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1.
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2.
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3.
Rationale and objective
The N-methyl-d-aspartate receptor agonist d-cycloserine (DCS) facilitates extinction following Pavlovian fear conditioning or conditioned place preference in rats, but its effects on extinction following operant conditioning are not previously established. We studied the effects of DCS on operant extinction with mice, previously shown to be facilitated by GABAergic potentiators including chlordiazepoxide.Materials and methods
Following training of lever pressing by C57Bl/6 male mice on a discrete-trial fixed-ratio food reinforcement schedule with six reinforcers per session, 48-trial extinction sessions were conducted at 3- (Experiment 1) or 4-day intervals (Experiment 2). Effects of DCS (15 or 30 mg/kg, i.p.) administered immediately after 48-trial extinction sessions were compared with those of saline injections.Results
With 3-day intervals between extinction sessions, post-session administration of DCS facilitated extinction, and this effect was stronger with 4-day intervals between extinction sessions. Facilitation of extinction by post-session drug administration persisted over a number of extinction sessions.Conclusions
Operant extinction in mice can be facilitated by DCS, a glutamatergic agonist, as well as by GABAergic potentiators. The relationship between glutamatergic and GABAergic processes in operant extinction is yet to be established. These findings strengthen the basis for clinical uses of DCS. 相似文献4.
Rationale and objective
The N-methyl-d-aspartate receptor agonist, d-cycloserine (DCS), accelerates extinction of a cocaine-induced conditioned place preference (CPP) when given after daily extinction tests. Here, we studied the effects of DCS in rats given spaced-extinction sessions at 3- or 7-day intervals using two different extinction procedures.Materials and methods
Rats were trained on a CPP (four cocaine, 10 mg/kg, i.p., and four saline pairings with one of two compartments). Immediately following the CPP test and all extinction tests (days 4, 7, 10, and 24, experiment 1), DCS (15 mg/kg, i.p.) or saline was administered. In experiment 2, extinction was conducted by exposing rats to the drug-paired cues for 2 or 20 min, three times, at 7-day intervals followed immediately by DCS or saline. After extinction, tests for retention and cocaine-induced reinstatement were given.Results
In experiment 1, rats given DCS lost the cocaine CPP after one extinction trial, an effect that persisted for 2 weeks after the last DCS injection and that was resistant to cocaine-induced reinstatement. In experiment 2, extinction was facilitated by DCS compared to saline when rats received 2-min exposures to the conditioned stimulus. Longer 20-min exposures minus/plus repeated testing led to retention of extinction in both groups regardless of DCS treatment.Conclusions
Extinction of appetitive conditioning is facilitated by DCS after 1–3 post-spaced trial injections, and retention is lasting and resistant to reinstatement. The facilitative effects appear early in extinction, but when extinction procedures are intensive, DCS appears to have no additional benefit. 相似文献5.
Madalyn Hafenbreidel Carolynn Rafa Todd Robert C. Twining Jennifer J. Tuscher Devin Mueller 《Psychopharmacology》2014,231(24):4585-4594
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6.
Florence R. M. Theberge Charles L. Pickens Evan Goldart Sanya Fanous Bruce T. Hope Qing-Rong Liu Yavin Shaham 《Psychopharmacology》2012,224(4):559-571
Rationale and objectives
Responding to heroin cues progressively increases after cessation of heroin self-administration (incubation of heroin craving). We investigated whether this incubation is associated with time-dependent changes in brain-derived neurotrophic factor (BDNF) and methyl-CpG binding protein 2 (MeCP2) signaling and mu opioid receptor (MOR) expression in nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC). We also investigated the effect of the preferential MOR antagonist naloxone on cue-induced heroin seeking during abstinence.Methods
We trained rats to self-administer heroin or saline for 9?C10?days and then dissected the NAc, DS, and mPFC at different abstinence days and measured mRNA and protein levels of BDNF, TrkB, and MeCP2, as well as MOR mRNA (Oprm1). In other groups, we assessed cue-induced heroin seeking in extinction tests after 1, 11, and 30 abstinence days, and naloxone??s (0?C1.0?mg/kg) effect on extinction responding after 1 and 15?days.Results
Cue-induced heroin seeking progressively increased or incubated during abstinence. This incubation was not associated with changes in BDNF, TrkB, or MeCP2 mRNA or protein levels in NAc, DS, or mPFC; additionally, no molecular changes were observed after extinction tests on day?11. In NAc, but not DS or mPFC, MOR mRNA decreased on abstinence day?1 and returned to basal levels over time. Naloxone significantly decreased cue-induced heroin seeking after 15 abstinence days but not 1?day.Conclusions
Results suggest a role of MOR in incubation of heroin craving. As previous studies implicated NAc BDNF in incubation of cocaine craving, our data suggest that different mechanisms contribute to incubation of heroin versus cocaine craving. 相似文献7.
