Cortical activation during cocaine use and extinction in rhesus monkeys

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.     

Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats

Rationale

Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.

Objective

Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.

Materials and methods

Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.

Results

Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.

Conclusion

These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.

     

Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats

Rationale

Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activity, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-h “binge” in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected.

Objective

This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited-access self-administration “binge.”

Methods

Long-Evans rats underwent episodic social defeat and were assessed 10 days later for either (1) behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, i.p.), (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3) intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited-access “binge.”

Results

Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer “binge” in both sexes, females had a significantly longer “binge” duration than males.

Conclusions

These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization.     

Stress-induced activation of ventral tegmental mu-opioid receptors reduces accumbens dopamine tone by enhancing dopamine transmission in the medial pre-frontal cortex

Rationale

Endogenous opioids could play a major role in the mesocorticolimbic dopamine (DA) responses to stress challenge. However, there is still no direct evidence of an influence of endogenous opioids on any of these responses.

Objective

We assessed whether and how endogenous opioids modulate fluctuations of mesocortical and mesoaccumbens DA tone in rats during a first experience with restraint stress.

Method

We first evaluated the effects of systemic naltrexone (NTRX) on DA outflow in the medial prefrontal cortex (mpFC) and in the nucleus accumbens (NAc) through dual-probe microdialysis. Second, we assessed the effect of perfusion, through reverse microdialysis, of direct DA receptor agonists in mpFC on NAc DA outflow in NTRX-pretreated stressed rats. Finally, we tested the effects of ventral tegmental area (VTA) perfusion of NTRX, the selective mu1 antagonist naloxonazine and the selective delta antagonist naltrindole on mpFC and NAc DA outflow in stressed rats, with multiple probe experiments.

Results

Systemic NTRX, at behaviorally effective doses, selectively prevented the increase of mpFC DA levels and the reduction of NAc DA levels observable during prolonged restraint. Local co-perfusion of D1 and D2 agonists in mpFC recovered inhibition of NAc DA in NTRX-pretreated restrained rats. Finally, intra-VTA perfusion of either NTRX or the mu1 antagonist, but not the delta antagonist, mimicked the effects of systemic NTRX.

Conclusion

During prolonged experience with a novel unavoidable/uncontrollable stressor, endogenous opioids, through stimulation of mu1 receptors in the VTA, elevate mesocortical DA tone thus reducing DA tone in the NAc DA.     

Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

Rationale

Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation.

Objectives

The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT).

Methods

Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters.

Results

ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT.

Conclusions

Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates.     

Region-specific role of Rac in nucleus accumbens core and basolateral amygdala in consolidation and reconsolidation of cocaine-associated cue memory in rats

Rationale and objectives

Drug reinforcement and the reinstatement of drug seeking are associated with the pathological processing of drug-associated cue memories that can be disrupted by manipulating memory consolidation and reconsolidation. Ras-related C3 botulinum toxin substrate (Rac) is involved in memory processing by regulating actin dynamics and neural structure plasticity. The nucleus accumbens (NAc) and amygdala have been implicated in the consolidation and reconsolidation of emotional memories. Therefore, we hypothesized that Rac in the NAc and amygdala plays a role in the consolidation and reconsolidation of cocaine-associated cue memory.

Methods

Conditioned place preference (CPP) and microinjection of Rac inhibitor NSC23766 were used to determine the role of Rac in the NAc and amygdala in the consolidation and reconsolidation of cocaine-associated cue memory in rats.

Results

Microinjections of NSC23766 into the NAc core but not shell, basolateral (BLA), or central amygdala (CeA) after each cocaine-conditioning session inhibited the consolidation of cocaine-induced CPP. A microinjection of NSC23766 into the BLA but not CeA, NAc core, or NAc shell immediately after memory reactivation induced by exposure to a previously cocaine-paired context disrupted the reconsolidation of cocaine-induced CPP. The effect of memory disruption on cocaine reconsolidation was specific to reactivated memory, persisted at least 2 weeks, and was not reinstated by a cocaine-priming injection.

Conclusions

Our findings indicate that Rac in the NAc core and BLA are required for the consolidation and reconsolidation of cocaine-associated cue memory, respectively.     

