Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats

Rationale

The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects.

Objective

This study established stimulus control with cocaine (10 mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine.

Method

Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine.

Results

Apomorphine, quinpirole, and lisuride occasioned >90 % responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90 % responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D₂/D₃ receptor antagonist raclopride and the D₃ receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D₂ receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats.

Conclusion

These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures.     

Cariprazine (RGH-188), a D3-preferring dopamine D3/D2 receptor partial agonist antipsychotic candidate demonstrates anti-abuse potential in rats

Rationale

Cariprazine (RGH-188) is a D₃-preferring dopamine D₃/D₂ receptor partial agonist antipsychotic candidate for the treatment of schizophrenia and bipolar mania. Substance abuse is a frequent comorbidity of both disorders and is associated with serious health issues. Based on preclinical efficacy, dopamine D₂ and D₃ receptor partial agonists and antagonists are assumed to have relapse-preventing potential in human cocaine addiction.

Objectives

We investigated the anti-abuse potential of cariprazine in cocaine self-administration paradigms. Aripiprazole and bifeprunox were used as comparators because of their pharmacological similarity to cariprazine.

Methods

The effects of compounds on cocaine's rewarding effect were investigated in a continuous self-administration regimen. The relapse-preventing potential of drugs was studied in rats with a history of cocaine self-administration after a period of complete abstinence in a relapse to cocaine-seeking paradigm.

Results

Cariprazine, as well as aripiprazole and bifeprunox, were able to reduce the rewarding effect of cocaine (minimum effective doses were 0.17, 1, and 0.1 mg/kg, respectively) and attenuated relapse to cocaine seeking with half maximal effective dose [ED₅₀] values of 0.2, 4.2, and 0.17 mg/kg, respectively.

Conclusions

These results may predict a relapse-preventing action for cariprazine in humans in addition to its already established antipsychotic and antimanic efficacy.     

Assessment of the abuse liability of ABT-288, a novel histamine H3 receptor antagonist

Rationale

Histamine H₃ receptor antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H₃ antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse.

Objectives

The aim of the present study was to further characterize whether ABT-288 possesses stimulant-like properties and whether its pharmacology gives rise to abuse liability.

Methods

The locomotor-stimulant effects of ABT-288 were measured in mice and rats, and potential development of sensitization was addressed. Drug discrimination was used to assess amphetamine-like stimulus properties, and drug self-administration was used to evaluate reinforcing effects of ABT-288. The potential development of physical dependence was also studied.

Results

ABT-288 lacked locomotor-stimulant effects in both rats and mice. Repeated administration of ABT-288 did not result in cross-sensitization to the stimulant effects of d-amphetamine in mice, suggesting that there is little overlap in circuitries upon which the two drugs interact for motor activity. ABT-288 did not produce amphetamine-like discriminative stimulus effects in drug discrimination studies nor was it self-administered by rats trained to self-administer cocaine. There were no signs of physical dependence upon termination of repeated administration of ABT-288 for 30 days.

Conclusions

The sum of these preclinical data, the first of their kind applied to H₃ antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H₃ antagonists, as a class, are similar in this regard.     

Hypothalamic Neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat

Rationale

Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)⁵]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat.

Methods

Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)⁵]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed.

Results

Intraperitoneal administration of NPSR-QA1 (15–30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15–30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)⁵]NPS (10–30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala.

Conclusions

The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.     

A within-subject assessment of the discriminative stimulus and reinforcing effects of self-administered cocaine in rhesus monkeys

Rationale

Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S^D) and reinforcing (S^R) effects in separate groups of subjects.

Objective

The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S^D and S^R effects using a within-subjects design.

Materials and methods

Adult male rhesus monkeys (n?=?4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule.

Results

Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S^D, such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S^D effects are not necessary for cocaine reinforcement.

Conclusions

This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.     

Influence of cocaine administration patterns on dopamine receptor regulation

Rationale

Chronic exposure to drugs of abuse induces important modifications on neuronal systems. Increasing evidence shows that the consequences to chronic cocaine exposure can be different depending on the administration pattern.

Objectives

The aim of the present study was to evaluate the consequences of two cocaine administration patterns on dopaminergic receptor regulation.

Methods

Male Sprague–Dawley rats were injected with cocaine (20 mg/kg, i.p.) for 14 days according to an intermittent (one daily injection) or a binge (three daily injections) pattern. By autoradiography, we compared the modifications of dopamine D₁ and D₂ receptor densities in the dopaminergic systems (mesocorticolimbic and nigrostriatal) 1 (WD1) and 14 (WD14) days after the last cocaine injection.

