Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice

Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear. In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5 g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens. Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5 mg/kg) or morphine (10 mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20 mg/kg) in adult mice. These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age.     

Cocaine responsiveness or anhedonia in rats treated with methylphenidate during adolescence

Methylphenidate (MPH) treatment in boys diagnosed with ADHD is reported to decrease the risk of drug abuse in adulthood. Similarly, MPH treatment appears to decrease the cocaine preference of male rats during conditioned place preference (CPP) tests. However, the effects of MPH treatment on later drug use of girls/women or CPP in female rodents have not been fully examined, nor have a clinically-relevant MPH dose and/or administration route been thoroughly studied. Here, Sprague–Dawley rats (n = 34/sex/treatment) were treated orally 3×/day on postnatal days (PNDs) 29–50 with water or 3 mg MPH/kg, a dose producing serum levels within the human clinical range. CPP assessments to cocaine (10 mg/kg, ip) (PNDs 62–71) indicated MPH-treated rats were less active during pre- and postconditioning sessions (p < .04), but there were no significant MPH-related differences in conditioning strength. Baseline open field activity at PND 84 indicated that MPH-treated females were more active than same-sex controls (p < .05). A cocaine challenge (10 mg/kg, ip) elevated activity similarly in MPH-treated and controls of both sexes. As an anhedonia measure, saccharin solution intake on PNDs 87–90 indicated no significant MPH effects. Estrous cycle phase did not appear to affect cocaine response during CPP or open field assessments. Hormonal levels at PND 90 indicated 63% higher corticosterone levels in MPH-treated females relative to same-sex controls (p < .05), a finding that deserves further investigation. These results address some of the major issues surrounding animal models of MPH treatment and provide additional support for a lack of severe long-term behavioral effects of adolescent MPH.     

Effects of morphine and methadone treatments on glutamatergic transmission in rat frontal cortex

The effects of repeated administration of morphine and methadone, followed by a challenge dose of either morphine or methadone were examined ex vivo in rat frontal cortical slices that were prepared 1 h after final drug administration. Morphine challenge dose (5 mg/kg), administered 14 days after the end of repeated morphine pretreatment (10 mg/kg, administered 7 times) decreased both the AMPA/kainate and the NMDA components of field potentials that were evoked in cortical layer II/III by electrical stimulation. This effect did not occur either when a methadone challenge dose (2.5 mg/kg) was administered instead of morphine or after repeated morphine treatment. Moreover, after repeated methadone treatment (2.5 mg/kg, administered 7 times), neither morphine nor methadone challenge affected AMPA/kainate or NMDA components of the field potentials. These data indicate a specific effect of repeated morphine followed by morphine challenge on cortical glutamatergic transmission.     

Treatment-like steady-state methadone in rats interferes with incubation of cocaine sensitization and associated alterations in gene expression

In a previous study, steady-state methadone treatment was found to prevent associative cocaine learning, as well as related decreases in mRNA expression of preprohypocretin/preproorexin (ppHcrt) in the lateral hypothalamus (LH) and dopamine D2 receptor (DR2) in the caudate-putamen (CP), and increases in mu-opioid receptor in the ventral striatum of rats. To investigate whether the same regimen of methadone exposure could prevent the incubation of cocaine sensitization and related alterations in gene expression, male Sprague–Dawley rats received 45 mg/kg/day steady-dose “binge” cocaine administration (IP) for 14 days followed by mini-pumps releasing 30 mg/kg/day methadone (SC). After 14 days of methadone, and a subsequent 10-day drug-free period, all rats were tested for sensitization (cocaine test dose: 15 mg/kg) and brain tissue was collected to quantify mRNA expression. Rats exposed to cocaine displayed cocaine-induced stereotypy at test, as well as enhanced ppHcrt mRNA in the LH and reduced DR2 mRNA in the CP. Importantly, these alterations were significantly reduced in rats treated with methadone following cocaine. These results suggest that steady-state methadone can interfere with the incubation of neuroadaptations underlying changes in behavioral responses to cocaine and cocaine-associated stimuli, and that these effects can be observed even after withdrawal from methadone.     

