Lamotrigine is a clinically used drug, which inhibits Na
+ channel activity that in turn reduces glutamate release. Its downstream activity on other neurotransmitter systems such as serotonergic and ...dopaminergic has also been reported. Since both glutamate and monoamines might be involved in alcohol craving and relapse, our aim was to examine the effects of lamotrigine on alcohol seeking and relapse-like drinking behaviour. Thus, lamotrigine (5 and 15
mg/kg) was tested in two behavioural models for alcohol seeking and relapse – the model of cue-induced reinstatement of alcohol-seeking behaviour and the alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats. Administration of 5
mg/kg of lamotrigine caused a significant decrease of cue-induced reinstatement of alcohol-seeking behaviour. The ADE was significantly reduced with both doses tested. However, the highest dose of lamotrigine produced sedation. The ability of lamotrigine to reduce alcohol seeking as well as relapse-like drinking behaviour provides further support for the proposed involvement of the glutamatergic and dopaminergic/serotonergic systems in alcohol craving and relapse, hence suggesting a good rationale for pharmacological intervention that may reduce craving and relapse in alcohol dependent patients.
Aripiprazole, a novel atypical antipsychotic drug, can significantly increase dopamine (DA) levels in the prefrontal cortex of rats, but only at low doses below 1
mg/kg Z. Li, J. Ichikawa, J. Dai, ...H.Y. Meltzer, Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain, Eur. J. Pharmacol. 493 (2004) 75–83. The aim of the present work was to test the effect of aripiprazole (0, 0.1, 0.3, 3 and 30
mg/kg, i.p.) on extracellular levels of monoamines in the prefrontal cortex of freely moving C57BL/6J mice. Concurrent horizontal locomotor activity was also assessed. Aripiprazole produced a significant increase in dialysate DA levels after the administration of a low dose of 0.3
mg/kg. Lower (0.1
mg/kg) or higher (3 and 30
mg/kg) doses failed to affect extracellular levels of DA. In addition, none of the doses tested in the present study produced significant changes in extracellular levels of noradrenaline (NA) and serotonin (5-HT). For the sake of comparison, clozapine (0, 3 and 10
mg/kg, s.c.) was also tested under similar conditions. Clozapine produced a dose-dependent increase in both dialysate DA and NA levels without affecting extracellular 5-HT. Locomotor activity was significantly decreased by both clozapine and aripiprazole. These data further support the hypothesis that selective activation of dopaminergic neurotransmission in the prefrontal cortex may contribute to the therapeutic efficacy of aripiprazole.
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.
Drugs of abuse, including, nicotine have been shown to enhance brain reward functions in the mesocortico-limbic dopamine (DA) system in general, and the nucleus accumbens in particular. The latter ...occupies a prominent position in the ventral striatum and expresses a high density of DA D(3) receptors. As such, the present study aimed at investigating the effect of the selective D(3) receptor antagonist SB-277011-A on both the stable maintenance of intravenous nicotine self-administration and nicotine-triggered relapse to nicotine-seeking behavior in the rat. SB-277011-A (3-10 mg/kg i.p.) significantly reduced reinstatement of nicotine-seeking behavior without affecting nicotine self-administration per se. These results suggest that DA D(3) receptors are involved in the reinstatement of nicotine-seeking behavior independently of any interaction with the primary reinforcing effects of nicotine itself. These findings point toward the potential use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of relapse to drug-seeking behaviors.
We determined the effect of the selective dopamine D3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or ...exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mg kg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 ml kg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D3 receptor antagonist SB-277011A (3-24 mg kg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mg kg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mg kg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D3 receptors.
Growing evidence indicates that dopamine (DA) D
3
receptors are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders. ...First, DA D
3
receptors are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse has been shown to produce neuroadaptations in the DA D
3
system. Third, the synthesis and characterization of highly potent and selective DA D
3
receptor antagonists has permitted to further define the role of the DA D
3
receptor in drug addiction. Provided that the available preclinical and preliminary clinical evidence can be translated into clinical proof of concept in human, selective DA D
3
receptor antagonists show promise for the treatment of substance use disorders as reflected by their potential to (1) regulate the motivation to self-administered drugs under schedules of reinforcement that require an increase in work demand and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in the reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior, or stress.
Orexin-expressing neurons are present in hypothalamic nuclei and send projections toward mesolimbic regions such as the nucleus accumbens (NAc), a key brain region implicated in the processing of the ...motivational significance of reinforcers. Recent evidence found that activation of the orexin system can lead to a state of hyperarousal that may facilitate drug craving or contribute to vulnerability to drug relapse. This study aimed at assessing the effects of the orexin-1 receptor antagonist SB-334867 1-(2-methylbenzoxazol-6-yl)-3-1,5naphthyridin-4-yl-urea hydrochloride on amphetamine-induced dopamine (DA) release in the shell subregion of the NAc by means of
in vivo microdialysis in freely moving rats. Since behavioral sensitization is thought to play a role in the maintenance of compulsive drug use, we also tested the effect of SB-334867 on the expression of sensitization to the locomotor activating effects of amphetamine. Acute administration of SB-334867 (30
mg/kg SC) significantly reduced the acute effects of amphetamine (1
mg/kg IP) on extracellular DA levels in the NAc shell. The expression of amphetamine sensitization was also significantly reduced by acute SB-334867 treatment. Altogether our findings show that selective orexin-1 antagonism both reduces the acute effects of amphetamine on DA outflow in the NAc shell and decreases the expression of locomotor sensitization to the repeated, intermittent administration of amphetamine.
Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist ...SB-334867 on aspects of psychostimulant-conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users.
Repeated exposure to drugs of abuse produces long‐term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as ...well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D
3
receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D
3
receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self‐administer drugs and disrupt drug‐associated cue‐induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D
3
receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D
2
/D
3
receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D
3
versus D
2
receptor, and their efficacy profile is related primarily to functional antagonism at D
2
receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D
3
receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so‐called proof‐of‐concept studies for drug addiction indications will be discussed.
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