased, while 5?mg/kg yohimbine decreased, reacquisition of oxycodone-induced place preference. A follow-up study (n?=?30) further indicated that the effect of yohimbine was specific to reacquisition.Conclusion
The observation that yohimbine can enhance reacquisition of oxycodone seeking supports the hypothesis that stress can facilitate learning processes involved in the unfolding of relapse. 相似文献10.
Background
Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues.Methods
Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine?+?cocaine-paired stimuli or cocaine?+?cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W?+?P).Results
In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W?+?P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W?+?P treatment was more effective than W or P alone.Conclusion
Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone. 相似文献11.
Rationale
The action of serotonin (5-HT) at the 5-HT2A receptor subtype is thought to be involved in cocaine-seeking behavior that is motivated by exposure to drug-associated cues and drug priming. 5-HT2A receptors are densely clustered in the ventromedial prefrontal cortex (vmPFC), an area that plays a role in mediating cocaine-seeking behavior.Objectives
This study examined the hypothesis that M100907, a 5-HT2A receptor antagonist, infused directly in the vmPFC attenuates cue- and cocaine-primed reinstatement of cocaine-seeking behavior.Methods
Rats trained to self-administer cocaine (0.75?mg/kg, i.v.) paired with light and tone cues underwent extinction training during which operant responses produced no consequences. Once behavior extinguished, rats were tested for reinstatement of responding elicited by either response-contingent presentations of the cocaine-paired light/tone cues or by cocaine-priming injections (10?mg/kg, i.p.) within 1?min after pretreatment with microinfusions of M100907 (0.1, 0.3, 1.0, or 1.5???g/0.2???l/side) into the vmPFC.Results
Intra-vmPFC M100907 decreased cue-elicited reinstatement at the two highest doses (1.0 and 1.5???g) but produced only a slight decrease in cocaine-primed reinstatement that was not dose dependent. The decrease in cue reinstatement was not likely due to impaired ability to respond since intra-vmPFC M100907 infusions had minimal effect on cocaine self-administration and no effect on cue-elicited sucrose-seeking behavior, or spontaneous or cocaine-induced locomotion. M100907 infusions into the adjacent anterior cingulate cortex had no effect on cue reinstatement.Conclusions
The results suggest that the blockade of 5-HT2A receptors in the vmPFC selectively attenuates the incentive motivational effects of cocaine-paired cues. 相似文献12.
Rationale
Systemic amphetamine (AMPH) administration increases the rate of 50-kHz ultrasonic vocalizations (USVs) in adult rats and preferentially enhances the ‘trill’ subtype; these effects of AMPH critically depend on noradrenergic transmission, but the possible contributions of dopamine are unclear.Objective
To assess the role of dopamine in 50-kHz USVs emitted drug-free and following systemic AMPH administration.Methods
Adult male Long–Evans rats pre-selected for high AMPH-induced calling rates were tested with AMPH (1 mg/kg, intraperitoneal (IP)) and saline following pretreatment with the following dopamine receptor antagonists: SCH 23390 (0.005–0.02 mg/kg, subcutaneous (SC)), SCH 39166 (0.03–0.3 mg/kg, SC), haloperidol (0.1, 0.2 mg/kg, IP), sulpiride (20–80 mg/kg, SC), raclopride (0.1–0.5 mg/kg, SC), clozapine (4 mg/kg, SC), risperidone (0.5 mg/kg, SC), and pimozide (1 mg/kg, IP). The dopamine and noradrenaline reuptake inhibitors (GBR 12909 and nisoxetine, respectively) were also tested, alone and in combination.Results
SCH 23390, SCH 39166, haloperidol, and raclopride dose-dependently inhibited vocalizations under AMPH and suppressed the proportion of trill calls. Sulpiride, however, had no discernable effect on call rate or profile, even at a high dose that reduced locomotor activity. Single doses of clozapine, risperidone, and pimozide all markedly decreased calling under saline and AMPH. Finally, GBR 12909 and nisoxetine failed to promote 50-kHz USVs detectably or alter the subtype profile, when tested alone or in combination.Conclusions
The rate of 50-kHz USVs and the call subtype profile following systemic AMPH administration depends on dopaminergic neurotransmission through D1-like and D2-like receptors. However, inhibiting dopamine and/or noradrenaline reuptake appears insufficient to induce calling. 相似文献13.
