Zheng-ong Xi

Agents in Development for the Management of Cocaine Abuse

Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence.Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site.The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial.Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methyl-phenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-β-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity.Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D1 receptor agonist; BP 897 is a D3 receptor partial agonist.A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a ‘cocaine vaccine’ found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation.

Cannabinoid CB1 Receptor Antagonist AM251 Inhibits Cocaine-Primed Relapse in Rats: Role of Glutamate in the Nucleus Accumbens

Blockade of cannabinoid CB1 receptors has been reported to inhibit cocaine- or cocaine cue-induced reinstatement of drug seeking. However, the mechanisms underlying this action are poorly understood. Given the importance of dopamine, glutamate, and GABA in cocaine reward and relapse, we studied the effects of AM251 [N-(piperidin-1-yl)-5-(4-iodophonyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a novel highly selective CB1 receptor antagonist, on cocaine-primed reinstatement of drug-seeking behavior and on cocaine-induced changes in extracellular DA, glutamate, and GABA in the nucleus accumbens (NAc) under reinstatement conditions. We found that systemic administration of AM251 selectively inhibited cocaine-induced, but not sucrose plus sucrose cue-induced, reinstatement of reward-seeking behavior. AM251 alone did not trigger reinstatement. Local perfusion of AM251 into the NAc or the dorsal striatum also inhibited cocaine-triggered reinstatement. AM251 alone dose dependently elevated NAc glutamate in a voltage-dependent Na+ channel-dependent manner. AM251 did not affect NAc DA or GABA. Pretreatment with AM251 dose dependently inhibited cocaine-induced increases in NAc glutamate but not in DA. Blockade of NAc metabotropic glutamate mGluR2/3 receptors by LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] slightly facilitated cocaine-enhanced glutamate release but blocked the antagonism of cocaine-induced reinstatement by AM251. These data suggest the following: (1) CB1 receptors exert tonic inhibition over NAc glutamate release under cocaine-extinction conditions; (2) blockade of CB1 receptors by AM251 inhibits cocaine-enhanced NAc glutamate release and cocaine-triggered reinstatement; and (3) these effects appear to be mediated by activation of presynaptic mGluR2/3 autoreceptors secondary to AM251-induced increase (disinhibition) of NAc glutamate release.

Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors-an in vivo electrochemical study.

The role of GABA receptors in regulating the mesolimbic dopamine (DA) system and drug reinforced behaviors has not been well characterized. Using fast-cyclic voltammetry, the effects of specific GABA receptor modulation on DA release in the nucleus accumbens (NAcc) and heroin self-administration (SA) behavior was investigated. The GABAA agonist muscimol, administered either intravenously or directly into the ventral tegmental area (VTA), significantly increased DA release in the NAcc in 7 of the 10 rats tested. DA release decreased in the remaining three rats; both effects were blocked by pretreatment with the GABAA receptor antagonist bicuculline. In contrast, the GABAB agonist baclofen decreased, while 2-OH-saclofen (a GABAB antagonist) increased DA release in the NAcc. However, when VTA GABAB receptors were previously activated or inactivated by microinjections of baclofen or 2-OH-saclofen, systemic injections of muscimol caused an inhibition of NAcc DA release. These results suggest that GABAA receptors may be co-localized on both DA neurons and non-DA (GABAergic) interneurons in the VTA, with the effects of GABAA determined by the net effect of both direct inhibition and indirect disinhibition of DA neurons. Finally, although a DA releaser, muscimol was neither self-administered in drug naive rats, nor did it substitute for heroin in rats previously trained to self-administer heroin, suggesting that GABAA receptors appear to play a complex role in mediating drug reinforcement, depending upon the dynamic functional state of GABAA receptors on both tegmental DA and non-DA neurons.

The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats.

Accumulating evidence indicates that dopamine (DA) D3 receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D3-selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long–Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1–10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D3-selective antagonist NGB 2904 attenuates cocaines rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.

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) D3 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 cocaines reinforcing efficacy. When substituted for cocaine, SB‐277011A alone did not sustain self‐administration behaviour. In contrast with the mixed DA D2/D3 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 D3 receptor antagonists may be useful in the treatment of cocaine addiction.