Rationale and objective
Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, d-cycloserine (DCS), in C57BL/6 mice were compared.Materials and methods
Following a palatability test (Experiment 1), Experiments 2–6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task.Results
CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 3–7) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre-session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two-lever food-reinforced task (Experiment 7).Conclusions
The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated. 相似文献8.
Michael E. Saladin Kevin M. Gray Aimee L. McRae-Clark Steven D. LaRowe Sharon D. Yeatts Nathaniel L. Baker Karen J. Hartwell Kathleen T. Brady 《Psychopharmacology》2013,226(4):721-737
Rationale/objectives
This study examined the effects of propranolol vs. placebo, administered immediately after a “retrieval” session of cocaine cue exposure (CCE), on craving and physiological responses occurring 24 h later during a subsequent “test” session of CCE. It was hypothesized that compared to placebo-treated cocaine-dependent (CD) individuals, propranolol-treated CD individuals would evidence attenuated craving and physiological reactivity during the test session. Secondarily, it was expected that group differences identified in the test session would be evident at a 1-week follow-up CCE session. Exploratory analyses of treatment effects on cocaine use were also performed at follow-up.Methods
CD participants received either 40 mg propranolol or placebo immediately following a “retrieval” CCE session. The next day, participants received a “test” session of CCE that was identical to the “retrieval” session except no medication was administered. Participants underwent a “follow-up” CCE session 1 week later. Craving and other reactivity measures were obtained at multiple time points during the CCE sessions.Results
Propranolol- vs. placebo-treated participants evidenced significantly greater attenuation of craving and cardiovascular reactivity during the test session. Analysis of the follow-up CCE session data did not reveal any group differences. Although there was no evidence of treatment effects on cocaine use during follow-up, this study was insufficiently powered to rigorously evaluate differential cocaine use.Conclusions
This double-blind, placebo-controlled laboratory study provides the first evidence that propranolol administration following CCE may modulate memories for learning processes that subserve cocaine craving/cue reactivity in CD humans. Alternative interpretations of the findings were considered, and implications of the results for treatment were noted. 相似文献9.
Danielle S. Counotte Christopher Schiefer Yavin Shaham Patricio O’Donnell 《Psychopharmacology》2014,231(8):1675-1684
Rationale and objective
There is evidence that cue-induced sucrose seeking progressively increases after cessation of oral sucrose self-administration (incubation of sucrose craving) in both adolescent and adult rats. The synaptic plasticity changes associated with this incubation at different age groups are unknown. We assessed whether incubation of sucrose craving in rats trained to self-administer sucrose as young adolescents, adolescents, or adults is associated with changes in 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio (a measure of postsynaptic changes in synaptic strength) in nucleus accumbens.Methods
Three age groups initiated oral sucrose self-administration training (10 days) on postnatal day (P) 35 (young adolescents), P42 (adolescents), or P70 (adults). They were then tested for cue-induced sucrose seeking (assessed in an extinction test) on abstinence days 1 and 21. Separate groups of rats were trained to self-administer sucrose or water (a control condition), and assessed for AMPA/NMDA ratio in nucleus accumbens on abstinence days 1–3 and 21.Results
Adult rats earned more sucrose rewards, but sucrose intake per body weight was higher in young adolescent rats. Time-dependent increases in cue-induced sucrose seeking (incubation of sucrose craving) were more pronounced in adult rats, less pronounced in adolescents, and not detected in young adolescents. On abstinence day 21, but not days 1–3, AMPA/NMDA ratio in nucleus accumbens were decreased in rats that self-administered sucrose as adults and adolescents, but not young adolescents.Conclusions
Our data demonstrate age-dependent changes in magnitude of incubation of sucrose craving and nucleus accumbens synaptic plasticity after cessation of sucrose self-administration. 相似文献10.
