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Morphine withdrawal increases locomotor sensitisation, relapse and impair regulation of serotonin system. We evaluated the effectiveness of Raha syrup on the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitisation in morphine-withdrawn rats receiving the opium tincture (OT). Morphine withdrawal rats gavaged daily with OT and Raha syrup (for 30 days) and then challenged with morphine and evaluated for locomotor activity and CSF serotonin levels before morphine challenge and 2 weeks after cessation of treatment. Raha syrup attenuated locomotor activity, increased the CSF serotonin after morphine challenge, and continued 2 weeks after cessation of treatment in rats receiving OT. Whereas, rats receiving OT alone after morphine challenge exhibited a relative decrease in locomotor activity, without changing CSF serotonin. Raha syrup attenuated locomotor sensitisation in morphine-withdrawn rats receiving OT probably by increasing serotonin. Therefore, administration of Raha syrup along with OT may benefit to treatment relapse in addicts receiving OT maintenance treatment.

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BACKGROUND: Individuals with schizophrenia have high rates of comorbid substance use problems. One potential explanation for this comorbidity is similar neuropathophysiology in substance use and schizophrenia, which may arise from shared genetic risk factors between the two disorders. Here we investigated if genetic risk for schizophrenia could affect drug reward and reinforcement for cocaine in an established mouse model of genetic risk for schizophrenia, the neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) mouse. METHODS: We examined drug-induced locomotor sensitization and conditioned place preference for several cocaine doses (5, 10, 20, 30 mg/kg) in male adult Nrg1 TM HET and wild-type-like (WT) littermates. We also investigated intravenous self-administration of and motivation for cocaine (doses 0.1, 0.5, 1 mg/kg/infusion), as well as extinction and cue-induced reinstatement of cocaine. In a follow-up experiment, we examined self-administration, extinction and cue-induced reinstatement of a natural reward, oral sucrose. RESULTS: Cocaine preference was similar between Nrg1 TM HET mice and WT littermates at all doses tested. Locomotor sensitization to cocaine was not affected by Nrg1 genotype at any dose. Although self-administration and motivation for cocaine was unaffected, extinction of cocaine self-administration was impaired in Nrg1 TM HET compared to WT controls, and cue-induced reinstatement was greater in Nrg1 mutants in the middle of the reinstatement session. Sucrose self-administration and extinction thereof was not affected by genotype, but inactive lever responding was elevated during cue-induced reinstatement for operant sucrose in Nrg1 TM HET mice compared to WTs. DISCUSSION: These results suggest impaired response inhibition for cocaine in Nrg1 TM HET mice and suggests Nrg1 mutation may contribute to behaviours which can limit control over cocaine use.

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BACKGROUND: Agomelatine is a melatoninergic antidepressant approved to treat the major depressive disorder. Agomelatine exerts its behavioural, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors and the blockade of 5-HT2B and 5-HT2C serotonin receptors. Some studies have reported that the activation of the MT1 and MT2 melatonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. These findings from another study showed that agomelatine decreased alcohol consumption. This study aimed to evaluate the effects of agomelatine administration on cocaine-induced behavioural (cocaine-induced locomotor activity and cocaine-induced locomotor sensitisation) and neurochemical (dopamine levels) effects. METHODS: Male Wistar rats (250-280 g) received cocaine (10 mg/kg) during the induction and expression of locomotor sensitisation. Agomelatine (10 mg/kg) was administered 30 minutes before cocaine. After each treatment, locomotor activity was recorded for 30 minutes. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with agomelatine and cocaine. Luzindole (30 mg/kg) was administered to block the agomelatine effect. RESULTS: In this study, we found that agomelatine decreased cocaine-induced locomotor activity and the induction and expression of locomotor sensitisation. In addition, agomelatine decreased cocaine-induced dopamine levels. Luzindole blocked the agomelatine-induced decrease in the expression of locomotor sensitisation in rats. CONCLUSION: Our results suggest (1) that agomelatine showed efficacy in decreasing cocaine psychostimulant effects and (2) that agomelatine can be a useful therapeutic agent to reduce cocaine abuse.