Cocaine-induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI)

Dynamic manganese-enhanced magnetic resonance imaging (MEMRI) detects neuronal activity based on the passage of Mn2+ into active neurons. Because this mechanism is independent of any hemodynamic response, it is potentially ideal for pharmacological studies and was applied to investigate the acute CNS effects of cocaine in the rat. Dose-dependent, region-specific MEMRI signals were seen mostly in cortical and subcortical mesocorticolimbic structures. To verify the spatial accuracy and physiological mechanisms of MEMRI, neuronal activation following electrical forepaw stimulation revealed somatotopic signal enhancement in the primary and secondary somatosensory cortices, which was blocked by diltiazem, a Ca2+ channel antagonist. These data suggest that MEMRI may serve as a tool for investigating the effects of pharmacological agents and opens an application of MRI to study CNS drug effects at a systems level.

Cannabinoid CB1 Receptor Antagonists Attenuate Cocaine's Rewarding Effects: Experiments with Self-Administration and Brain-Stimulation Reward in Rats

Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaines rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1–10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30–70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1–3 mg/kg) also significantly and dose-dependently inhibited (by 25–90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaines BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaines rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications.

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.

YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice

The dopamine (DA) D3 receptor is posited to be importantly involved in drug reward and addiction, and D3 receptor antagonists have shown extraordinary promise as potential anti‐addiction pharmacotherapeutic agents in animal models of drug addiction. SB‐277011A is the best characterized D3 receptor antagonist in such models. However, the potential use of SB‐277011A in humans is precluded by pharmacokinetic and toxicity problems. We here report a novel D3 receptor antagonist YQA14 that shows similar pharmacological properties as SB‐277011A. In vitro receptor binding assays suggest that YQA14 has two binding sites on human cloned D3 receptors with Ki‐High (0.68 × 10−4 nM) and Ki‐Low (2.11 nM), and displays > 150‐fold selectivity for D3 over D2 receptors and > 1000‐fold selectivity for D3 over other DA receptors. Systemic administration of YQA14 (6.25–25 mg/kg) or SB‐277011A (12.5–25 mg/kg) significantly and dose‐dependently reduced intravenous cocaine self‐administration under both low fixed‐ratio and progressive‐ratio reinforcement conditions in rats, while failing to alter oral sucrose self‐administration and locomotor activity, suggesting a selective inhibition of drug reward. However, when the drug dose was increased to 50 mg/kg, YQA14 and SB‐277011A significantly inhibited basal and cocaine‐enhanced locomotion in rats. Finally, both D3 antagonists dose‐dependently inhibited intravenous cocaine self‐administration in wild‐type mice, but not in D3 receptor‐knockout mice, suggesting that their action is mediated by D3 receptor blockade. These findings suggest that YQA14 has a similar anti‐addiction profile as SB‐277011A, and deserves further study and development.

Attenuation of basal and cocaine-enhanced locomotion and nucleus accumbens dopamine in cannabinoid CB1-receptor-knockout mice

RationaleEffect of cannabinoid CB1 receptor deletion on cocaine’s actions is controversial. This is partly based on findings in CB1-receptor-knockout (CB1−/−) mice with CD1 genetic background.ObjectivesIn the present study, we used CB1−/− mice with a C57BL/6J genetic background to further investigate the role of CB1 receptors in cocaine’s action.Materials and methodsLocomotor activity was assessed using AccuScan locomotor chambers. Brain extracellular dopamine (DA) levels were measured by in vivo microdialysis and by fast-scan cyclic voltammetry in the nucleus accumbens (NAc).ResultsCB1−/− mice displayed a significant reduction in basal levels of locomotion and extracellular DA, as well as in cocaine-enhanced locomotion and extracellular DA, as compared to their wild-type (CB1+/+) littermates. The reduction in basal and cocaine-enhanced DA appears to be related to a reduction in basal DA release, not to an increase in DA clearance, as indicated by fast-scan cyclic voltammetry in brain slices. Pharmacological blockade of CB1 receptors by SR141716 inhibited locomotion and NAc DA release in CB1+/+ mice.ConclusionsThe present findings suggest an important role for CB1 receptors in mediating cocaine’s behavioral and neurochemical effects.