Effects of time of feeding on psychostimulant reward, conditioned place preference, metabolic hormone levels, and nucleus accumbens biochemical measures in food-restricted rats

Rationale

Chronic food restriction (FR) increases rewarding effects of abused drugs and persistence of a cocaine-conditioned place preference (CPP). When there is a single daily meal, circadian rhythms are correspondingly entrained, and pre- and postprandial periods are accompanied by different circulating levels of metabolic hormones that modulate brain dopamine function.

Objectives

The present study assessed whether rewarding effects of d-amphetamine, cocaine, and persistence of cocaine-CPP differ between FR subjects tested in the pre- and postprandial periods.

Materials and methods

Rats were stereotaxically implanted with intracerebral microinjection cannulae and an electrode in lateral hypothalamus. Rewarding effects of d-amphetamine and cocaine were assessed using electrical self-stimulation in rats tested 1–4 or 18–21 h after the daily meal. Nonimplanted subjects acquired a cocaine-CPP while ad libitum fed and then were switched to FR and tested for CPP at these same times.

Results

Rewarding effects of intranucleus accumbens (NAc) d-amphetamine, intraventricular cocaine, and persistence of cocaine-CPP did not differ between rats tested 18–21 h food-deprived, when ghrelin and insulin levels were at peak and nadir, respectively, and those tested 1–4 h after feeding. Rats that expressed a persistent CPP had elevated levels of p-ERK1, GluA1, and p-Ser845-GluA1 in NAc core, and the latter correlated with CPP expression.

Conclusions

Psychostimulant reward and persistence of CPP in FR rats are unaffected by time of testing relative to the daily meal. Further, NAc biochemical responses previously associated with enhanced drug responsiveness in FR rats are associated with persistent CPP expression.     

Differential influence of morphine sensitization on accumbens shell and core dopamine responses to morphine- and food-conditioned stimuli

Rationale

Sensitization of the incentive and dopamine (DA) stimulant properties of drug-conditioned stimuli (CSs) by repeated exposure to drugs of abuse has been assigned an important role in the genesis of drug addiction.

Objective

To test in rats if morphine-induced sensitization potentiates incentive and DA-releasing properties in the nucleus accumbens (NAc) shell and core elicited by presentation of a morphine-conditioned stimulus(CS) and if this property generalizes to a non-drug-(palatable food, Fonzies)-CS.

Methods

Controls and rats previously sensitized by morphine were trained via three daily sessions consisting of a 10-min presentation of CS (Fonzies filled box, FB) followed by s.c. saline and morphine (1 mg/kg) or by standard food and Fonzies. Rats were implanted with microdialysis probes and the next-day incentive reactions and NAc shell and core DA were monitored during CS presentation and subsequent morphine (1 mg/kg) administration or Fonzies feeding.

Results

Morphine sensitization increased incentive and NAc shell and core DA responses to morphine-CS. Morphine conditioning per se increased incentive reactions and NAc shell but not core DA responses to FB presentation. Morphine sensitization potentiated incentive responses but did not affect NAc shell and core DA responses to Fonzies-CS. Fonzies conditioning increased incentive reactions and NAc core but not shell DA responses to FB presentation.

Conclusions

These observations confirm the prediction of the incentive sensitization theory in the case of drug-CS but not of non-drug-CS. NAc DA might be differentially involved in the expression of incentive sensitization of drug- and non-drug-CSs, thus providing a clue for the abnormal incentive properties of drug CSs.     

Effects of chronic alcohol exposure on dopamine uptake in rat nucleus accumbens and caudate putamen

Rationale

Existing data strongly suggest that alcohol affects dopamine (DA) neurotransmission in the brain. However, many questions remain about the effects of alcohol on the delicate equilibrium between such neurochemical processes as DA release and uptake. Dysregulation of these processes in the mesolimbic and nigrostriatal systems after chronic alcohol ingestion could be a neuroadaptation contributing to dependence.

Objectives

In the present study, we have employed an alcohol vapor inhalation model to characterize the effects of chronic alcohol exposure on DA dynamics in rat nucleus accumbens (NAc) and caudate putamen (CP) using fast-scan cyclic voltammetry (FSCV) in brain slices. This method provides a unique view of real-time, spatially resolved changes in DA concentration.

Results

We found that chronic alcohol exposure enhanced DA uptake rates in rat NAc and CP. These changes would have the effect of down-regulating extracellular DA levels, presumably a compensatory effect related to increased DA release by repeated alcohol exposure. The sensitivity of terminal release-regulating DA autoreceptors was not different in alcohol-exposed rats compared with alcohol-naïve animals.