Megan M. Moran-Santa Maria Aimee McRae-Clark Nathaniel L. Baker Viswanathan Ramakrishnan Kathleen T. Brady 《Psychopharmacology》2014,231(21):4157-4165
Rationale
Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations.Objectives
The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women.Methods
In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n?=?32), cocaine-dependent women (n?=?30), control men (n?=?32), and control women (n?=?25) received either yohimbine or placebo prior to two cocaine cue exposure sessions.Results
Yohimbine increased ratings of anxiety both before (p?0.001) and after (p?=?0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p?=?0.001). Yohimbine also significantly increased craving, compared with placebo (p?0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p?=?0.006). Yohimbine also increased salivary cortisol (p?0.001) and dehydroepiandrosterone (p?=?0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p?0.001).Conclusions
Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions. 相似文献11.
Rationale
Continuous administration of d-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of d-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19–0.75 mg/kg/inf.Objectives
The present study tested whether these effects were a reflection of pharmacological interactions between d-amphetamine and cocaine or if they resulted from associative learning mechanismsMethods
After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic minipumps filled with either d-amphetamine (5 mg/kg/day—groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with d-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions.Results
In replication of previous studies, d-amphetamine treatment resulted in a significant (35 %) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2).Conclusions
Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous d-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking. 相似文献12.
Leonard L. Howell John R. Votaw Mark M. Goodman Kimberly P. Lindsey 《Psychopharmacology》2010,208(2):191-199
Rationale
Acute re-exposure to cocaine or drug cues associated with cocaine use can elicit drug craving and relapse. Neuroimaging studies have begun to define neurobiological substrates underlying the acute effects of cocaine or cocaine cues in cocaine-dependent subjects.Objective
The present study was the first to use functional brain imaging to document acute cocaine-induced changes in brain activity during active drug use in nonhuman primates.Materials and methods
Positron emission tomography imaging with O15-labeled water was used to measure drug-induced changes in cerebral blood flow. The acute effects of cocaine administered noncontingently were characterized in four drug-naïve rhesus monkeys. The same subjects were trained to self-administer cocaine under a fixed ratio schedule during image acquisition. Subsequently, three subjects with an extensive history of cocaine use were trained to self-administer cocaine under a second-order schedule. The same subjects also underwent extinction sessions during which saline was substituted for cocaine under the second-order schedule.Results
Noncontingent administration of cocaine in drug-naïve subjects induced robust activation of prefrontal cortex localized primarily to the dorsolateral regions. In contrast, the pattern of brain activation induced by self-administered cocaine differed qualitatively and included anterior cingulate cortex. Moreover, drug-associated stimuli during extinction also induced robust activation of prefrontal cortex.Conclusions
The effects of cocaine and associated cues extend beyond the limbic system to engage brain areas involved in cognitive processes. The identification of neural circuits underlying the direct pharmacological and conditioned stimulus effects of cocaine may be highly relevant toward efforts to develop treatments for cocaine addiction. 相似文献13.
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14.