Thermal sensitivity as a measure of spontaneous morphine withdrawal in mice

IntroductionOpioid withdrawal syndrome is a critical component of opioid abuse and consists of a wide array of symptoms including increases in pain sensitivity (hyperalgesia). A reliable preclinical model of hyperalgesia during opioid withdrawal is needed to evaluate possible interventions to alleviate withdrawal. The following study describes a method for assessing increases in thermal sensitivity on the hotplate in a mouse model of spontaneous morphine withdrawal.MethodsC57BL/6J mice received 5.5 days of 30, 56, or 100 mg/kg morphine or saline (s.c., twice daily). In Experiment I, thermal sensitivity data were collected at baseline and at 8, 24, 32, 48 h and 1 week following the final injection. Thermal sensitivity was assessed by examining latency to respond on a hotplate across a range of temperatures (50, 52, 54, and 56 °C). In Experiment II, 0.01 mg/kg buprenorphine was administered 30 min prior to each testing session during the withdrawal period. In Experiment III, jumping during a 30 min period was assessed at baseline and at 0, 8, 24, 32, and 48 h following the final morphine injection.ResultsDuring the withdrawal period, thermal sensitivity increased significantly in all morphine-treated mice as compared to saline-treated mice. Thermal sensitivity was greater in mice treated with 56 mg/kg morphine compared to 30 mg/kg and peaked earlier than in mice treated with 100 mg/kg (32 h v 1 wk). The increase in thermal sensitivity following 56 mg/kg morphine was attenuated by a dose of buprenorphine that did not produce antinociception alone (i.e., 0.01 mg/kg). In general, the results of the jumping experiment paralleled those obtained in Experiment I.DiscussionResponse latency on the hotplate is a reliable and sensitive measure of spontaneous morphine withdrawal in mice, making it an ideal behavior for assessing the potential of medications and environmental interventions to alleviate opioid withdrawal.     

Stress-opioid interactions: a comparison of morphine and methadone

The utility of methadone and morphine for analgesia and of methadone for substitution therapy for heroin addiction is a consequence of these drugs acting as opioid receptor agonists.We compared the cataleptogenic and antinociceptive effects of single subcutaneous doses of methadone hydrochloride (1–4 mg/kg) and morphine sulfate (2.5–10 mg/kg) using catalepsy and hot-plate tests, and examined the effects of the highest doses of the drugs on Fos protein expression in selected brain regions in male Sprague-Dawley rats. Methadone had greater cataleptogenic and analgesic potency than morphine. Fos immunohistochemistry revealed substantial effects on the Fos response of both the stress induced by the experimental procedures and of the drug exposure itself. There were three response patterns identified: 1) drug exposure, but not stress, significantly elevated Fos-positive cell counts in the caudate-putamen; 2) stress alone and stress combined with drug exposure similarly elevated Fos-positive cell counts in the nucleus accumbens and cingulate cortex; and 3) methadone and morphine (to a lesser extent) counteracted the stimulatory effect of nonpharmacological stressors on Fos protein expression in the somatosensory cortex barrel field, and Fos-positive cell counts in this region correlated negatively with both the duration of catalepsy and the latency time in the hot-plate test. The overlap between brain regions reacting to nonpharmacological stressors and those responding to exogenous opioids suggests that stress contributes to opioid-induced neuronal activation.     

