Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys

Rationale Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour.Objectives The present study, using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S⁺) and a 1-s cue light (CS⁺) or for water in the presence of anise odour (S^–) and 1-s white noise (CS^–), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated.Results Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 g or 1.0 g N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 g of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/OFQ (1.0–2.0 g per rat) significantly inhibited the reinstatement of extinguished ethanol responding under an S⁺/CS⁺ condition, whereas lever pressing under S^–/CS^– was not altered.Conclusions The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli.     

Extended-release venlafaxine in relapse prevention for patients with major depressive disorder

Many studies have demonstrated that venlafaxine is an efficacious and safe treatment for major depressive disorder (MDD). This double-blind, placebo-controlled study was performed to evaluate the efficacy of venlafaxine extended-release (XR) (75-225 mg/day) in the prevention of relapse of depression. Patients with MDD who responded to an 8-week course of venlafaxine XR treatment, i.e., had a score < or = 3 on the Clinical Global Impressions scale-Severity of Illness item (CGI-S) and a 21-item Hamilton Rating Scale for Depression (HAM-D(21)) score < or = 10, were randomly assigned to receive continuation treatment (up to 6 months) with venlafaxine XR (n=161) or placebo (n=157). The main efficacy outcome measure was the number of patients who experienced a relapse of depression. Relapse was defined by either a combination of a patient meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for MDD and a CGI-S score > or = 4, two consecutive CGI-S scores > or = 4, or a final CGI-S score > or = 4 for a patient who withdrew from the study. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. During the 6-month evaluation period, significantly more patients in the placebo group had a relapse of MDD than did patients who continued treatment with venlafaxine XR. Cumulative relapse rates at 3 and 6 months were 19 and 28%, respectively, for venlafaxine XR, and 44 and 52%, respectively, for placebo. This study demonstrates that venlafaxine XR is an effective and safe continuation therapy.     

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics

Rationale Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior.Objectives Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients.Methods We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded.Results Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning.Conclusions This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.     

Infusion of the substance P analogue, DiMe-C7, into the ventral tegmental area induces reinstatement of cocaine-seeking behaviour in rats

Rationale The mesocorticolimbic dopamine (DA) system is critically involved in mediating reinstatement of drug-seeking behaviour. Substance P (SP) is a neuropeptide that significantly interacts with the mesocorticolimbic system, therefore suggesting a possible role for the SP system in the mediation of relapse.Objectives This study examined the effects of injections of the SP analogue, DiMe-C7, into the ventral tegmental area (VTA) on reinstatement of cocaine-seeking behaviour, as well as on locomotor activity in rats. Additionally, this study examined whether these effects are DA-dependent.Methods Rats were trained to self-administer cocaine for 15 days followed by 15 days of extinction. Reinstatement of cocaine-seeking behaviour was then measured in response to bilateral intra-VTA microinjections of DiMe-C7 (0, 0.1, 0.5 and 2.5 g). In a separate group of rats, locomotor activity was measured in response to intra-VTA injections of DiMe-C7 (0, 0.5, 1.5 and 3 g). The effects of pre-treatment with DA receptor antagonists on DiMe-C7-induced reinstatement and locomotor activity were also examined. Animals were pre-treated with the D₁ and D₂ receptor antagonists, SCH23390 and haloperidol (0, 0.01 and 0.03 mg/kg, IP), respectively, prior to receiving intra-VTA injections of DiMe-C7 (0 and 2.5 g).Results Infusion of DiMe-C7 into the VTA increased locomotor activity and induced reinstatement of cocaine-seeking behaviour. Both SCH23390 and haloperidol blocked intra-VTA DiMe-C7-induced locomotor activation. In addition, SCH23390 attenuated DiMe-C7-induced reinstatement of cocaine-seeking behaviour, while haloperidol had no effect.Conclusions These results suggest that interactions between SP and the mesocorticolimbic DA system may play a role in mediating reinstatement of cocaine-seeking behaviour and that the involvement of these interactions in reinstatement are dependent upon D₁ receptor mechanisms.Canadian Institutes of Health Research grant to Franco J. Vaccarino.     

Patterns of abdominal relapse and role of sonography in Wilms tumor

This study characterizes the patterns of abdominal recurrence of Wilms tumor and describes the role of sonography in its detection. Twelve patients who had initial tumor recurrence in the abdomen were evaluated. Five patients had recurrence in the kidney; all had nephrogenic rests detected by computed tomography (CT) or magnetic resonance (MR) imaging but not by sonography. The remaining 7 patients had recurrence in the peritoneum (4), the nephrectomy site (2), or the regional lymph nodes (1); tumor spillage had occurred in five of these patients. Four recurrences were detected during therapy, and eight within 3 years after completion of therapy. Seven of the 12 recurrences were first detected by sonography. All 11 sonograms obtained at the time of relapse showed tumor recurrence. Nine patients died a median of 10 months after relapse. The results suggest that regular sonographic surveillance for 3 years after therapy is likely to reveal most abdominal recurrences. Supplementation with CT or MR imaging is indicated for detection of nephrogenic rests.     