Results

On WD1, we observed modifications of D₁ receptors after the binge cocaine treatment pattern while no modification was observed after the intermittent pattern, suggesting that multiple daily injections are needed to induce early D₁ receptor modifications. On the contrary, densities of the D₂ receptors were modified by both cocaine administration patterns, and interestingly, they were opposite depending on the administration pattern. On WD14, we observed different modifications of D₁ and D₂ receptors depending on the administration pattern, suggesting that the cocaine administration pattern promoted long-term regulations of the dopaminergic system.

Conclusion

Two cocaine administration patterns induce different modifications of the dopaminergic receptor densities.     

Discriminative stimulus effects of N,N-diisopropyltryptamine

Rationale

Serotonergic hallucinogens such as (+)-lysergic acid diethylamide (LSD) and dimethyltryptamine (DMT) produce distinctive visual effects, whereas the synthetic hallucinogen N,N-diisopropyltryptamine (DiPT) is known for its production of auditory distortions.

Objective

This study compares the discriminative stimulus effects of DiPT to those of visual hallucinogens.

Methods

Adult male rats were trained to discriminate DiPT (5 mg/kg, 15 min) from saline under a FR10 schedule. A dose–effect and time course of DiPT's discriminative stimulus effects were established. DMT, (?)-2,5-dimethoxy-4-methylamphetamine (DOM), LSD, (±)-methylenedioxymethamphetamine (MDMA), and (+)-methamphetamine were tested for cross-substitution in DiPT-trained animals.

Results

Rats learned to discriminate DiPT from saline in an average of 60 training sessions (30 drug and 30 saline). DiPT (0.5–5 mg/kg) produced dose-dependent increases in drug-appropriate responding (DAR) to 99 % (ED₅₀?=?2.47 mg/kg). Onset of the discriminative stimulus effects was within 5 min, and the effects dissipated within 4 h. Full substitution for the discriminative stimulus effects of DiPT occurred with LSD, DOM, and MDMA. DMT only partially substituted for DiPT (65 % DAR), whereas (+)-methamphetamine failed to substitute for DiPT (29 % DAR).

Conclusions

The discriminative stimulus effects of DiPT were similar those of a number of synthetic hallucinogens, only partially similar to those of DMT, but not similar to (+)-methamphetamine. The putative DiPT-induced auditory distortions do not lead to discriminative stimulus effects distinguishable from other hallucinogens.     

Discrimination of ethanol–nicotine drug mixtures in mice: dual interactive mechanisms of overshadowing and potentiation

Rationale

One possible basis for the proclivity of ethanol and nicotine co-abuse is an interaction between the discriminative stimulus (S^D) effects of each drug.

Objectives

The current work sought to assess the discriminative control of ethanol and nicotine cues in mice trained with drug mixtures and to determine whether interactive mechanisms of overshadowing and potentiation occur.

Methods

Male C57BL/6J mice were trained to discriminate ethanol (1.5?g/kg) alone or ethanol plus nicotine (0.4, 0.8, or 1.2?mg/kg base) in experiment 1 and nicotine (0.8?mg/kg) alone or nicotine plus ethanol (0.5, 1.0, or 2.0?g/kg) in experiment 2. Stimulus generalizations of the training mixtures to ethanol, nicotine, and the drug combination were assessed.

Results

Ethanol (1.5?g/kg) retained discriminative control despite the inclusion of a progressively larger nicotine dose within the training mixtures in experiment 1. Although the nicotine S^D was overshadowed by ethanol training doses > 0.5?g/kg in experiment 2, nicotine did potentiate the effects of low-dose ethanol.

Conclusions

These findings are suggestive of dual mechanisms whereby ethanol (>0.5?g/kg) overshadows the S^D effects of nicotine, and at lower doses (<1?g/kg) the salience of ethanol??s S^D effects is potentiated by nicotine. These mechanisms may contribute to the escalation of concurrent drinking and smoking in a binge-like fashion.     

The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Objective

To review the evidence that agents which preferentially affect serotonin (5-HT) attenuate the ability of N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (NMDA-RA), e.g., phencyclidine (PCP), dizocilpine (MK-801), and ketamine, to stimulate locomotor activity (LA), and to impair novel object recognition (NOR).

