Selective antagonism at dopamine D3 receptors attenuates cocaine-seeking behaviour in the rat.

Dopamine (DA) D3 receptors have been suggested to play a role in mechanisms underlying the ability of drug-associated cues to induce drug-seeking behaviour. The present study investigated whether SB-277011-A, a selective DA D3 receptor antagonist, modulates reinstatement of cocaine-seeking behaviour induced by cocaine-associated stimuli. The study also explored whether or not this modulation is generable to seeking behaviours associated with a nutritive reinforcer such as sucrose. Separate groups of rats were trained to associate discriminative stimuli (SD) with the availability of cocaine or sucrose pellets vs. non-reward under a FR1 schedule of reinforcement. Each reinforced response was followed by a response-cue signalling a 20-s time-out (TO). After the self-administration training criterion was met, rats underwent extinction during which cocaine, sucrose pellets and SDs were withheld. Reinstatement tests, separated by 3 d during which rates of responding under extinction conditions remained at the criterion, were performed by presenting SDs non-contingently together with the contingent presentation of response-cues signalling a 20-s TO. Within- and between-subjects experimental designs revealed that 10 and 30 mg/kg SB-277011-A attenuated reinstatement of cocaine-seeking. SB-277011-A (10 mg/kg) did not modify conditioned reinstatement triggered by sucrose pellet-associated cues. These results, provided they can be extrapolated to abstinent human addicts, suggest the potential therapeutic use of selective DA D3 receptor antagonists for the prevention of cue-controlled cocaine-seeking and relapse

Enhancement of cortical extracellular 5-HT by 5-HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-responder mice.

We recently found that the response of DBA/2 mice to SSRIs in the forced swim test (FST) was impaired and they also had a smaller basal and citalopram-stimulated increase in brain extracellular serotonin (5-HT) than 'responder' strains. We employed intracerebral microdialysis, FST and selective antagonists of 5-HT1A and 5-HT2C receptors to investigate whether enhancing the increase in extracellular 5-HT reinstated the anti-immobility effect of citalopram in the FST. WAY 100635 (0.3 mg/kg s.c.) or SB 242084 (1 mg/kg s.c.), respectively a selective 5-HT1A and 5-HT2C receptor antagonist, raised the effect of citalopram (5 mg/kg) on extracellular 5-HT in the medial prefrontal cortex of DBA/2N mice (citalopram alone 5.2+/-0.3 fmol/20 microl, WAY 100635+citalopram 9.9+/-2.1 fmol/20 microl, SB 242084+ citalopram 7.6+/-1.0 fmol/20 microl) to the level reached in 'responder' mice given citalopram alone. The 5-HT receptor antagonists had no effect on the citalopram-induced increase in extracellular 5-HT in the dorsal hippocampus. The combination of citalopram with WAY 100635 or SB 242084 significantly reduced immobility time in DBA/2N mice that otherwise did not respond to either drug singly. Brain levels of citalopram in mice given citalopram alone or with 5-HT antagonists did not significantly differ. The results confirm that impaired 5-HT transmission accounts for the lack of effect of citalopram in the FST and suggest that enhancing the effect of SSRIs on extracellular 5-HT, through selective blockade of 5-HT1A and 5-HT2C receptors, could be a useful strategy to restore the response in treatment-resistant depression

Short-term abstinence from cocaine self-administration, but not passive cocaine infusion, elevates αCaMKII autophosphorylation in the rat nucleus accumbens and medial prefrontal cortex

Increases in alpha calcium/calmodulin-dependent protein kinase type II ( α CaMKII) activity in the nucleus accumbens shell has been proposed as a core component in the motivation to self-administer cocaine and in priming-induced drug-seeking. Since cocaine withdrawal promotes drug-seeking, we hypothesized that abstinence from cocaine self-administration should enhance α CaMKII as well. We found that short-term abstinence from contingent, but not non-contingent, cocaine i.v. self-administration (2 h/d for 14 d; 0.25 mg/0.1 ml, 6s infusion) elevates α CaMKII autophosphorylation, but not the kinase expression, in a dynamic, time- and brain region-dependent manner. Increased α CaMKII autophosphorylation in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), but not dorsolateral striatum (dlS), was found 24 h, but not immediately, after the last cocaine self-administration session. Notably, in the mPFC, but not NAc and dlS, α CaMKII autophosphorylation was still enhanced 7 d later. The persistent enhancement in the mPFC of abstinent rats may represent a previously unappreciated contribution to initial incubation of cocaine-seeking

Gamma-hydroxybutyrate does not maintain self-administration but induces conditioned place preference when injected in the ventral tegmental area

Gamma-hydroxybutyric acid (GHB) is an endogenous brain substance that has diverse neuropharmacological actions, including rewarding properties in different animal species and in humans. As other drugs of abuse, GHB affects the firing of ventral tegmental neurons (VTA) in anaesthetized animals and hyperpolarizes dopaminergic neurons in VTA slices. However, no direct behavioural data on the effects of GHB applied in the VTA or in the target regions of its dopaminergic neurons, e.g. the nucleus accumbens (NAc), are available. Here, we investigated the effects of various doses of intravenous GHB in maintaining self-administration (from 0.001 to 10 mg/kg per infusion), and its ability to induce conditioned place preference (CPP) in rats when given orally (175-350 mg/kg) or injected directly either in the VTA or NAc (from 10 to 300 microg/0.5 microl per side). Our results indicate that while only 0.01 mg/kg per infusion GHB maintained self-administration, although not on every test day, 350 mg/kg GHB given orally induced CPP. CPP was also observed when GHB was injected in the VTA (30-100 microg/0.5 microl per side) but not in the NAc. Together with recent in-vitro findings, these results suggest that the rewarding properties of GHB mainly occur via disinhibition of VTA dopaminergic neurons

