Xiao-Qing Peng

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.

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.

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.

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.

The preferential dopamine D3 receptor antagonist S33138 inhibits cocaine reward and cocaine-triggered relapse to drug-seeking behavior in rats

We have previously reported that selective dopamine (DA) D3 receptor antagonists are effective in a number of animal models of drug addiction, but not in intravenous drug self-administration, suggesting a limited ability to modify drug reward. In the present study, we evaluated the actions ofS33138, a novel partially selective D3 receptor antagonist, in animal models relevant to drug addiction. S33138, at doses of 0.156 or 0.625 mg/kg (i.p.), attenuated cocaine-enhanced brain-stimulation reward (BSR), and the highest dose tested (2.5 mg/kg) produced a significant aversive-like rightward shift in BSR rate-frequency reward functions. Further, S33138 produced biphasic effects on cocaine self-administration, i.e., a moderate dose (2.5 mg/kg, p.o.) increased, while a higher dose (5 mg/kg, p.o.) inhibited, cocaine self-administration. The increase in cocaine self-administration likely reflects a compensatory response to a partial reduction in drug reward after S33138. In addition, S33138 (0.156-2.5 mg/kg, p.o.) also dose-dependently inhibited cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-enhanced BSR and cocaine-triggered reinstatement produced by lower effective doses (e.g., 0.156 or 0.625 mg/kg) of 533138 is unlikely due to impaired locomotion, as lower effective doses of S33138 decreased neither Ymax levels in the BSR paradigm, rotarod performance, nor locomotion. However, the higher doses (2.5 or 5 mg/kg) of S33138 also significantly inhibited sucrose self-administration and rotarod performance, suggesting non-D3 receptor-mediated effects on non-drug reward and locomotion. These data suggest that lower doses of S33138 interacting essentially with D3 receptors have pharmacotherapeutic potential in treatment of cocaine addiction, while higher doses occupying D2 receptors may influence locomotion and non-drug reward.

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats.

It was recently reported that levo-tetrahydropalmatine (l-THP), a dopamine (DA) D1 and D2 receptor antagonist purified from the Chinese herb Stephanie, appears to be effective in attenuating cocaine self-administration, cocaine-triggered reinstatement and cocaine-induced conditioned place preference in preclinical animal models. The present study was designed to contrast l-THPs effects on cocaine self-administration under fixed-ratio (FR) and progressive-ratio (PR) reinforcement, and to study l-THPs effects on cocaine-enhanced brain stimulation reward (BSR). Systemic administration of l-THP produced dose-dependent, biphasic effects, i.e., low-to-moderate doses (1, 3, 10 mg/kg) increased, while a high dose (20 mg/kg) inhibited cocaine self-administration behavior under FR2 reinforcement. The increased cocaine self-administration is likely a compensatory response to a reduction in cocaines rewarding effects, because the same low doses of l-THP dose-dependently attenuated cocaine self-administration under PR reinforcement and also attenuated cocaine-enhanced BSR. These attenuations of PR cocaine self-administration and cocaine-enhanced BSR are unlikely due to l-THP-induced sedation or locomotor inhibition, because only 10 mg/kg, but not 1-3 mg/kg, of l-THP inhibited locomotion, sucrose self-administration and asymptotic operant performance in the BSR paradigm. In vivo microdialysis demonstrated that l-THP slightly elevates extracellular nucleus accumbens DA by itself, but dose-dependently potentiates cocaine-augmented DA, suggesting that a postsynaptic, rather than presynaptic, DA receptor antagonism underlies l-THPs actions on cocaine reward. Together, the present data, combined with previous findings, support the potential use of l-THP for treatment of cocaine addiction.

N-acetylaspartylglutamate (NAAG) inhibits intravenous cocaine self-administration and cocaine-enhanced brain-stimulation reward in rats