Rationale

NMDA-RA-induced increased LA and impairment of NOR are widely used models of the pathophysiology of schizophrenia, the mechanism of action of antipsychotic drugs (APDs), and the identification of novel treatments. Serotonin (5-HT) plays an important role in attenuating these effects of NMDA-RA.

Results

Selective 5-HT_2A inverse agonists, e.g., M100907 and ACP-103, and atypical APDs, which are more potent 5-HT_2A than D₂ antagonists, e.g., clozapine and lurasidone, are more effective than selective D₂ receptor antagonists to attenuate NMDA-RA-induced increased LA. 5-HT_2A inverse agonists alone are not effective to improve NMDA-RA-impaired NOR, but augment the effects of atypical, but not typical APDs, to improve NOR. The 5-HT_1A receptor partial agonist tandospirone alone and the 5-HT_1A agonist effects of atypical APDs may substitute for, or contribute to, the effects of D₂ and 5-HT_2A receptor antagonism to reverse the NMDA-RA impairment in NOR. 5-HT₆ and 5-HT₇ receptor antagonists may also attenuate these NMDA-RA-induced behaviors. 5-HT_2C receptor inverse agonist, but not neutral antagonists, block NOR in na?ve rats and the effects of atypical APDs to restore NOR in PCP-treated rats, suggesting the importance of the constitutive activity of 5-HT_2C receptors in NOR.

Conclusions

Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.     

Interactions between dopamine transporter and cannabinoid receptor ligands in rhesus monkeys

Rationale

??⁹-tetrahydrocannabinol (??⁹-THC) modifies dopamine efflux. However, the extent to which cannabinoid and dopamine drugs modify each other??s behavioral effects has not been fully established.

Objectives

This study examined dopamine releasers and/or transport inhibitors alone and in combination with cannabinoids in two drug discrimination assays.

Methods

Experimentally and pharmacologically experienced rhesus monkeys (n?=?5) discriminated ??⁹-THC (0.1?mg/kg i.v.) from vehicle while responding under a fixed ratio 5 schedule of stimulus-shock termination. A separate group (n?=?6) of monkeys responded under the same schedule, received daily ??⁹-THC (1?mg/kg/12?h?s.c.), and discriminated the cannabinoid antagonist rimonabant (1?mg/kg i.v.), i.e., cannabinoid withdrawal, from vehicle. A sign of withdrawal sign (head shaking) was examined in monkeys receiving ??⁹-THC daily.

Results

Rimonabant antagonized the ??⁹-THC discriminative stimulus and a dose of ??⁹-THC greater than the daily treatment attenuated the rimonabant discriminative stimulus. In monkeys discriminating ??⁹-THC, the dopamine transporter ligands cocaine, amphetamine, bupropion, RTI 113, and RTI 177 produced a maximum of 2% responding on the drug lever and blocked the discriminative stimulus effects of ??⁹-THC. In ??⁹-THC treated monkeys discriminating rimonabant, the dopamine transporter ligands partially substituted for and increased the potency of rimonabant to produce discriminative stimulus effects. The dopamine antagonist haloperidol enhanced the ??⁹-THC discriminative stimulus without significantly modifying the rimonabant discriminative stimulus. Imipramine and desipramine, which have low affinity for dopamine transporters, were less effective in modifying either the ??⁹-THC or rimonabant discriminations. The dopamine transporter ligands and haloperidol attenuated head shaking, whereas imipramine and desipramine did not.

Conclusions

Dopamine release and/or inhibition of dopamine transport blocks detection of ??⁹-THC and is potentially the mechanism by which some therapeutics (e.g., bupropion) reduce the subjective effects of marijuana and enhance the subjective effects of marijuana withdrawal.     

Discriminative stimulus effects of pregnanolone in rats: role of training dose in determining mechanism of action

Rationale

Positive γ-aminobutyric acid_A (GABA_A) modulators acting at different binding sites often produce similar behavioral effects; however, their effects are not identical. Actions of neuroactive steroids at other receptors, in addition to GABA_A receptors, might account for some differences between neuroactive steroids and other positive modulators, like benzodiazepines.

Objective

Multiple mechanisms of other drugs (e.g., ethanol) have been elucidated by comparing their discriminative stimulus effects across different training doses; the current study used that approach to examine the mechanisms of action of the neuroactive steroid pregnanolone.

Methods

Separate groups of rats (n?=?6–8/group) discriminated pregnanolone from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Two groups initially discriminated 3.2 mg/kg; once stimulus control was established, the training dose was systematically decreased to 1.33 mg/kg in one group and increased to 7.5 mg/kg in the other group. Other rats discriminated either 1.33 or 7.5 mg/kg without training at another dose.