A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats 总被引:11,自引:3,他引:8
Rationale and objective.
It is well established that stress induces reinstatement of drug seeking in an animal model of relapse. Here we studied the
role of the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) in foot-shock stress-induced reinstatement of cocaine
seeking.
Methods.
Groups of rats were trained to self-administer cocaine (0.5 mg/kg per infusion, i.v., 3 h/day for 9 days) and after ten drug-free
days were exposed to extinction and reinstatement test sessions. Each 60 min of extinction was separated by a 30-min time-out
period after which the lever and stimulus lights were reintroduced. Rats were given four 1-h extinction sessions on day 1
and then on subsequent days were given two to three 1-h extinction sessions that were followed by a 3-h test for reinstatement.
Tests were run every 48 h. In one set of experiments, the effects of inactivation of the prelimbic (PL), infralimbic (IL)
or OFC by tetrodotoxin (TTX, 5 ng/0.5 μl per side) on reinstatement induced by foot shock (5 min, intermittent, 1 mA) or priming
injections of cocaine (20 mg/kg, i.p.) were determined. In a second set, the effects of infusions of the D1-like and D2-like
dopamine receptor antagonists (SCH 23390 and raclopride) were studied using the same methods.
Results.
TTX infusions into the PL cortex blocked both foot shock and cocaine-induced reinstatement. TTX into OFC attenuated foot-shock-induced,
but not cocaine-induced reinstatement. Infusions into IL were ineffective. Infusions of SCH 22390 (0.25 μg/0.5 μl per side)
into either PL or OFC blocked foot-shock-induced reinstatement, but infusions into PL had no effect on cocaine-induced reinstatement.
Raclopride (5 μg/0.5 μl per side) had no effect on foot-shock-induced reinstatement in either PL or OFC or on cocaine-induced
reinstatement when infused into PL. Neither TTX nor SCH23390 infusions into PL or OFC had any effect on lever pressing for
sucrose.
Conclusions.
These results suggest that the PL and OFC regions form part of the circuitry mediating the effects of foot shock stress on
reinstatement of drug seeking and that the PL region may be a common pathway for cue, drug and foot-shock stress-induced reinstatement
of drug seeking. 相似文献
14.
Rose-Marie Karlsson Daniel M. Kircher Yavin Shaham Patricio O’Donnell 《Psychopharmacology》2013,226(1):45-51
Rationale
Patients with schizophrenia exhibit high comorbidity for substance abuse, but the biological underpinnings of this dual-diagnosis condition are still unclear. Previous studies have shown that rats with a neonatal ventral hippocampal lesion (NVHL), a widely used developmental animal model of schizophrenia, exhibit increased cocaine and methamphetamine self-administration and cocaine-induced reinstatement.Objective
Here, we assessed whether a NVHL would also potentiate cue-induced reinstatement of cocaine seeking and the time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving) in adult rats.Methods
Rats were trained to self-administer cocaine (3 or 6 h/day with 0.75 mg?kg?1?infusion?1 paired with a tone-light cue) for 10 days, followed by extinction training (3 h/day) and cue-induced reinstatement of cocaine seeking. Other rats were tested for incubation of cocaine craving, assessed in extinction tests 1 and 30 days after the last self-administration session.Results
Although there was no significant difference in cocaine intake between NVHL and sham controls, NVHL rats took significantly longer to reach an a priori set extinction criterion and exhibited enhanced cue-induced reinstatement. However, while cue-induced cocaine seeking was higher after 30 days than after 1 day of withdrawal (incubation of cocaine craving), the NVHL had no effect on this incubation.Conclusion
These data confirm previous reports on enhanced resistance to extinction after NVHL and demonstrate that NVHL rats exhibit enhanced cue-induced reinstatement of cocaine seeking after extinction, a measure of drug relapse. 相似文献15.