O-Seok Kang Song-Yi Kim Geon-Ho Jahng Hackjin Kim Jong-Woo Kim Sun-Yong Chung Jun-Won Kim Seung-In Yang Hi-Joon Park Hyejung Lee Younbyoung Chae 《Psychopharmacology》2013,228(1):119-127
Rationale
Cue reactivity is a key factor in modulating motivational and goal-directed behaviors associated with compulsive drug intake and relapse. Smoking-associated cues produce smoking urges and cravings and are accompanied by the activation of brain regions involved in attention, motivation, and reward.Objectives
We investigated whether acupuncture ameliorates cravings induced by smoking-related visual cues, and we explored the neural mechanisms underlying the effects of acupuncture on modulating smoking urges.Methods
After 36 h of smoking abstinence, 25 right-handed male smokers underwent fMRI, during which smoking-related and neutral visual cues were presented. Twelve subjects were treated with real acupuncture (RA) at HT7 and 13 subjects received sham acupuncture (SA). During the scanning sessions, craving scores to smoking-related visual cues were assessed before and after RA or SA treatment. The differences in brain responses to smoking vs. neutral cues after treatment between the RA and SA groups were detected using three-way ANOVAs (Cue × Session × Group).Results
After treatment, the craving scores were significantly decreased in the RA group, as compared to the SA group. When we explored the neural substrates of acupuncture on the modulation of cravings induced by smoking cues, significant differences were found in the medial prefrontal cortex, the premotor cortex, the amygdala, the hippocampus, and the thalamus.Conclusions
These findings suggest that acupuncture alleviates cue-induced cravings through the regulation of activity in brain regions involved in attention, motivation, and reward relative to craving scores in the initial abstinence phase. 相似文献15.
Joshua A. Peck Racheli Wercberger Elina Kariyeva Robert Ranaldi 《Psychopharmacology》2013,228(4):651-658
Rationale and objectives
Most animal research on drug relapse involves the reinstatement model where abstinence is a result of drug removal (extinction). However, abstinence in humans often results from the aversive consequences that accompany drug seeking (conflict situation). This study was aimed at using a conflict-based animal model of abstinence/relapse in rats self-administering heroin or cocaine.Methods
Rats were trained to self-administer heroin (0.05 mg kg?1 injection?1) or cocaine (0.5 mg kg?1 injection?1) with each injection paired with a light cue. After stable responding was demonstrated, the floor near the levers was electrified, creating a barrier, in order to model the negative consequences of continued drug seeking. Shock intensities were increased over sessions until no responses occurred for three consecutive sessions. During a relapse test, where shock was maintained,the capacity of noncontingent drug cue presentations to induce active lever pressing was assessed.Results
Ten of ten heroin animals and three of eight cocaine animals exposed to noncontingent cue presentations resumed responding. During the relapse test, for both drug groups, active lever pressing was significantly higher than during abstinence but only in the heroin group was it significantly higher than inactive lever pressing.Conclusions
The implementation of negative consequences for drug seeking can result in its cessation just as they might in human addicts. Similarly, exposure to drug cues can lead to resumption of drug seeking. This model may be useful for studying the mechanisms underlying abstinence and relapse and for developing strategies to prevent relapse. 相似文献16.
Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery 总被引:3,自引:0,他引:3
Smolka MN Bühler M Klein S Zimmermann U Mann K Heinz A Braus DF 《Psychopharmacology》2006,184(3-4):577-588
Rationale
In nicotine-dependent subjects, cues related to smoking elicit activity in brain regions linked to attention, memory, emotion and motivation. Cue-induced brain activation is associated with self-reported craving but further correlates are widely unknown.Objectives
This study was conducted to investigate whether brain activity elicited by smoking cues increases with severity of nicotine dependence and intensity of cue-elicited craving.Methods
Ten healthy male smokers whose degree of nicotine dependence ranged from absent to severe were investigated. Visual smoking cues and neutral stimuli were presented in a block design during functional magnetic resonance imaging (fMRI). Using multiple linear regression analysis, the blood oxygen level dependent (BOLD) response to smoking cues was correlated with severity of nicotine dependence assessed with the Fagerström Test of Nicotine Dependence (FTND) and with cue-induced craving.Results
Significant positive correlations between the BOLD activity and FTND scores were found in brain areas related to visuospatial attention (anterior cingulate cortex, parietal cortex, parahippocampal gyrus and cuneus) and in regions involved in motor preparation and imagery (primary and premotor cortex, supplementary motor area). Intensity of cue-induced craving was significantly associated with greater BOLD activation in mesocorticolimbic areas engaged in incentive motivation and in brain regions related to episodic memory.Conclusions
Our study suggests that severity of nicotine dependence and intensity of craving are independently associated with cue-induced brain activation in separate neuronal networks. The observed association between severity of dependence and brain activity in regions involved in allocation of attention, motor preparation and imagery might reflect preparation of automated drug taking behavior thereby facilitating cue-induced relapse. 相似文献17.