Results

Stimulus control was established in 24–28 sessions in all groups. Positive GABA_A modulators produced ≥80 % pregnanolone-lever responding, regardless of training dose; rank-order potency was flunitrazepam?>?midazolam?>?pregnanolone?=?pentobarbital. Ethanol produced some drug-lever responding (42 %) only in rats discriminating 1.33 mg/kg, whereas the N-methyl-d-aspartate receptor antagonist ketamine and the serotonin receptor agonist 1-(m-chlorophenyl)-biguanide occasioned predominantly vehicle-lever responding in all rats.

Conclusions

There was little difference in discriminative stimulus effects of pregnanolone across different training conditions, confirming a predominant, if not exclusive, role of GABA_A receptors in these effects of pregnanolone.     

Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D<Subscript>3</Subscript> and D<Subscript>2</Subscript> receptor sensitivity

Rationale

Cocaine-induced changes in D₂ receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D₃ receptors is less clear.

Objectives

To characterize the effects of repeated cocaine administration on the sensitivity of rats to D₂- and D₃-mediated behaviors, as well as the binding properties of ventral striatal D₂-like and D₃ receptors.

Methods

Pramipexole was used to assess the sensitivity of rats to D₃/D₂ agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D₂-like and D₃ receptors (24 h and 42 days) were also evaluated.

Results

Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h–42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose–response curve. Cocaine treatment also decreased B _max and K _d for D₂-like receptors and increased D₃ receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists.

Conclusions

These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D₃ and D₂ receptors, with enhancements of D₃-mediated behavioral effects observed within 72 h and enhancements of D₂-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D₃ receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.

     

Discriminative stimulus effects of pregnanolone in rhesus monkeys

Rationale

Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABA_A receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABA_A, N-methyl-d-aspartate (NMDA), σ₁, or 5-HT₃ receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators.

Objective

The current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABA_A receptors might contribute to its discriminative stimulus effects.

Methods

Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.

Results

Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABA_A receptors, such as extrasynaptic GABA_A, NMDA, σ₁, and 5-HT₃ receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA₂ values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.

Conclusion

While these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABA_A receptors, they indicate a primary and possibly exclusive role of synaptic GABA_A receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABA_A receptors.     

Sensitization to cocaine is inhibited after intra-accumbal GR103691 or rimonabant, but it is enhanced after co-infusion indicating functional interaction between accumbens D3 and CB1 receptors

Rationale

Dopamine D₃ receptors and cannabinoid CB₁ receptors are both expressed in the nucleus accumbens, and they have been involved in motor sensitization to cocaine. The objectives were: (1) to study the effects of blockade of these receptors on sensitization to repeated cocaine, by using GR103691, D₃ receptor blocker, and rimonabant, CB₁ receptor ligand, and (2) to discern if both receptors interact by co-infusing them.

Materials and methods

Cocaine (10?mg/kg) was injected daily for 3?days (induction phase) and later on day?8 (expression phase), and locomotor activity was measured during 2?h after cocaine. GR103691 and rimonabant were bilaterally injected (0.5???l volume of each infusion) in the nucleus accumbens through cannulae (GR103691, 0, 4.85, and 9.7???g/??l; rimonabant, 0, 0.5, and 1.5???g/??l), before cocaine, during either induction or expression phases of sensitization.

Results

The findings indicated that sensitizing effects of cocaine were abolished after D₃ receptor blocking during both induction and expression phases, as well as rimonabant infusion during the expression (not induction) phase. A functional interaction between both receptors was also observed, because if GR103691 was injected during induction and rimonabant during expression, sensitizing effects of cocaine were observed to be normal or further enhanced.

Conclusion

Dopamine D₃ receptors within the nucleus accumbens are critical for the development and consolidation of sensitization, and cannabinoid CB₁ receptors are critical for the expression of sensitization. Co-blockade of D₃ and CB₁ receptors exert opposite effects to blockade of these receptors separately, revealing the existence of a functional interaction between them.     

An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

Rationale

The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M₄ acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M₄ receptors could be a novel target for modulating psychostimulant effects of cocaine.

Objectives

For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M₄ receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice.

Methods

To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition, the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated.

Results

We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M₄ receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M₄ receptor knockout mice. Furthermore, selective deletion of the M₄ receptor gene in dopamine D₁ receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M₄ receptors co-localized with D₁ receptors.