Cocaine-seeking behaviour by drug associated stimuli : reversal by dopamine D₃ partial agonists and antagonists

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Operant, oral alcoholic-beer self-administration in C57BL/6J mice: modulation by BHF177, a positive allosteric modulator of GABAB receptors

Rationale. Because of its high palatability, near-beer has been successfully used in rats as vehicle to induce large amount of ethanol oral self-administration. Objectives. To develop an operant model of oral alcoholic-beer self-administration promoting in free-feeding C57BL/6J mice a stable intake of pharmacologically relevant amount of ethanol. To assess the model predictive validity evaluating the ability of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, to influence alcoholic-beer self-administration. Methods. Mice were trained to self-administer, under a fixed-ratio 3 schedule of reinforcement, 10 µL of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30-min sessions. The effects of alcoholic-beer self-administration on motor coordination (rotarod), locomotor activity (open field and automated cages) and anxiety-like behaviour (elevated plus maze) were evaluated. Moreover, the ability of baclofen (1.25-5 mg/kg, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) to modulate 9% alcoholic-beer and near-beer self-administration was assessed. Results. Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer, decreased the number of active lever presses whereas the corresponding amount of ethanol self-administered remained stable (0.8-1.0 g/kg/30-min). Motor impairment and a slight, but consistent, hyper-locomotion was observed when the amount of ethanol self-administered with beer was higher than 1.3 g/kg/30-min and 0.9-1.0 g/kg/30-min, respectively. Finally, BHF177 (15 mg/kg) preferentially reduced 9% alcoholic-beer self-administration whereas higher dose (30 mg/kg), similarly to baclofen (5 mg/kg), reduced also near-beer self-administration. Conclusions. The operant model of oral alcoholic-beer self-administration in C57BL/6J mice should prove a useful tool to study ethanol reinforced behaviours and to identify potential candidate compounds in the pharmacological management of alcohol addiction

Chronic but not acute N-acetylcysteine promotes extinction of nicotine-cue conditioned responding

A growing body of evidence indicates that restoring basal concentrations of extracellular glutamate and thereby increasing tonic activation of the mGluR2/3 receptors could be an important target for treatment of nicotine dependence. In fact, administration of N-acetylcysteine (N-AC), a cysteine prodrug, by restoring extracellular glutamate concentrations prevents relapse to cocaine- and heroin-seeking behavior in rats following drug self-administration. Thus, using a reliable procedure of extinction-reinstatement following nicotine self-administration inducing robust and lasting drug-seeking behavior (Di Clemente et al., 2012; Cervo et al., 2013) we characterized the efficacy of N-AC in modulating nicotine-seeking behavior in Wistar male rat. Acute pre-treatment with N-AC 100 mg/kg i.p., but not 30 and 60 mg/kg, induced a short-term attenuation of conditioned nicotine- but not saccharin-seeking behavior without influencing rats\u2019 locomotor activity. This effect was completely prevented by 1 mg/kg LY341495, a selective group II metabotropic glutamate receptors (mGluR2/3) antagonist. Chronic treatment with N-AC 100 mg/kg i.p., but not 60 mg/kg, during 14th days exposure to nicotine-associated cues reduced drug-seeking without any tolerance. Moreover, chronic N-AC induced a long-term anti-relapse activity that was still present 14 days after the end of the treatment. In conclusion, N-AC might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking and that chronic treatment with N-AC may promote extinction of nicotine-cue conditioned responding

Chronic n-acetylcysteine treatment promotes extinction of conditioned cue-induced nicotine-seeking behavior in the rat

Tobacco smoking is a chronic relapsing disorder and resumption is recurrent after abstinence. Although some pharmacological and psychosocial support can help smokers to quit, the high relapse rates indicate a need for more efficacious treatments. A large body of evidence indicate that the cysteine pro-drug N-acetylcysteine (N-AC) may have beneficial therapeutic effects in the treatment of drug addiction. In humans, pilot studies have shown that N-AC decreases drug cues-induced craving for cocaine, number of cigarettes smoked, and marijuana use and craving. Pre-clinically N-AC reduced conditioned cues-induced cocaine- and heroin-seeking by restoring cystine-glutamate exchange, which normalize extracellular glutamate (Glu), restoring tone on pre-synaptic inhibitory mGluR2/3 auto-receptors in the nucleus accumbens, thus blunting the increased Glu release associated with drug cues-induced reinstatement of drug-seeking. Although nicotine-cues reinstate drug-seeking and increase extracellular Glu in the nucleus accumbens, it is still unclear whether N-AC would inhibit cue-induced reinstatement in abstinent rats after nicotine self-administration. Moreover, it is unknown whether restoring Glu homeostasis by chronic N-AC treatment would enhance the outcome of cue-exposure therapy for smoking cessation. To gain such information, we used an animal model of cue-induced robust and lasting nicotine-seeking in abstinent rats. We found that a single dose of N-AC (100 mg/kg) increased Glu extracellular release in the nucleus accumbens and induced a short-term reduction of cues-induced nicotine-seeking without altering cues-induced saccharin-seeking and rats\u2019 locomotor activity. Pre-treatment with LY341495 (1 mg/kg), a selective mGluR2/3 antagonist, completely prevented N-AC from reducing cues-induced nicotine-seeking behavior. When N-AC (100 mg/kg) was given chronically before daily lever-presses extinction, during abstinence or in combination with nicotine-associated cues induced reinstatement, it was found that only in the latter condition N-AC not only showed efficacy when biologically available during testing, but also produced a long-lasting anti-relapse activity that was still present 2 weeks later. These results suggest that N-AC might offer a therapeutic opportunity in promoting extinction of nicotine-cue conditioned responding