Rationale
Disruption of acquired drug–cue associations can effectively decrease relapse. The benefits of extinction training as opposed to abstinence have been reported. Timing of extinction trials is an important variable. Finding an effective extinction regimen can optimize addiction therapies.Objective
To determine the effects of different drug-free periods on cocaine-conditioned place preference (CPP) in rats that either did or did not receive non-reinforced exposure to drug-associated stimuli.Materials and methods
Male adolescent rats were trained for cocaine-CPP (5, 10, or 15 mg/kg, i.p.) in a biased manner for 8 days and then tested following different intervals.Results
Rats treated with 15 mg/kg cocaine displayed high and equal CPP on the first test, performed 1, 4, 7, or 14 days following conditioning. Expression of CPP during the test performed 1 day after conditioning was equal in the groups conditioned with 5, 10, or 15 mg/kg cocaine. When the interval before the first test was extended to 14 days, the group treated with 5 mg/kg did not show CPP. Rats treated with the three doses and tested repeatedly at 1, 7, and 14 days did not display CPP on the third test. CPP after treatment with 10 or 15 mg/kg cocaine was already extinguished in the second test but only for an interval of 1–14 days.Conclusions
Maintenance of CPP was evident at least 2 weeks after forced abstinence. Extinguished CPP can be obtained after a single extinction trial, performed close to original training and followed by prolonged abstinence. However, with low doses of cocaine, abstinence alone may be sufficient to disrupt drug–cue associations. 相似文献18.
Matthew P. Bradstreet Stephen T. Higgins F. Joseph McClernon Rachel V. Kozink Joan M. Skelly Yukiko Washio Alexa A. Lopez Marie A. Parry 《Psychopharmacology》2014,231(10):2145-2158
Rationale
Research is needed on initial smoking abstinence and relapse risk.Objective
This study aims to investigate the effects of different durations of initial abstinence on sensitivity to smoking-related stimuli and response inhibition in the context of a larger battery of outcome measures.Methods
Smokers were randomly assigned to receive payment contingent on smoking abstinence across all 15 study days (15C) or just the final 2 days (2C). Smoking status and subject ratings were assessed daily. Participants completed fMRI sessions at baseline and day 14 during which they completed craving ratings after exposure to smoking-related and neutral stimuli and performed a response inhibition task. On day 15, participants completed a smoking preference session involving 20 exclusive choices between smoking and money.Results
The payment contingencies were effective in producing greater smoking abstinence in the 15C vs. 2C conditions. Ratings of withdrawal decreased, while ratings of ease and confidence in abstaining increased in the 15C vs. 2C conditions across the 15-day study. 15C participants were less likely to choose the smoking option in the preference session. 15C participants reported greater reductions in craving compared to the 2C participants in the presence of smoking-related and neutral stimuli (i.e., decreases in generalized craving), but no differences were noted in cue reactivity per se or in response inhibition.Conclusions
Results systematically replicate prior observations that a period 2 weeks of initial abstinence decreases the relative reinforcing effects of smoking and improves other outcomes associated with relapse risk compared to the initial day or two of a cessation effort, and extends them by underscoring the importance of generalized rather than cue-induced craving in relation to relapse risk during the initial weeks of smoking cessation. 相似文献19.
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20.