The selective dopamine D3 receptor antagonist SB-277011A attenuates drug- or food-deprivation reactivation of expression of conditioned place preference for cocaine in male Sprague-Dawley rats.

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.

The selective D3 receptor antagonist SB-277011A attenuates morphine-triggered reactivation of expression of cocaine-induced conditioned place preference.

We examined the effect of acute administration of the selective D3 receptor antagonist SB-277011A on morphine-triggered reactivation of cocaine-induced conditioned place preference (CPP) in adult male Sprague-Dawley rats. Repeated pairing of animals with 15 mg/kg i.p. of cocaine HCl or vehicle to cue-specific CPP chambers produced a significant CPP response compared to animals paired only with vehicle in both chambers. Expression of the CPP response to cocaine was then extinguished by repeatedly giving the animals vehicle injections in the cocaine-paired chambers. The magnitude of the CPP response after extinction was not significantly different from that of animals paired only with vehicle. Expression of the extinguished CPP response was reactivated by acute administration of 5 mg/kg i.p. of morphine but not by vehicle. Acute administration of 6 or 12 mg/kg i.p. (but not 3 mg/kg) of SB-277011A significantly attenuated morphine-triggered reactivation of the cocaine-induced CPP. SB-277011A itself (12 mg/kg i.p.) did not reactivate the extinguished CPP response. Overall, SB-277011A decreases the incentive motivational actions of morphine. The present findings suggest that central D3 dopamine receptors are involved in relapse to cocaine-seeking behavior, that a final common neural mechanism exists to mediate the incentive motivational effects of psychostimulants and opiates, and that selective dopamine D3 receptor antagonists constitute promising compounds for treating addiction.

The acute administration of the selective dopamine D(3) receptor antagonist SB-277011A reverses conditioned place aversion produced by naloxone precipitated withdrawal from acute morphine administration in rats.

We examined the effect of SB-277011A, a selective D(3) receptor antagonist, on the conditioned place aversion (CPA) response associated with naloxone-induced withdrawal from acute morphine administration in male Sprague-Dawley rats. Morphine (5.6 mg/kg i.p.) was given, followed 4 hrs later by naloxone (0.3 mg/kg i.p.) and prior to placing the animals in one specific chamber of the test apparatus. All animals were subjected to 2 of these trials. A significant CPA occurred in animals that received an i.p. injection of vehicle 30 minutes prior to the measurement of chamber preference. The pretreatment of animals (30 minutes prior to testing) with 3 mg/kg i.p. of SB-277011A did not significantly alter the CPA compared to animals treated with vehicle (1 ml/kg i.p. of deionized distilled water). In contrast, the acute pretreatment of animals with 6, 12 or 24 mg/kg i.p. of SB-277011A significantly decreased the CPA compared to vehicle-treated animals. In fact, the 12 and 24 mg/kg doses of SB-277011A significantly increased the time spent in the chamber where animals were paired with morphine and naloxone. These results suggest that the selective antagonism of D(3) receptors attenuates the CPA produced by a model of naloxone-induced withdrawal from acute morphine dependence.

The GABA-B positive modulator GS39783 decreases psychostimulant conditioned-reinforcement and conditioned-reward.

Baclofen, a γ-amino-butyric-acid (GABA)(B) receptor agonist, can reduce cue-enhanced cocaine-seeking in rats and attenuate cue-evoked craving in cocaine addicts. However, baclofen also has sedative effects that might interfere with its efficacy in reducing cocaine's rewarding effects. The present study aimed at comparing the effects of baclofen with the GABA(B) -receptor positive allosteric modulator GS39783 on psychostimulant conditioned cues. Two identically trained groups of male Lister-Hooded rats were baselined on a new responding for a light stimulus previously paired with cocaine self-administration. One group was treated with the GABA(B) -receptor positive allosteric modulator GS39783 (0, 10, 30, 100 mg/kg, i.p.), the other with baclofen (0, 0.6, 1.25, 1.9, 2.5 mg/kg, i.p.). In another series of experiments, male Wistar rats received GS39783 (0, 10, 30, 100 mg/kg, i.p.) or baclofen (1.25 mg/kg) prior to the expression of a conditioned place preference (CPP) to amphetamine (2 mg/kg i.p.). Both GS39783 (30 and 100 mg/kg) and baclofen (2.5 mg/kg) significantly decreased responding for the cocaine cue; however, only GS39783 (30 mg/kg) reduced lever pressing responding without interfering with locomotor activity. Both GS39783 (30 and 100 mg/kg) and baclofen (1.25 mg/kg), significantly blocked the expression of amphetamine CPP without affecting locomotor activity. These findings suggest that GABA(B) positive allosteric modulators can modulate discrete and contextual psychostimulant conditioned stimuli in a manner dissociable from unwanted sedative effects and may offer a novel therapeutic approach to treat cravings and relapse to drug-taking triggered by stimuli associated with psychostimulant use.

Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders.

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.

Chronic fluoxetine differentially modulates the hippocampal microtubular and serotonergic system in grouped and isolation reared rats.

Social isolation from weaning in rats produces behavioural and hippocampal structural changes at adulthood. Here, rats were group or isolation reared for eight-weeks. Following the initial four-week period of rearing, fluoxetine (10 mg/kg i.p.) was administered for 28 days. Changes in recognition memory, hippocampal monoamines, and cytoskeletal microtubules were investigated. Isolation-rearing for four- or eight-weeks produced recognition memory deficits that were not reversed by fluoxetine. Eight-weeks of isolation decreased alpha-tubulin acetylation (Acet-Tub) and the tyrosinated/detyrosinated alpha-tubulin ratio (Tyr/Glu-Tub), suggesting major alterations in microtubule dynamics and neuronal plasticity. In grouped rats, fluoxetine decreased Acet-Tub without changes in Tyr/Glu-Tub. In isolates, fluoxetine did not affect Acet-Tub but increased Tyr/Glu-Tub. Finally, fluoxetine altered serotonin metabolism in grouped, but not in isolated animals. Therefore, isolation-rearing changes the hippocampal responses of the serotonergic and microtubular system to fluoxetine. These findings show that early-life experience induces behavioural changes paralleled by alterations in cytoskeletal and neurochemical functions.

Fluoxetine administration modulates the cytoskeletal microtubular system in the rat hippocampus.

A number of studies suggest that stressful conditions can induce structural alterations in the hippocampus and that antidepressant drugs may prevent such deficits. In particular, the selective serotonin reuptake inhibitor (SSRI) fluoxetine was more effective in modulating different neuronal plasticity phenomena and related molecules in rat hippocampus. Cytoskeletal microtubule dynamics are fundamental to dendrites and axons remodeling, leading to the hypothesis that fluoxetine may affect the microtubular system. However, despite reports of stress-induced alterations in microtubule dynamics by different stressors, only few studies investigated the in vivo effects of antidepressants on microtubules in specific rat brain regions. The present study investigated the dose-related (1, 5, or 10 mg/kg i.p.) effects of acute and chronic (21 days) treatments with fluoxetine on the ratio of hippocampal alpha-tubulin isoforms which is thought to reflect microtubule dynamics. Western Blot analysis was used to quantify alpha-tubulin isoforms, high-performance liquid chromatography and fluorescence detection was used to measure ex vivo monoamine metabolism. The results showed that acute fluoxetine increased the stable forms acetylated and detyrosinated alpha-tubulin. Conversely, chronic fluoxetine decreased acetylated alpha-tubulin, indicative of increased microtubule dynamics. The neuron-specific Delta2-Tubulin was increased by chronic fluoxetine indicating neuronal involvement in the observed cytoskeletal changes. Although acute and chronic fluoxetine similarly altered serotonin metabolism by inhibition of serotonin reuptake, this showed no apparent correlation to the cytoskeletal perturbations. Our findings demonstrate that fluoxetine administration modulates microtubule dynamics in rat hippocampus. The cytoskeletal effect exerted by fluoxetine may eventually culminate in promoting events of structural neuronal remodeling.

The effects of two highly selective dopamine D3 receptor antagonists (SB-277011A and NGB-2904) on food self-administration in a rodent model of obesity.