A comparison of mecamylamine and bupropion effects on memory-related responses induced by nicotine and scopolamine in the novel object recognition test in mice

BackgroundThe aim of the present study was to evaluate the involvement of the cholinergic receptors ligands in the memory-related responses in mice, using the novel object recognition (NOR) test.MethodsThe NOR test is based on natural, exploratory abilities of animals exposed to a new environment. In the first session, two copies of the same object were presented. In the next sessions (30 min and 24 h after), one of the familiar object and a new object were presented.ResultsThe mice injected with nicotine (0.035 and 0.175 mg/kg, free base, sc) before the first session spent more time exploring the new object than the familiar one at the second and third session, indicating that nicotine improved cognition. In turn, the mice injected with scopolamine (0.3 and 1 mg/kg, ip) before the first session spent less time exploring the new object than the familiar one at the second and third trial, indicating that scopolamine impaired the memory performance. Additionally, the acute injection of drugs used in smoking cessation in humans: mecamylamine (0.5 and 1 mg/kg) and bupropion (5 and 10 mg/kg), prior to injections of nicotine (0.035 mg/kg) or scopolamine (1 mg/kg), significantly prevented nicotine-induced memory improvement or scopolamine-induced memory impairment, at the second and third session.ConclusionsThe results of our studies unveiling neuronal mechanisms for cholinergic system of memory processes, via both nicotinic and muscarinic cholinergic receptors, will be useful for development of more effective pharmacotherapies for memory impairment-like treatment of human disorders in which cholinergic pathways have been implicated.     

Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain.

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.     

Inhibitory actions of mGlu4 receptor ligands on cocaine-, but not nicotine-, induced sensitizing and conditioning locomotor responses in rats

BackgroundMale Wistar rats were used to verify the hypothesis that metabotropic glutamate 4 (mGlu₄) receptor ligands may modulate the locomotor effects evoked by cocaine or nicotine.MethodsThe preferential mGlu₄ receptor orthosteric agonist (2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl]phosphoryl]butanoic acid (LSP1-2111) and the mGlu₄ receptor positive allosteric modulator (+)-cis-N¹-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide (Lu AF21934) were used in the study. Rats were given repeated pairings of a test environment with cocaine (10 mg/kg), nicotine (0.4 mg/kg) or the respective vehicles for 5 days. On day 10, animals were challenged with cocaine (10 mg/kg, cocaine sensitization), nicotine (0.4 mg/kg, nicotine sensitization) or vehicle (conditioned hyperlocomotion) in experimental cages.ResultsGiven on day 10, LSP1-2111 (3 mg/kg) as well as Lu AF21934 (2.5–5 mg/kg) decreased the expression of cocaine sensitization. In another set of experiments, LSP1-2111 (3 mg/kg) and Lu AF21934 (5 mg/kg) administered on day 10 attenuated the conditioned hyperlocomotion in rats treated repeatedly with cocaine. Neither LSP1-2111 (1–3 mg/kg) nor Lu AF21934 (2.5–5 mg/kg) changed the expression of nicotine sensitization and conditioned hyperlocomotion in rats treated repeatedly with nicotine. None of the mGlu₄ receptor agonist/modulator altered the basal locomotor activity or acute hyperactivity to cocaine or nicotine.ConclusionsThe present data indicate that pharmacological stimulation of mGlu₄ receptors reduces the cocaine-induced expression of sensitization as well as conditioned hyperactivity. In contrast, mGlu₄ receptor activation seems to be devoid of any effect on the locomotor effects of nicotine.     

Critical evaluation of the use of extinction paradigms for the assessment of opioid-induced conditioned place preference in rats