Aftercare attendance and post-treatment functioning of severely substance dependent residential treatment clients

The present study evaluated the impact of a structured aftercare programme following residential treatment for severe alcohol and/or heroin dependent clients. Over 17 months, 77 participants were recruited to the study and allocated randomly to either a structured aftercare (SA) programme or to unstructured aftercare (UA) of crisis counselling on request. Independent clinicians interviewed participants and collaterals, at 4-month (median) intervals, for 12 months following residential treatment. SA compared to UA was associated with a fourfold increase in aftercare attendance and one-third the rate of uncontrolled principal substance use at follow-up. Participants who attended either type of aftercare relapsed a median of 134 days later than those who attended no aftercare. Overall, 23% of monitored participants remained abstinent throughout, 21% maintained controlled substance use and 56% relapsed, within a median of 36 days following residential treatment. The only significant predictor of days to relapse, controlling for age, was pretreatment use of additional substances. Participants with pretreatment additional substance use relapsed a median of 192 days earlier than those who had used no other substances. The degree of agreement between participant self-reports and collateral reports was fair-to-moderate and moderate among collaterals. Intention-to-treat analyses revealed significant and clinically meaningful reductions in substance use in this sample of severely dependent residential treatment clients. The generalizability of these results is limited because of significant differences in age and presenting substance between the study sample and other clients admitted to the service during the study. This latter group of younger, male, heroin-dependent clients with polydrug use who refuse opioid pharmacotherapy, are more likely to drop out of treatment or relapse early following treatment and continue to present a challenge to treatment services. [Sannibale C, Van den Bossche E, O'Connor D, Zador D, Capus C, Gregory K, McKenzie M. Aftercare attendance and post-treatment functioning of severely substance dependent residential treatment clients. Drug Alcohol Rev 2003;22:181 - 190]     

The reinstatement model of drug relapse: history,methodology and major findings

Rational and objectives. The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. Conclusions. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.     

Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats

Rationale and objective Alcohol and tobacco are often co-abused in humans and previous studies found that nicotine increases alcohol consumption in rats. Here, we studied whether nicotine would reinstate alcohol-taking behavior in drug-free rats and whether this effect would be enhanced by prior exposure to nicotine during alcohol self-administration training. Methods Rats were trained to press a lever for alcohol (12% w/v, 1 h/day), and following stable alcohol intake groups of rats (n=11–12) were given daily vehicle or nicotine (0.2, 0.4 or 0.8 mg/kg, SC) injections just prior to the self-administration sessions for 10 days. Rats were then given 6 days of alcohol self-administration in the absence of nicotine and an additional 5–10 drug-free days during which lever presses were not reinforced (extinction). Subsequently, rats were tested for reinstatement of alcohol seeking following exposure to priming injections of vehicle or nicotine (0.4 mg/kg, SC). Results Nicotine increased alcohol self-administration in a dose- and time-dependent manner over the 10-day period. Nicotine also reinstated alcohol seeking after extinction of the alcohol-reinforced behavior, and this effect was strongly enhanced by prior nicotine exposure. Conclusions The present data extend previous studies on the effect of nicotine on alcohol self-administration, and further indicate that nicotine is an effective stimulus for reinstatement of alcohol seeking during drug-free periods.     

Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats

Rationale Recently, we provided evidence for a cannabinoid mechanism in relapse to cocaine seeking in rats. There is also increasing evidence for functional cross-talk between cannabinoid and opioid systems in several physiological processes. Objectives This study was designed to evaluate whether the cannabinoid system plays a role in mediating the reinforcing and motivational effects of heroin and heroin-paired stimuli. Methods Male Wistar rats were trained to self-administer heroin (50 μg/kg per infusion) on fixed (FR5) or progressive ratio schedules of reinforcement in the presence of a discriminative and discrete heroin-associated cue. The selective cannabinoid CB1 antagonist SR141716A was given 30 min before the session to determine its effect on responding for heroin. Separate groups of rats were subjected to extinction training during which heroin-associated cues were absent and no heroin was delivered. During subsequent reinstatement tests, the effects of the cannabinoid agonist HU210 and the antagonist SR141716A on reinstatement of heroin seeking were evaluated. Results The cannabinoid antagonist dose-dependently reduced responding for heroin on the FR5 schedule and to a greater extent on the progressive ratio schedule. HU210 (20 μg/kg) reinstated heroin seeking behaviour following a 2-week extinction period, whereas SR141716A dose-dependently attenuated heroin seeking that was provoked by a priming injection of heroin (0.25 mg/kg) and heroin seeking that was triggered by re-exposure to heroin paired stimuli. Conclusions The results show that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors. Therefore, the present study provides a rationale for the use of cannabinoid antagonists in the treatment of opiate addiction.     

Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone

Rationale A positive relationship exists between chronic ethanol intoxication experiences and the severity of neural hyperactivity and withdrawal seizures. An important possibility is that withdrawal reactions also influence the motivation to obtain and consume ethanol. Objectives To test this hypothesis, the effects of ethanol-cues on the recovery of extinguished ethanol-seeking and the reversal of this effect by naltrexone, were determined in non-dependent rats and in rats subjected to single versus repeated ethanol intoxications. Methods Rats were trained to self-administer and discriminate between 10% ethanol and water. Instrumental responding then was extinguished and the effects of exposure to ethanol and water cues were determined. Subsequently, rats were divided into three groups and exposed to control vapor (CTRL), to 12-day ethanol vapor prior to withdrawal (SW), or to three cycles of 3-day intoxication experiences (MW), respectively. Following intoxication, reacquisition and breaking point for ethanol self-administration and cues-induced reinstatement of drug-seeking were investigated. Results Ethanol cues significantly reinstated responding in the pre- and post-dependence test, but no significant differences between groups was observed. However, the ability of naltrexone to attenuate the response-reinstatement was significantly reduced in MW rats. Moreover, in the progressive ratio schedule, the breaking points for ethanol were significantly increased in the MW animals. Conclusions The results suggest that repeated intoxication did not enhance cue-induced reinstatement of ethanol-seeking. However, naltrexone effects on cues-induced "relapse" appear to be attenuated in MW rats.