Conclusions

These results show that positive allosteric modulators of the M₄ receptor deserve attention as agents in the future treatment of cocaine abuse.     

Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice

Rationale

Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined.

Objectives

To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.

Methods

The Y5 antagonist L-152,804 and Y5-knockout (Y5-KO) mice were tested in two models of cocaine addiction-related behaviour: acute self-administration and cocaine-induced hyperactivity. We also studied effects of Y5 receptor antagonism on cocaine-induced c-fos expression and extracellular dopamine with microdialysis as well as dopamine transporter-mediated uptake of dopamine in vitro. Immunocytochemistry was used to determine whether dopamine neurons express Y5-like immunoreactivity.

Results

In self-administration, L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose–response curve for cocaine downward. Y5-KO mice also showed modestly attenuated self-administration. Cocaine-induced hyperactivity was attenuated by L-152,804 and in Y5-KO mice. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L-152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behaviour by regulating dopamine. Consistent with this concept, dopamine neurons in the ventral tegmental area appeared to contain Y5 receptors. In contrast, neither L-152,804 nor NPY influenced dopamine transporter-mediated dopamine uptake.

Conclusions

The present data indicate that Y5 antagonism may attenuate cocaine-induced behavioural effects, suggesting that Y5 receptors could be a potential therapeutic target in cocaine addiction.     

Effects of the selective sigma receptor ligand, 1-(2-phenethyl)piperidine oxalate (AC927), on the behavioral and toxic effects of cocaine

Background

Sigma receptors represent a unique structural class of proteins and they have become increasingly studied as viable medication development targets for neurological and psychiatric disorders, including drug abuse. Earlier studies have shown that cocaine and many other abused substances interact with sigma receptors and that antagonism of these proteins can mitigate their actions.

Methods

In the present study, AC927 (1-(2-phenethyl)piperidine oxalate), a selective sigma receptor ligand, was tested against the behavioral and toxic effects of cocaine in laboratory animals.

Results

Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Subchronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug discrimination studies in male, Sprague-Dawley rats, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-response curve to the left, suggesting an enhancement of the discriminative stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine.

Conclusion

The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse.     

Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonist SCH 23390

To investigate the role of D₁ dopamine receptors in the discriminative stimulus effects of cocaine, two rhesus monkeys were trained in a two-lever, food-reinforced, drug discrimination paradigm to discriminate cocaine (0.2 mg/kg, IM) from saline. Administration of various doses of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. Administration of the D₁ antagonist SCH 23390 20 min before cocaine reduced drug-appropriate responding from 100% to 0% in all subjects and increased by 4–8-fold the cocaine dose necessary to induce drug-appropriate responding. A mutual antagonism of the rate-decreasing effects of cocaine and SCH 23390 was also observed. These findings suggest that D₁ receptors play a significant role in the discriminative stimulus and rate-decreasing effects of cocaine.     

Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats

Rationale

We previously showed that the M₁/M₄-preferring muscarinic agonist xanomeline can acutely attenuate or eliminate cocaine self-administration in mice.

Objective

Medications used to treat addictions will arguably be administered in (sub)chronic or repeated regimens. Tests of acute effects often fail to predict chronic effects, highlighting the need for chronic testing of candidate medications.

Methods

Rats were trained to lever press under a concurrent FR5 FR5 schedule of intravenous cocaine and food reinforcement. Once baseline behavior stabilized, the effects of 7 days once-daily injections of xanomeline were evaluated.

Results

Xanomeline pretreatment dose-dependently (1.8–10 mg/kg/day) shifted the dose-effect curve for cocaine rightward (up to 5.6-fold increase in A ₅₀), with reallocation of behavior to the food-reinforced lever. There was no indication of tolerance, rather effects grew over days. The suppression of cocaine choice appeared surmountable at high cocaine doses, and xanomeline treatment did not significantly decrease total-session cocaine or food intake.

Conclusions

In terms of xanomeline's potential for promoting abstinence from cocaine in humans, the findings were mixed. Xanomeline did produce reallocation of behavior from cocaine to food with a robust increase in food reinforcers earned at some cocaine/xanomeline dose combinations. However, effects appeared surmountable, and food-maintained behavior was also decreased at some xanomeline/cocaine dose combinations, suggesting clinical usefulness may be limited. These data nevertheless support the notion that chronic muscarinic receptor stimulation can reduce cocaine self-administration. Future studies should show whether ligands with higher selectivity for M₁ or M₁/M₄ subtypes would be less limited by undesired effects and can achieve higher efficacy.