In the current study, we examined the effect of the selective D(3) receptor antagonists SB-277011A and NGB 2904 on operant food self-administration (FSA) in Zucker obese and lean rats. Obese (Ob) and lean (Le) Zucker rats were maintained under a restricted feeding regimen (70% of ad-libitum rat chow) and were trained to lever press for food during daily, 2 hour fixed-ratio 4 (FR4) schedules. Once rats reached a stable baseline for FSA, they were injected with vehicle until a stable FSA criterion was achieved. Animals then received daily injections of different random doses of SB-277011A (3, 10, and 30 mg/kg i.p.), and NGB-2904 (0.3, 1 and 3 mg/kg i.p.). SB-277011A produced a significant decrease in both food intake and active lever responses in both Ob and Le rats. In contrast, NGB-2904 did not decrease food intake levels or lever presses for food in Ob and Le rats. These results suggest that along with its involvement in seeking behavior for drugs of abuse, the D(3) dopamine receptor may also be involved in seeking behavior for natural reinforcers such as food.

Role of dopamine D3 receptors in the expression of conditioned fear in rats.

There has been considerable interest in the role of dopamine D(3) receptors in appetitive conditioning but few studies have examined their role in aversive conditioning. The present study examined the effect of the dopamine D(3) receptor-preferring partial agonist BP 897 (1-(4-(2-naphthoyl-amino)butyl)-4-(2-methoxyhenyl)-1A-piperazine hydrochloride) and the selective dopamine D(3) receptor antagonist SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]syclohexyl]4-quinolininecarboxamide]) on the expression and acquisition of fear conditioning. Rats (N=143) received 3 conditioned stimulus-shock pairings and then received 15 conditioned stimulus-alone presentations (3 per day) while lever pressing for food. Response suppression was taken as the behavioral measure of fear. Rats showed strong suppression to the conditioned stimulus after it had been paired with shock and suppression progressively weakened over conditioned stimulus-alone presentations. In experiment 1, rats that received BP 897 (1.0, 2.0 mg/kg i.p.) or SB-277011A (10.0 mg/kg i.p.) prior to conditioned stimulus-alone presentation sessions showed reduced suppression to the conditioned stimulus as compared to rats that received vehicle or lower doses of drug (0, 0.1 mg/kg BP 897; 0, 0.5, 5.0 mg/kg SB-277011A). Injections of BP 897 (1.0, 2.0 mg/kg) or SB-277011A (10.0 mg/kg) prior to conditioned stimulus-shock pairings did not significantly affect subsequent response suppression. Thus, BP 897 and SB-277011A dose-dependently attenuated the expression but not the acquisition of conditioned fear. These findings suggest that BP 897 and SB-277011A reduce the control of responding by aversively conditioned stimuli.

The effects of lamotrigine on alcohol seeking and relapse.

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 15mg/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 5mg/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.

Correlation between serum ghrelin levels and cocaine-seeking behaviour triggered by cocaine-associated conditioned stimuli in rats.

Ghrelin is a brain-gut peptide with growth hormone-releasing and appetite-inducing activities. A growing body of evidence suggests that ghrelin may affect the central reward system and modulate the activity of the mesolimbic system. Recent clinical studies also showed a significant positive correlation between plasma ghrelin levels and craving in alcoholics. Accordingly, the present study investigated the potential role of serum ghrelin levels in the reinstatement of cocaine-seeking behaviour triggered by cocaine-associated cues. In addition, serum corticosterone levels were determined in the light of evidence suggesting that corticosterone plays a modulatory role in cocaine-seeking behaviour. Male Lister Hooded rats under a restricted diet regime were first trained to intravenously self-administer cocaine under a fixed ratio-1 schedule of reinforcement. Conditioned stimuli (CS: tone and cue-light on for 5 seconds) were presented contingently with cocaine delivery. Once a stable baseline of cocaine self-administration was observed, lever presses were extinguished to less than 30% of baseline rates by removing both cocaine and CS. Reinstatement of responding was then induced by re-exposure to cocaine-associated CS. Blood samples for the enzyme immunoassay determination of serum ghrelin and the radioimmunoassay determination of serum corticosterone levels were collected 30 minutes before the beginning of reinstatement sessions. Rats significantly reinstated their responding when exposed to CS. A positive and significant correlation was observed between ghrelin levels (r = 0.64; P < 0.05), but not corticosterone (r = 0.37; NS), and the increased active lever presses only in animals exposed to CS. These findings suggest a potential role of ghrelin in the modulation of cue-triggered reinstatement of cocaine-seeking behaviour.