Pharmacological activation of group II metabotropic glutamate (mGlu2 and mGlu3) receptors inhibits reward-seeking behavior and/or rewarding efficacy induced by drugs (cocaine, nicotine) or natural rewards (food, sucrose). In the present study, we investigated whether elevation of brain N-acetylaspartylglutamate (NAAG), an endogenous group II mGlu receptor agonist, by the NAAG peptidase inhibitor 2-PMPA attenuates cocaines rewarding effects, as assessed by intravenous cocaine self-administration and intracranial electrical brain-stimulation reward (BSR) in rats. Systemic administration of 2-PMPA (10, 30, 100 mg/kg, i.p.) or intranasal administration of NAAG (100, 300 microg/10 microl/nostril) significantly inhibited intravenous cocaine self-administration under progressive-ratio (PR), but not under fixed-ratio 2 (FR2), reinforcement conditions. In addition, 2-PMPA (1, 10, 30 mg/kg, i.p) or NAAG (50, 100 microg/10 microl/nostril) significantly inhibited cocaine-enhanced BSR, but not basal BSR. Pretreatment with LY341495 (1 mg/kg, i.p.), a selective mGlu2/3 receptor antagonist, prevented the inhibitory effects produced by 2-PMPA or NAAG in both the self-administration and BSR paradigms. In vivo microdialysis demonstrated that 2-PMPA (10, 30, 100 mg/kg) dose-dependently attenuated cocaine-enhanced extracellular dopamine (DA) in the nucleus accumbens (NAc). 2-PMPA alone inhibited basal NAc DA release, an effect that was prevented by LY341495. These findings suggest that systemic administration of 2-PMPA or intranasal administration of NAAG inhibits cocaines rewarding efficacy and cocaine-enhanced NAc DA - likely by activation of presynaptic mGlu2/3 receptors in the NAc. These data suggest a potential utility for 2-PMPA or NAAG in the treatment of cocaine addiction.

Blockade of Dopamine D3 Receptors in the Nucleus Accumbens and Central Amygdala Inhibits Incubation of Cocaine Craving in Rats

Cue‐induced drug seeking progressively increases over time of withdrawal from drug self‐administration in rats, a phenomenon called ‘incubation of craving’. The underlying mechanisms have been linked to increased expression of brain‐derived neurotrophic factor and GluR2‐lacking AMPA receptors in the mesolimbic dopamine (DA) system and also to increased extracellular signal‐regulated kinase activation in the central amygdala (CeA). However, it remains unclear whether any DA mechanism is also involved in incubation of craving. Recent research demonstrates that cue‐induced cocaine seeking appears to parallel increased DA D3, but not D1 or D2, receptor expression in the nucleus accumbens (NAc) of rats over time of withdrawal, suggesting possible involvement of D3 receptors (D3Rs) in incubation of cocaine craving. Here, we report that systemic or local administration of SB‐277011A, a highly selective D3R antagonist, into the NAc (core and shell) or the CeA, but not the dorsal striatum or basolateral amygdala, significantly inhibits expression of incubation of cocaine craving in rats after 2–30 days of withdrawal from previous cocaine self‐administration but had no effect on sucrose‐seeking behavior in rats after 10–30 days of withdrawal. These data suggest that DA D3Rs in both the NAc and the CeA play an important role in incubation of cocaine craving in rats and support the potential utility of D3R antagonists in the treatment of cocaine addiction.

Is Slow-Onset Long-Acting Monoamine Transport Blockade to Cocaine as Methadone is to Heroin? Implication for Anti-Addiction Medications

The success of methadone in treating opiate addiction has suggested that long-acting agonist therapies may be similarly useful for treating cocaine addiction. Here, we examined this hypothesis, using the slow-onset long-acting monoamine reuptake inhibitor 31,345, a trans-aminotetralin analog, in a variety of addiction-related animal models, and compared it with methadones effects on heroins actions in the same animal models. Systemic administration of 31,345 produced long-lasting enhancement of electrical brain-stimulation reward (BSR) and extracellular nucleus accumbens (NAc) dopamine (DA). Pretreatment with 31,345 augmented cocaine-enhanced BSR, prolonged cocaine-enhanced NAc DA, and produced a long-term (24-48 h) reduction in cocaine self-administration rate without obvious extinction pattern, suggesting an additive effect of 31,345 with cocaine. In contrast, methadone pretreatment not only dose-dependently inhibited heroin self-administration with an extinction pattern but also dose-dependently inhibited heroin-enhanced BSR and NAc DA, suggesting functional antagonism by methadone of heroins actions. In addition, 31,345 appears to possess significant abuse liability, as it produces dose-dependent enhancement of BSR and NAc DA, maintains a low rate of self-administration behavior, and dose-dependently reinstates drug-seeking behavior. In contrast, methadone only partially maintains self-administration with an extinction pattern, and fails to induce reinstatement of drug-seeking behavior. These findings suggest that 31,345 is a cocaine-like slow-onset long-acting monoamine transporter inhibitor that may act as an agonist therapy for cocaine addiction. However, its pattern of action appears to be significantly different from that of methadone. Ideal agonist substitutes for cocaine should fully emulate methadones actions, that is, functionally antagonizing cocaines action while blocking monoamine transporters to augment synaptic DA.