The rewarding effects of drugs of abuse are often studied by means of the conditioned place preference (CPP) paradigm. CPP is one of the most widely used models in behavioral pharmacology, yet its theoretical underpinnings are not well understood, and there are very few studies on the methodological and theoretical aspects of this model. An important drawback of the classical CPP paradigm is that it often does not show dose-dependent results. The persistence of the conditioned response, i.e. the time required until the CPP effect is extinct, may be related to the strength of conditioning, which in turn may be related to the rewarding efficacy of a drug. Resistance to extinction may therefore be a useful additional measure to quantify the rewarding effect of drugs. In the present study we examined the persistence of drug-environment associations after conditioning with morphine (1, 3 and 10 mg/kg i.p.), oxycodone (0.3, 1 and 3 mg/kg i.p.) and heroin (0.05, 0.25 and 0.5 mg/kg i.p.) by repeated retesting in the CPP apparatus (15-min sessions, 5 days/week) until the rats reached extinction (i.e. less than 55% preference over 3 consecutive sessions). Following an unbiased CPP protocol, morphine, oxycodone and heroin induced CPP with minimal effective doses of 3, 1 and 0.25 mg/kg, respectively, and with similar effect sizes for each CPP-inducing dose. The number of sessions required for extinction was positively correlated with the dose of the drug (experiment 1: 18 and 45 sessions for 3 and 10 mg/kg morphine, and 19 and 27 sessions for 1 and 3 mg/kg oxycodone; experiment 2: 12 and 24 sessions for 3 and 10 mg/kg morphine, and 10 and 14 sessions for 0.25 and 0.5 mg/kg heroin). These findings suggest that the use of an extinction paradigm can extend the quantitative assessment of the rewarding effect of drugs - however, within certain limits only. The present paradigm appears to be less suited for comparing the rewarding efficacy of different drugs due to great test-retest variability. Finally, the additional potential gain of information using this paradigm has to be weighed against the considerably large amount of additional time and effort.     

Effect of combined treatment with mirtazapine and risperidone on the MK-801-induced changes in the object recognition test in mice

BackgroundSeveral clinical reports have suggested that the mirtazapine-induced augmentation of risperidone activity may effectively improve treatment of the negative and certain cognitive symptoms of schizophrenia.MethodsThe aim of the present study was to evaluate the effect of mirtazapine and risperidone, given separately or jointly, on the impact of MK-801(an NMDA receptor antagonist), given prior to the first introductory session, on the object recognition memory in mice. To this end, we used the object recognition test in which animals were tested for the ability to discriminate between an old, familiar and a novel object. Mirtazapine (2.5 or 5 mg/kg) and risperidone (0.01 mg/kg) were given 30 min before MK-801, and MK-801 (0.1 or 0.2 mg/kg) was administered 30 min before the first introductory session. Memory retention was evaluated 1.5 h after the introductory session.ResultsThe obtained results showed that MK-801 (0.2 mg/kg) decreased memory retention when given before the introductory session. Co-treatment with risperidone (0.01 mg/kg) and mirtazapine (2.5 or 5 mg/kg) abolished the effect of MK-801, whereas those drugs given separately did not change the action of MK-801.ConclusionsThe obtained results suggest that mirtazapine may enhance the antipsychotic-like effect of risperidone in the animal test modeling some cognitive symptoms of schizophrenia. Further studies are necessary to elucidate its mechanism of action.     

The role of beta-endorphin in the acute motor stimulatory and rewarding actions of cocaine in mice

Rationale Opioid receptor antagonists have been shown to attenuate the rewarding and addictive effects of cocaine. Furthermore, cocaine has been shown to cause the release of beta-endorphin, an endogenous opioid peptide. Objective We assessed whether this neuropeptide would play a functional role in cocaine-induced motor stimulation and conditioned place preference (CPP). Materials and methods Mice lacking beta-endorphin and their wild-type littermates were habituated to motor activity chambers for 1 h, then injected with cocaine (0, 15, 30, or 60 mg/kg, intraperitoneally) or morphine (0, 5, or 10 mg/kg, subcutaneously), and motor activity was recorded for 1 h. In the CPP paradigm, mice were tested for baseline place preference on day 1. On days 2 and 3, mice received an alternate-day saline/cocaine (15, 30, or 60 mg/kg) or saline/morphine (10 mg/kg) conditioning session and then tested for postconditioning place preference on day 4. Results Cocaine-induced motor stimulation and CPP were both reduced in mice lacking beta-endorphin. On the other hand, motor stimulation and CPP induced by morphine were not altered in mutant mice. Conclusion The present results demonstrate that the endogenous opioid peptide beta-endorphin plays a modulatory role in the motor stimulatory and rewarding actions of acute cocaine.     