Evidence for the role of dopamine D3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice.

The present study examined the effects of the acute intraperitoneal (i.p.) administration of the selective dopamine (DA) D(3) receptor antagonist SB-277011A (10, 20 or 30 mg/kg i.p.) on the oral operant self-administration of alcohol in male C57BL/6N mice. These effects were compared with those of naltrexone (0.5, 1 and 2 mg/kg i.p.) and acamprosate (100, 200 and 400 mg/kg i.p.). Compared with vehicle, the acute administration of SB-277011A (10 or 20 mg/kg) did not significantly alter the operant self-administration of alcohol, whereas the 30 mg/kg dose significantly reduced alcohol intake (g/kg), the number of reinforcers, and the number of active lever presses. The oral self-administration of alcohol was not significantly altered by the acute administration of either naltrexone or acamprosate, compared with vehicle-treated mice. SB-277011A, naltrexone and acamprosate were also tested in a model of drug/cue-triggered reinstatement of alcohol-seeking behavior. In this model, neither naltrexone (2 mg/kg) nor acamprosate (400 mg/kg) prevented relapse to alcohol-seeking behavior. In contrast, SB-277011A significantly reduced reinstatement of alcohol seeking in a dose-dependent manner. Provided these results can be extrapolated to humans, they suggest that selective DA D(3) receptor antagonists may be useful in the pharmacotherapeutic management of alcohol intake and prevention of relapse to alcohol-seeking behavior.

Pharmacological modulation of functional connectivity: the correlation structure underlying the phMRI response to d-amphetamine modified by selective dopamine D3 receptor antagonist SB277011A.

Pharmacological MRI (phMRI) experiments utilise fMRI time series methods to map the central effect of pharmaceutical compounds. The typical univariate maps may, however, integrate the effects of several different neurotransmitter systems or underlying mechanisms. The results may thus be spatially and/or mechanistically nonspecific. Intersubject correlation analysis based on the phMRI response amplitude can more directly identify patterns of functional connectivity underlying the central effects of an acutely administered compound. In this article, we extend this approach to experiments where the effects of one compound in modulating the response to another are of interest. Specifically, we show a modulation of the correlation structure of a probe compound (d-amphetamine) by pretreatment with the selective dopamine D3 receptor antagonist SB277011A in the rat. The strongest modifications in the correlation patterns occurred in connection with the ventral tegmental area, the source of mesolimbic dopamine projections and a key substrate in the reward system.

Effects of the selective dopamine D3 receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats.

The dopamine D3 receptor is primarily localized within the mesocorticolimbic system, and may therefore have potential as a pharmacotherapeutic target for the treatment of drug dependence. Studies have shown that the selective dopamine D3 receptor antagonist SB-277011A reduces a variety of dependence-related behavioral effects of cocaine, alcohol and heroin. A previous study examining SB-277011A on nicotine self-administration using relatively low doses of the antagonist and a low response requirement for nicotine found no effect on drug-taking behavior per se, whereas reinstatement of nicotine-seeking was reduced. The purpose of the present study was to further examine the effects of higher doses of SB-277011A on nicotine self-administration in rats under a progressive-ratio (PR) schedule, which imposes relatively high response requirements for nicotine. Rats were trained to respond under a PR schedule of either nicotine or food reinforcement. Once responding was stable, SB-277011A (3-56 mg/kg) or vehicle was administered i.p. 1 h prior to the operant session. The highest dose tested significantly decreased the mean number of reinforcers and mean response rates in the nicotine self-administration group, but had no effect on either the mean number of reinforcers or response rate in the food group. In a separate set of experiments, the effects of SB-277011A on locomotor activity were measured. At the dose that significantly decreased nicotine self-administration, total distance traveled was also significantly decreased, suggesting that the effect on operant responding at the high dose of SB-277011A is at a threshold for motor effects and may not be directly mediated by an action at dopamine D3 receptors.

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.

SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models.

SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide) has high affinity for human recombinant and native 5-HT(6) receptors, with pK(i) values 9.11+/-0.03 and 9.02+/-0.05, respectively and is a potent competitive antagonist (pA(2) 7.85+/-0.04). It displays over 200-fold selectivity for the 5-HT(6) receptor over all other receptors, ion channels and enzymes tested to date. SB-399885 inhibited ex vivo [(125)I]SB-258585 (4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide) binding with an ED(50) of 2.0+/-0.24 mg/kg p.o. in rats. It had a minimum effective dose of 1 mg/kg p.o. in a rat maximal electroshock seizure threshold test and a long duration of action, overall demonstrating an excellent pharmacokinetic-pharmacodynamic correlation. Repeated administration of this agent (10 mg/kg p.o., b.i.d. for 7 days) significantly reversed a scopolamine-induced deficit (0.5 mg/kg i.p.) in a rat novel object recognition paradigm. Moreover, in aged rats (22 months old) SB-399885 (10 mg/kg p.o., b.i.d. for 7 days) fully reversed the age-dependent deficit in water maze spatial learning compared to vehicle-treated age-matched controls and significantly improved recall of the task measured by increases in the searching of the target quadrant on post-training days 1, 3 and 7. In vivo microdialysis in the rat medial prefrontal cortex demonstrated that acute SB-399885 (10 mg/kg p.o.) significantly increased extracellular acetylcholine levels. These data demonstrate that SB-399885 is a potent, selective, brain penetrant, orally active 5-HT(6) receptor antagonist with cognitive enhancing properties that are likely to be mediated by enhancements of cholinergic function. These studies provide further support for the potential therapeutic utility of 5-HT(6) receptor antagonists in disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.

The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions.

Increasing evidence suggests that enhanced dopamine (DA) neurotransmission in the nucleus accumbens (NAc) may play a role in mediating the reward and reinforcement produced by addictive drugs and in the attentional processing of drug-associated environmental cues. The meso-accumbens DA system is selectively enriched with DA D3 receptors, a DA receptor subtype increasingly implicated in reward-related brain and behavioural processes. From a variety of evidence, it has been suggested that selective DA D3 receptor antagonism may be a useful pharmacotherapeutic approach for treating addiction. The present experiments tested the efficacy of SB-277011A, a selective DA D3 receptor antagonist, in rat models of nicotine-enhanced electrical brain-stimulation reward (BSR), nicotine-induced conditioned locomotor activity (LMA), and nicotine-induced conditioned place preference (CPP). Nicotine was given subcutaneously within the dose range of 0.25-0.6 mg/kg (nicotine-free base). SB-277011A, given intraperitoneally within the dose range of 1-12 mg/kg, dose-dependently reduced nicotine-enhanced BSR, nicotine-induced conditioned LMA, and nicotine-induced CPP. The results suggest that selective D3 receptor antagonism constitutes a new and promising pharmacotherapeutic approach to the treatment of nicotine dependence.

Selective dopamine D3 receptor antagonists enhance cortical acetylcholine levels measured with high-performance liquid chromatography/tandem mass spectrometry without anti-cholinesterases.

The present study compared the effects of two selective dopamine (DA) D(3) receptor antagonists, SB-277011A (3, 10 and 30 mg/kg i.p.) and SB-414796A (3, 10 and 30 mg/kg i.p.) on extracellular levels of acetylcholine (ACh) in the rat medial prefrontal cortex (mPFC) by using a LC/MS-MS analytical method that permitted the detection of ACh without the necessity of adding acetylcholinesterase inhibitors to the perfusate. Furthermore, the present LC/MS-MS method permitted the simultaneous measurement of the respective concentrations of SB-277011A and SB-414796A in the same extracellular samples from the mPFC. The systemic administration of both selective DA D(3) receptor antagonists produced a significant increase in extracellular levels of Ach compared to vehicle-treated animals, which was associated with increases in extracellular concentrations of SB-277011A and SB-414796. Overall, the present findings further strengthen the likelihood of a modulation of cortical cholinergic function through a DA D(3)-mediated mechanism and suggest that selective DA D(3) receptor antagonism may be beneficial in the treatment of psychiatric diseases, such as schizophrenia, which are characterized by cognitive dysfunction.

Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats.

In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D(3) receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost-variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3-24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125-0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6-24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25-1.0 mg/kg) dose-response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D(2)/D(3) receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D(3) receptor antagonists may be useful in the treatment of cocaine addiction.