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Objectives: Concurrent abuse of cocaine and nicotine is considered a public health problem. To date, no effective therapy has been known to reduce the reinforcing effects of concurrent use of cocaine and nicotine. Mirtazapine, an antagonist of the α2-adrenoceptor and the 5-HT2A/C and the 5-HT3 receptors has proven effective in reducing the cocaine, nicotine and methamphetamine behavioural effects in humans and animals. Our study evaluated the effect of mirtazapine on enhancing locomotor activity during the induction and expression of locomotor sensitisation induced by a cocaine + nicotine mixture.Methods: Wistar rats were dosed with cocaine, nicotine or cocaine + nicotine combination. Mirtazapine (30 mg/kg, i.p.) was administered during the extinction phase.Results: Mirtazapine decreased cocaine + nicotine-induced locomotor activity and induction and expression of locomotor sensitisation. In addition, we found that co-administration of mecamylamine and mirtazapine significantly enhanced the effect of mirtazapine on cocaine + nicotine-induced locomotor activity during induction and expression of behavioural sensitisation.Conclusions: Our results suggest that mirtazapine demonstrated efficacy in decreasing the psycho-stimulant effects of concurrent use of cocaine and nicotine.

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Smoking tobacco is highly addictive and a leading preventable cause of death. The main addictive constituent is nicotine; consequently it has been administered to laboratory animals to model tobacco dependence. Despite extensive use, this model might not best reflect the powerful nature of tobacco dependence because nicotine is a weak reinforcer, the pharmacology of smoke is complex and non-pharmacological factors have a critical role. These limitations have led researchers to expose animals to smoke via the inhalative route, or to administer aqueous smoke extracts to produce more representative models. The aim was to review the findings from molecular/behavioural studies comparing the effects of nicotine to tobacco/smoke extracts to determine whether the extracts produce a distinct model. Indeed, nicotine and tobacco extracts yielded differential effects, supporting the initiative to use extracts as a complement to nicotine. Of the behavioural tests, intravenous self-administration experiments most clearly revealed behavioural differences between nicotine and extracts. Thus, future applications for use of this behavioural model were proposed that could offer new insights into tobacco dependence.

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Drug addiction is a chronic relapsing brain disease for which many of the underlying neuronal mechanisms are yet to be unravelled. There seems to be an interaction between the melanocortin system and drugs of abuse. For instance, infusion of the melanocortin MC4 receptor antagonist SHU9119 (Ac-Nle-cyclo(-Asp-His-D-2-Nal-Arg-Trp-Lys)-NH2) into the nucleus accumbens results in conditioned place avoidance, reduces the amount of lever presses for cocaine and blocks development of cocaine-induced locomotor sensitisation. The aim of this study is to determine whether the induction of locomotor sensitisation to repeated cocaine is inhibited by the melanocortin MC4 receptor inverse agonist Agouti Related Peptide (AgRP83-132). Rats were sensitised to daily cocaine injections for 5 consecutive days and 30 min prior to every daily cocaine injection, rats received an intracerebroventricular (i.c.v.) or intra nucleus accumbens injection with AgRP(83-132) or saline, to determine whether we could inhibit cocaine-induced locomotor sensitisation. We show that i.c.v. injections of AgRP(83-132) inhibit cocaine-induced locomotor sensitisation. This effect is not regulated via the nucleus accumbens, since injecting the melanocortin receptor inverse agonist AgRP(83-132) directly into the nucleus accumbens was unable to inhibit the cocaine-induced locomotor sensitisation. This implicates that the nucleus accumbens is an unlikely site to inhibit the induction of locomotor sensitisation via the melanocortin MC4 receptor. This is in contrast to other studies that show an effect of the melanocortin MC4 receptor antagonist SHU9119 on locomotor sensitisation when injected into the nucleus accumbens.

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