Effects of GABAB receptor agonists on cocaine hyperlocomotor and sensitizing effects in rats

The present study was designed to find out whether pharmacological activation of GABA_B receptors played a role in cocaine sensitization. To this end, male Wistar rats were injected with baclofen or 3-aminopropyl(methyl)phosphinic acid (SKF 97541), the potent and selective GABA_B receptor agonists. The rats, which were repeatedly (for 5 days) administered with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) after 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in saline-pretreated and cocaine challenged rats. Baclofen (1.25, 2.5 and 5 mg/kg), administered for 5 days prior to cocaine, dose-dependently attenuated cocaine sensitization. When injected in the same treatment regimen, SKF 97541 (0.03 mg/kg) reduced the development of cocaine sensitization. To examine the effects of baclofen and SKF 97541 on the expression of cocaine sensitization, the drugs were given acutely before a challenge dose of cocaine (10 mg/kg) on day 10. Either baclofen (2.5 and 5 mg/kg) or SKF 97541 (0.1 mg/kg) decreased sensitization to cocaine. Our findings implicate a role of GABA_B receptors in locomotor responses to cocaine. More specifically, they show that stimulation of GABA_B receptors exerted inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, what may offer a therapeutic potential of GABA_B receptor agonists in the treatment of cocaine dependence.     

Dimenhydrinate produces a conditioned place preference in rats

Dimenhydrinate (DMH; trade names Gravol and Dramamine) is a compound of diphenhydramine (DP) and 8-chlorotheophylline in equimolar ratios. DMH has been reported to be abused by humans for its euphoric and hallucinogenic properties but few studies have evaluated its reinforcing effects in animals. To evaluate the hypothesis that DMH and its constituents DP and 8-chlorotheophylline are rewarding in animals, rats were tested for conditioned place preference (CPP). The paradigm consisted of pre-exposure (three 15-min sessions of access to both sides of the chamber), conditioning [eight 30-min pairings of one side with drug (four sessions) and, on alternate days, the other side with vehicle (four sessions)] and test phases (three 15-min sessions of access to both sides of the chamber). Significant preferences for the drug-paired location were found on test session one after conditioning with 60.0, but not 25.0, 40.0 or 50.0 mg/kg of DMH, and after conditioning with 37.8 but not 27.0 or 32.4 mg/kg of DP. No preference was found after conditioning with 23.0, 27.6 or 32.2 mg/kg of 8-chlorotheophylline. All three drugs stimulated locomotor activity during conditioning sessions and DMH and DP showed sensitization over conditioning sessions. DMH doses that showed sensitization (25.0 and 40.0 mg/kg) were lower than the dose (60.0 mg/kg) that produced a CPP revealing a dissociation of locomotor stimulating versus rewarding effects. Results reveal that DMH and DP have rewarding properties, although the molar equivalent dose-response curve for DP appeared to be further to the right than that for DMH. Future investigations into the neurotransmitter systems modulating this effect are awaited.     

Assessment of propofol,midazolam and ziprasidone,or the combinations for the prevention of acute cocaine toxicity in a mouse model