Marsida Kallupi Giordano de Guglielmo Nazzareno Cannella Hong Wu Li Girolamo Caló Remo Guerrini Massimo Ubaldi John J. Renger Victor N. Uebele Roberto Ciccocioppo 《Psychopharmacology》2013,226(2):347-355
Rationale
Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)5]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat.Methods
Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)5]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed.Results
Intraperitoneal administration of NPSR-QA1 (15–30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15–30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)5]NPS (10–30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala.Conclusions
The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment. 相似文献16.
Rationale Neurotensin (NT) has been implicated in some of the behavioral effects of psychostimulants. Thus, there is reason to think
that NT may play a role in the reinstatement of cocaine seeking, and that it may do so via an interaction with dopamine (DA).
Objectives To assess (1) whether NT and an NT analog, D-TYR[11]NT, induce reinstatement of cocaine seeking; (2) whether the effects of
NT receptor activation on reinstatement can be modulated by D1/D5 or D2/D3 antagonists; (3) the specificity of the effects
of NT receptor activation on the reinstatement of cocaine seeking.
Methods In Experiment 1, rats were initially trained to self-administer cocaine. Following a subsequent period of extinction training,
they were tested for the reinstatement of cocaine seeking by NT or D-TYR[11]NT (15, 30 μg i.c.v.). In Experiment 2, rats were
pretreated with the D1/D5 antagonist, SCH 23390 (0.05, 0.10 mg/kg i.p.) or the D2/D3 antagonist, raclopride (0.25, 0.50 mg/kg
i.p.), prior to testing for reinstatement by D-TYR[11]NT (15 μg i.c.v.). In Experiment 3, rats that had been trained to self-administer
sucrose pellets were tested for the reinstatement of sucrose seeking by D-TYR[11]NT (15, 30 μg i.c.v.).
Results (1) Both NT and D-TYR[11]NT produced robust reinstatement of cocaine seeking; (2) the effect of the analog was attenuated
by pretreatment with the D1/D5, but not D2/D3, receptor antagonist; (3) the analog did not induce the reinstatement of sucrose
seeking.
Conclusions The findings suggest that an interaction between NT and DA may contribute to the neurobiology of reinstatement in animals
with a history of cocaine self-administration. 相似文献
17.
Rationale
GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine.Objective
We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure.Methods
α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg).Results
No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not.Conclusions
Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking. 相似文献18.
Rationale
Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success.Objectives
The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration.Methods
Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction.Results
Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test.Conclusion
Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users. 相似文献19.
Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat 总被引:1,自引:0,他引:1
Rationale Corticotropin-releasing factor (CRF) and noradrenaline (NA) have been shown in independent studies to mediate stress-induced
reinstatement of drug seeking. To date, however, a functional interaction between the systems in reinstatement has not been
demonstrated.
Objectives The objectives of this study were to determine whether CRF and NA systems can interact to influence reinstatement responding
and, if so, in what direction the interaction occurs.
Materials and methods Rats were trained to self-administer cocaine (0.23 mg/kg per infusion) for 8–10 days. Subsequently, responding for drug was
extinguished, and tests for reinstatement were conducted following: (1) pretreatment with the CRF receptor antagonist, d-Phe CRF12–41 [1 μg, intracerebroventricular (i.c.v.)], prior to i.c.v. injections of NA (10 μg; Experiment 1); (2) pretreatment with the
α2 adrenoceptor agonist, clonidine (40 μg/kg, i.p.), prior to i.c.v. injections of CRF (0.5 μg; Experiment 2); (3) pretreatment
with d-Phe (1, 5 μg, i.c.v.), prior to systemic injections of the α2 adrenoceptor antagonist, yohimbine (1.25 mg/kg; Experiment 3A); or (4) pretreatment with clonidine (40 μg/kg, i.p.) prior
to systemic injections of yohimbine (0.625 mg/kg, 1.25 mg/kg; Experiment 3B).
Results NA reliably induced reinstatement, an effect that was blocked by pretreatment with d-Phe. In contrast, CRF-induced reinstatement was not attenuated by pretreatment with clonidine. Pretreatment with neither
d-Phe nor clonidine was effective in blocking yohimbine-induced reinstatement.
Conclusion Together, the present findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement
of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA. 相似文献
20.