Conclusions

The DA uptake changes after chronic alcohol exposure documented here using FSCV may be associated with a compensatory response of the DA system aimed at decreasing DA signaling. Alterations in autoreceptor function may require relatively long lasting alcohol exposure.

     

Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats

Rationale

The serotonin 5-HT_2A and 5-HT_2C receptors regulate the capacity of acute cocaine to augment behavior and monoamine levels within the nucleus accumbens (NAC), a brain region involved in cocaine??s addictive and psychotogenic properties.

Objectives

In the present study, we tested the hypothesis that NAC 5-HT_2A and 5-HT_2C receptor activation is involved in the expression of cocaine-induced neuroplasticity following protracted withdrawal from a sensitizing repeated cocaine regimen (days?1 and 7, 15?mg/kg; days?2?C6, 30?mg/kg, i.p.).

Methods

The effects of intra-NAC infusions of the 5-HT_2A antagonist R-(+)-??-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (MDL 100907; 0, 50, 100, 500?nM) or the 5-HT_2C antagonist [6-chloro-5-methyl-1-(6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] inodoline dihydrochloride (SB 242084; 0, 50, 100, 500?nM) were first assessed upon the expression of locomotor activity elicited by a 15-mg/kg cocaine challenge injection administered at 3-week withdrawal. A follow-up in vivo microdialysis experiment then compared the effects of the local perfusion of 0, 50, or 100?nM of each antagonist upon cocaine-induced dopamine and glutamate sensitization in the NAC.

Results

Although neither MDL 100907 nor SB 242084 altered acute cocaine-induced locomotion, SB 242084 reduced acute cocaine-elevated NAC dopamine and glutamate levels. Intra-NAC perfusion with either compound blocked the expression of cocaine-induced locomotor and glutamate sensitization, but only MDL 100907 pretreatment prevented the expression of cocaine-induced dopamine sensitization.

Conclusions

These data provide the first evidence that NAC 5-HT_2A and 5-HT_2C receptors are critical for the expression of cocaine-induced neuroplasticity following protracted withdrawal, which has relevance for their therapeutic utility in the treatment of addiction.     

Speedball induced changes in electrically stimulated dopamine overflow in rat nucleus accumbens

Cocaine/heroin combinations (speedball) induce a synergistic elevation in extracellular dopamine concentrations ([DA]_e) in the nucleus accumbens (NAc) that can explain the increased abuse liability of speedball. To further delineate the mechanism of this neurochemical synergism, in vivo fast-scan cyclic voltammetry (FSCV) was used to compare NAc DA release and reuptake kinetic parameters following acute administration of cocaine, heroin and speedball in drug-naïve rats. These parameters were extracted from accumbal DA overflow induced by electrical stimulation of the ventral tegmental area. Evoked DA efflux was increased following both cocaine and speedball delivery, whereas heroin did not significantly change evoked DA release from baseline. DA efflux was significantly greater following cocaine compared to speedball. However, DA transporter (DAT) apparent affinity (K_m) values were similarly elevated following cocaine and speedball administration, but unaffected by heroin. Neither drug induced substantial changes in the maximal reuptake rate (V_max). These data, combined with published microdialysis and electrophysiological results, indicate that the combination of cocaine-induced competitive inhibition of DAT and the increase in the DA release elicited by heroin is responsible for the synergistic increase in ([DA]_e) induced by speedball.     

The effect of chronic amphetamine treatment on cocaine-induced facilitation of intracranial self-stimulation in rats

Rationale

Chronic amphetamine treatment reduces cocaine self-administration in pre-clinical and clinical settings, and amphetamine has been proposed as a candidate medication for treatment of cocaine abuse.

Objective

The objective of the present study was to investigate whether chronic amphetamine treatment can decrease abuse-related cocaine effects in an assay of intracranial self-stimulation (ICSS).

Methods

Thirteen adult male Sprague-Dawley rats were equipped with intracranial electrodes targeting the medial forebrain bundle and trained to lever press for pulses of brain stimulation in a “frequency-rate” ICSS procedure. Cocaine (10 mg/kg) was administered before (day 0), during (days 7 and 14), and after (posttreatment days 1 and 3) 2 weeks of continuous treatment with either amphetamine (0.32 mg/kg/h, n?=?7) or saline (n?=?6) via osmotic pump.