Study objectiveTo evaluate the effects of pretreatment, midazolam (M), propofol (P), ziprasidone (Z), and two combinations of [(midazolam plus propofol (MP); midazolam plus ziprasidone (MZ)] in mice models in the prevention of seizures, and death due to acute cocaine toxicity.Methods180 male CF-1 mice were randomized to 6 groups (30/group) in this experimental study. The animals were administered intraperitoneal injections of M (2 mg/kg), P (25 mg/kg), Z (4 mg/kg), MP (2 mg/kg and 25 mg/kg) and MZ (2 mg/kg and 4 mg/kg) or saline (S) as a pretreatment. 10 min later, the mice were administered intraperitoneal injections of 105 mg/kg cocaine. The groups were observed for cocaine-induced seizure and lethality.ResultsThe MP and MZ combinations showed the highest protective effect in terms of seizure and lethality relative to P and S (p < 0.001). M and Z were found effective compared to P and S (p < 0.001). There were no significant differences among MP and MZ, however there were significant differences between MP and Z in terms of lethality (p = 0.05). There were no significant differences among MP, MZ, M and Z groups in terms of seizure (p > 0.05). No death was observed in the MP combination group. Seizure rate was observed o be least in the MZ group with respect to the other groups.ConclusionAccording to our particular mouse model, this study suggests that MP and MZ combinations may be more effective than M or Z only for the prevention of cocaine-induced seizure and lethality. However, P alone does not prevent cocaine-induced seizure and lethality.     

Characterization of conditioned place preference to cocaine in congenic dopamine transporter knockout female mice

Rationale The dopamine transporter (DAT) is thought to play a major role in the rewarding effects of cocaine. Therefore, it is surprising that cocaine reveals conditioned effects in DAT knockout (DAT-KO) mice.Objectives To examine these findings further, we obtained complete dose–effect curves for DAT-KO and DAT wild-type (DAT-WT) mice in a cocaine conditioned place preference (CPP) procedure.Methods Congenic C57BL6 background female DAT-KO and DAT-WT mice were conditioned in a three-compartment place preference apparatus. Conditioning consisted of three 30-min sessions with cocaine (2.5, 5.0, 10.0, 20.0, or 40.0 mg/kg) and three 30-min sessions with saline. The distribution of time in each choice compartment was determined after each pair of conditioning sessions (one cocaine and one saline session).Results DAT-WT mice revealed CPP over a wide range of cocaine doses (5.0–40 mg/kg), whereas DAT-KO mice revealed CPP over a more restricted range of doses, with consistent CPP only occurring with 10 mg/kg of cocaine.Conclusions CPP for cocaine develops in both DAT-KO and DAT-WT mice; however, the dose range at which CPP develops is much more restricted in DAT-KO mice than in DAT-WT mice. These observations corroborate the significant role of DAT inhibition in cocaines conditioned effects.     

5-HT3 receptor antagonists do not modify cocaine place conditioning or the rise in extracellular dopamine in the nucleus accumbens of rats

Three 5-HT₃ receptor antagonists, MDL 72222, tropisetron, and ondansetron were studied for their ability to modify the conditioned place preference (CPP) induced by 10 mg/kg IP cocaine in rats. MDL 72222 (0.03–3 mg/kg SC) and tropisetron (0.01–0.1 mg/kg SC) administered, respectively, 30 min and 1 h before each conditioning session, did not affect the acquisition of cocaine CPP. Ondansetron (0.01–0.1 mg/kg SC) administered 30 min before each conditioning session or just before testing likewise had no effect. At 0.1 mg/kg SC ondansetron did not modify the increase of extracellular dopamine caused by 10 mg/kg cocaine in the nucleus accumbens. The results suggest that 5-HT₃ receptor antagonists have no effect on the rewarding properties of cocaine or on the behaviour elicited by the stimuli previously associated with the drug's action.     

The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine

The effects of the anti-relapse compound acamprosate (calcium acetylhomotaurinate) on the conditioned rewarding effects of ethanol, cocaine and morphine were studied using the conditioned place preference (CPP) paradigm. During 3 days of drug conditioning, mice were pretreated with saline or acamprosate (30, 100 or 300 mg kg(-1) i.p.) 10 min prior to the administration of ethanol (2 g kg(-1) i.p.), cocaine (15 mg kg(-1) i.p.) or morphine (10 mg kg(-1) i.p.), and subsequently confined to one of two distinct conditioning chambers. On the following day, mice were tested for the expression of CPP. Acamprosate dose-dependently reduced the development of CPP to ethanol and cocaine but not morphine. When tested as the conditioning drug, acamprosate alone produced neither a conditioned place preference nor aversion. These data suggest that acamprosate can suppress the conditioned rewarding effects of ethanol and certain classes of abused substances.     

Improvements in health-related quality of life among methadone maintenance clients in Dar es Salaam,Tanzania

BackgroundInjection of heroin has become widespread in Dar es Salaam, Tanzania and is spreading throughout the country. To prevent potential bridging of HIV epidemics, the Tanzanian government established a methadone maintenance treatment (MMT) clinic in February 2011. We assess the effect of MMT on health-related quality of life (HRQOL) and examine factors, particularly HIV infection and methadone dose, associated with changes in HRQOL.MethodsThis study utilized routine data on clients enrolling in methadone from February 2011 to April 2012 at Muhimbili National Hospital. Change in physical (PCS) and mental health (MCS) composite scores, as measured by the SF-12 tool, were the primary outcomes. Backward stepwise linear regression, with a criterion of p < 0.2 was used to identify baseline exposure variables for inclusion in multivariable models, while adjusting for baseline scores.ResultsA total of 288 MMT clients received baseline and follow-up assessments. Mean methadone dose administered was 45 mg (SD ± 25) and 76 (27%) were confirmed HIV-positive. Significant improvements were observed in PCS and MCS, with mean increases of 15.7 and 3.3, respectively. In multivariable models, clients who had previous poly-substance use with cocaine [p = 0.040] had a significantly higher mean change in PCS. Clients who were living with HIV [p = 0.002]; satisfied with current marital situation [p = 0.045]; had a history of suicidal thoughts [p = 0.021]; and previously experienced cognitive difficulties [p = 0.012] had significantly lower mean change in PCS. Clients with shorter history of heroin use [p = 0.012] and who received higher methadone doses [p = 0.028] had significantly higher mean change in MCS, compared to their counterparts.ConclusionAspects of mental and physical health, risk behaviors and quality of life among drug users are intertwined and complex. Our research revealed positive short-term effects of MMT on HRQOL and highlights the importance of sustained retention for optimal benefits. Comprehensive supportive services in addition to provision of methadone are needed to address the complex health needs of people who inject drugs.     

Protective effect of HMG CoA reductase inhibitors against running wheel activity induced fatigue,anxiety like behavior,oxidative stress and mitochondrial dysfunction in mice

BackgroundChronic fatigue stress (CFS) is an important health problem with unknown causes and unsatisfactory prevention strategies, often characterized by long-lasting and debilitating fatigue, myalgia, impairment of neuro-cognitive functions along with other common symptoms. The present study has been designed to explore the protective effect of statins against running wheel activity induced fatigue anxiety.MethodsMale albino Laca mice (20–30 g) were subjected to swim stress induced fatigue in a running wheel activity apparatus. Atorvastatin (10, 20 mg/kg, po) and fluvastatin (5, 10 mg/kg, po) were administered daily for 21 days, one hour prior to the animals being subjected to running wheel activity test session of 6 min. Various behavioral tests (running wheel activity, locomotor activity and elevated plus maze test), biochemical parameters (lipid peroxidation, nitrite concentration, glutathione levels and catalase activity) and mitochondrial complex enzyme dysfunctions (complex I, II, III and IV) were subsequently assessed.ResultsAnimals exposed to 6 min test session on running wheel for 21 days showed a significant decrease in number of wheel rotations per 6 min indicating fatigue stress like behavior. Treatment with atorvastatin (10 and 20 mg/kg) and fluvastatin (10 mg/kg) for 21 days significantly improved the behavioral alterations [increased number of wheel rotations and locomotor activity, and anxiety like behavior (decreased number of entries and time spent in open arm)], oxidative defence and mitochondrial complex enzyme activities in brain.ConclusionPresent study suggests the protective role of statins against chronic fatigue induced behavioral, biochemical and mito-chondrial dysfunctions.