Results

Prior to treatment, cocaine facilitated ICSS in all rats. Saline treatment had no effect on baseline ICSS or cocaine-induced facilitation of ICSS at any time. Conversely, amphetamine produced a sustained though submaximal facilitation of baseline ICSS, and cocaine produced little additional facilitation of ICSS during amphetamine treatment. Termination of amphetamine treatment produced a depression of baseline ICSS and recovery of cocaine-induced facilitation of ICSS.

Conclusions

These data suggest that chronic amphetamine treatment blunts expression of abuse-related cocaine effects on ICSS in rats.     

Ventral tegmental area α6β2 nicotinic acetylcholine receptors modulate phasic dopamine release in the nucleus accumbens core

Rationale

Phasic dopamine (DA) signaling underlies reward learning. Cholinergic and glutamatergic inputs into the ventral tegmental area (VTA) are crucial for modulating burst firing activity and subsequent phasic DA release in the nucleus accumbens (NAc), but the specific VTA nicotinic receptor subtypes that regulate phasic DA release have not been identified.

Objective

The goal was to determine the role of VTA N-methyl-d-aspartate receptors (NMDARs) and specific subtypes of nicotinic acetylcholine receptors (nAChRs) in regulating phasic DA release in the NAc core.

Methods

Fast-scan cyclic voltammetry in anesthetized rats was combined with intra-VTA micro-infusion to evaluate the ability of glutamatergic and cholinergic drugs to modulate stimulated phasic DA release in the NAc core.

Results

VTA NMDAR blockade with AP-5 decreased, while VTA NMDAR activation with NMDA increased NAc peak phasic DA release. Intra-VTA administration of the nonspecific nAChR antagonist mecamylamine produced a persistent decrease in phasic DA release. Infusion of the α6-selective antagonist α-conotoxin MII (α-ctx MII) produced a robust, but transient decrease in phasic DA, whereas infusion of selective doses of either the α4β2-selective antagonist, dihydro-beta-erythroidine, or the α7 antagonist, methyllycaconitine, had no effect. Co-infusion of AP-5 and α-ctx MII produced a similar phasic DA decrease as either drug alone, with no additive effect.

Conclusions

The results suggest that VTA α6β2 nAChRs, but not α4β2 or α7 nAChRs, regulate phasic DA release in the NAc core and that VTA α6β2 nAChRs and NMDA receptors act at a common site or target to regulate NAc phasic DA signaling.     

Attenuation of cocaine-induced conditioned locomotion is associated with altered expression of hippocampal glutamate receptors in mice lacking LPA1 receptors

Rationale

Lysophosphatidic acid is a phospholipid mediator that modulates neurodevelopment and neurogenesis in the hippocampus through its actions on LPA1 receptors. Emerging evidences support LPA₁ as a mediator of learning and emotional behaviour. There are no studies addressing its role on behaviours associated to drug abuse.

Objectives

We examined whether genetic deletion of LPA1 receptor in maLPA₁-null mice affected either cocaine-induced conditioned locomotion (CL) or behavioural sensitization (BS) induced by repeated cocaine exposure. We also analysed whether cocaine induced changes in the expression of functional markers of both dopamine- and glutamate-related genes in the striatum and the dorsal hippocampus.

Methods

We monitored cocaine-induced CL and BS in both genotypes of mice. Striatal dopamine and hippocampal glutamate-related genes were measured by real-time quantitative PCR, Western blot, and immunohistochemistry.

Results

maLPA₁-null mice exhibit an attenuated CL response after cocaine conditioning but a normal BS after repeated cocaine exposure. These behavioural changes were associated to alterations on the expression of metabotropic mGLUR3 glutamate receptors and on the actions of cocaine on the GLUR1 subunit of AMPA glutamate receptors in the hippocampus of maLPA₁ animals. Striatal dopaminergic markers (tyrosine hydroxylase, dopamine D1 receptor, and dopamine transporter DAT), were similar in both genotypes and were equally affected by cocaine exposure.

Conclusion

The present results indicate that the lack of LPA1 receptor affect cocaine-induced conditioned locomotion but not behavioural sensitization. The findings suggest that LPA1 receptor may be necessary for a normal associative contextual learning associated to cocaine, probably through the modulation of hippocampal glutamatergic circuits.     

Association of time-dependent changes in mu opioid receptor mRNA, but not BDNF, TrkB, or MeCP2 mRNA and protein expression in the rat nucleus accumbens with incubation of heroin craving

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.     

Serum levels of sFas and sFasL in subjects with type 2 diabetes — the impact of arterial hypertension

Aim

To evaluate the serum levels of sFas and sFasL in normotensive subjects with different degree of impairment of glucose tolerance as well as in type 2 diabetic patients with treated and treatment-naïve hypertension (AHT).

Material and methods

124 subjects (63 males and 61 females), of mean age 46,31±10,78 years are included in the study, divided in 5 age-matched groups: 19 subjects with type 2 diabetes (DM) and drug-controlled AHT; 30 subjects with type 2 DM and drug-naïve AHT; 30 normotensive subjects with type 2 DM; 26 normotensive subjects with prediabetes and 19 healthy controls. Serum sFas and sFasL levels are determined by highly sensitive enzyme immunoassay technique.

Results

No significant differences in sFas are observed among the studied groups. The levels of sFasL are decreased in normotensive subjects with type 2 DM (p<0,05), while subjects with prediabetes have intermediate values. In both hypertensive groups with DM sFasL levels are further decreased.

Conclusions

Serum sFas levels probably are not associated with the presence of impairment of glucose tolerance or AHT. Serum sFasL values tend to be decreased in subjects with impairment in glucose tolerance; further decrease is observed in hypertensive subjects with type 2 DM. Antihypertensive treatment does not influence the levels of sFasL.     

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration

Rationale Buprenorphine reduces both heroin and cocaine intake in opioid addicts, but the mechanisms remain unclear.Objectives To determine the effects of chronic buprenorphine treatment on intake of heroin and/or cocaine and measure nucleus accumbens (NAc) dopamine (DA) levels during self-administration.Methods In experiment 1, plasma levels of buprenorphine were determined in rats with buprenorphine osmotic minipumps (3.0 mg/kg/day) using an ELISA. In experiment 2, rats self-administered (FR1) one dose of heroin [(0.025, 0.05, or 0.1 mg/kg/infusion (inf)] and one dose of cocaine (0.25, 0.5, or 1.0 mg/kg/inf) before and under sham or chronic buprenorphine treatment (1.5 or 3.0 mg/kg/day). In experiment 3, the effect of sham or chronic buprenorphine treatment (3.0) on heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration under FR5 and progressive ratio (PR) schedules was evaluated. In experiment 4, in vivo microdialysis sampling from the NAc was carried out during heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration (FR1) under sham or buprenorphine treatment (3.0).Results Buprenorphine levels in plasma were stable over time. Buprenorphine treatment had no effect on total heroin intake at any dose or under any schedule, whereas it suppressed cocaine intake at all doses and under all schedules. Buprenorphine enhanced basal levels of DA, attenuated the NAc DA response to heroin, and enhanced the DA response to cocaine. It is interesting to note that buprenorphine increased the latency to respond to drug-associated cues at the start of self-administration sessions.Conclusions Chronic buprenorphine reduces cocaine, but not heroin, intake and possibly reduces drug seeking by reducing the salience of the drug-associated cues.     

ERP evidence suggests executive dysfunction in ecstasy polydrug users

Background

Deficits in executive functions such as access to semantic/long-term memory have been shown in ecstasy users in previous research. Equally, there have been many reports of equivocal findings in this area. The current study sought to further investigate behavioural and electro-physiological measures of this executive function in ecstasy users.

Method

Twenty ecstasy–polydrug users, 20 non-ecstasy–polydrug users and 20 drug-naïve controls were recruited. Participants completed background questionnaires about their drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a semantic retrieval task whilst 64 channel Electroencephalography (EEG) measures were recorded.

Results

Analysis of Variance (ANOVA) revealed no between-group differences in behavioural performance on the task. Mixed ANOVA on event-related potential (ERP) components P2, N2 and P3 revealed significant between-group differences in the N2 component. Subsequent exploratory univariate ANOVAs on the N2 component revealed marginally significant between-group differences, generally showing greater negativity at occipito-parietal electrodes in ecstasy users compared to drug-naïve controls. Despite absence of behavioural differences, differences in N2 magnitude are evidence of abnormal executive functioning in ecstasy–polydrug users.     

Increased breakpoints on a progressive ratio schedule reinforced by IV cocaine are associated with reduced locomotor activation and reduced dopamine efflux in nucleus accumbens shell in rats

Rationale

It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction.

Objectives

The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule.

Materials and methods

Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined.

Results

Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens.

Conclusion

The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.