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Effects of muscarinic M₁ receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.

ABSTRACT: Cocaine addiction is a chronic illness characterized by maladaptive drug-induced neuroplastic changes that confer lasting vulnerability to relapse. Over several weeks we observed the effects of the M₁ receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. food choice procedure. The drug showed unusual long-lasting effects, as rats gradually stopped self-administering cocaine, reallocating behavior towards the food reinforcer. The effect lasted as long as tested and at least 4 weeks. To begin to elucidate how VU0364572 modulates cocaine self-administration, we then examined its long-term effects using dual-probe in vivo dopamine and glutamate microdialysis in nucleus accumbens and medial prefrontal cortex, and ex vivo striatal dopamine reuptake. Microdialysis revealed marked decreases in cocaine-induced dopamine and glutamate outflow 4 weeks after VU0364572 treatment, without significant changes in dopamine uptake function. These lasting and marked effects of M₁ receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M₁ receptors are known to modulate medium spiny neuron responses to corticostriatal glutamatergic signaling acutely, and we hypothesize that VU0364572 may oppose the addiction-related effects of cocaine by causing lasting changes in this system.

SUBMITTER: Weikop P

PROVIDER: S-EPMC7547714 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Effects of muscarinic M<sub>1</sub> receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.

Weikop Pia P Jensen Kathrine L KL Thomsen Morgane M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20200428 12

Cocaine addiction is a chronic illness characterized by maladaptive drug-induced neuroplastic changes that confer lasting vulnerability to relapse. Over several weeks we observed the effects of the M<sub>1</sub> receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. food choice procedure. The drug showed unusual long-lasting effects, as rats gradually stopped self-administering cocaine, reallocating behavior towards the food reinforcer. The effect l ...[more]

PMID: 32344426

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Project description:Muscarinic cholinergic receptors modulate dopaminergic function in brain pathways thought to mediate cocaine's abuse-related effects. Here, we sought to confirm and extend in the mouse species findings that nonselective muscarinic receptor antagonists can enhance cocaine's discriminative stimulus. More importantly, we tested the hypothesis that muscarinic receptor agonists with varied receptor subtype selectivity can blunt cocaine's discriminative stimulus and reinforcing effects; we hypothesized a critical role for the M(1) and/or M(4) receptor subtypes in this modulation. Mice were trained to discriminate cocaine from saline, or to self-administer intravenous cocaine chronically. The nonselective muscarinic antagonists scopolamine and methylscopolamine, the nonselective muscarinic agonists oxotremorine and pilocarpine, the M(1)/M(4)-preferring agonist xanomeline, the putative M(1)-selective agonist (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343), and the novel M(1)-selective agonist 1-(1-2-methylbenzyl)-1,4-bipiperidin-4-yl)-1H benzo[d]imidazol-2(3H)-one (TBPB) were tested as substitution and/or pretreatment to cocaine. Both muscarinic antagonists partially substituted for cocaine and enhanced its discriminative stimulus. Conversely, muscarinic agonists blunted cocaine discrimination and abolished cocaine self-administration with varying effects on food-maintained behavior. Specifically, increasing selectivity for the M(1) subtype (oxotremorine < xanomeline < TBPB) conferred lesser nonspecific rate-suppressing effects, with no rate suppression for TBPB. In mutant mice lacking M(1) and M(4) receptors, xanomeline failed to diminish cocaine discrimination while rate-decreasing effects were intact. Our data suggest that central M(1) receptor activation attenuates cocaine's abuse-related effects, whereas non-M(1)/M(4) receptors probably contribute to undesirable effects of muscarinic stimulation. These data provide the first demonstration of anticocaine effects of systemically applied, M(1) receptor agonists and suggest the possibility of a new approach to pharmacotherapy for cocaine addiction.

Project description:Due to its high prevalence, obesity is considered an epidemic, which stimulated research on non-invasive methods to reduce excess body fat. Transcranial direct current stimulation (tDCS) is a non-invasive technique used to modulate the activity of cerebral cortex, which has already found increasing interest in medicine as a promising methodology. The aim of this study was to analyze the impact of tDCS on feeding behavior, metabolic abnormalities and neurotransmitters in certain brain areas involved in appetite control of obese rats. The male Wistar rats were divided into five subgroups depending on consumed diet effect (lean, obese) and tDCS type (anodal, cathodal, sham, and no stimulation). Two 10-min daily sessions of tDCS for 8 consecutive days of the study were applied. Rats subjected to active tDCS (anodal right or cathodal left of the prefrontal cortex) had reduced appetite and showed lesser body weight gain than the animals subjected to sham procedure or those receiving no stimulation at all. Furthermore, tDCS contributed to reduction of epididymal fat pads and to a decrease in blood concentration of leptin. Neurochemical examination revealed that tDCS modulated serotonin pathways of the reward-related brain areas and contributed to a significant decrease in the density of D2 but not D1 dopamine receptors in the dorsal striatum, recorded 5 h after the last stimulation. No significant effect of tDCS on dopamine and it's metabolites in examined brain regions was observed. It seems that the hypothalamus was not affected by tDCS application as no changes in measured neurotransmitters were detected at any examined time point. However, these results do not exclude the possibility of the delayed response of the monoamines in the examined brain areas to tDCS application. Altogether, these findings imply that repeated tDCS of the prefrontal cortex may change feeding behavior of obese rats. Either right anodal or left cathodal tDCS were sufficient to decrease food intake, to reduce body adiposity and to normalize other metabolic anomalies. These beneficial effects can be at least partially explained by changes in serotoninergic and in lesser extent dopaminergic system activity within some brain areas belonging to reward system.

Project description:ObjectiveAcetylcholine modulates the activity of the direct and indirect pathways within the striatum through interaction with muscarinic M4 and M1 receptors. M4 receptors are uniquely positioned to regulate plasticity within the direct pathway and play a substantial role in reward and addiction-related behaviors. However, the role of M4 receptors on cholinergic neurons has been less explored. This study aims to fill this gap by addressing the role of M4 receptors on cholinergic neurons in these behaviors.MethodsTo investigate the significance of M4-dependent inhibitory signaling in cholinergic neurons we created mutant mice that lack M4 receptors on cholinergic neurons. Cholinergic neuron-specific depletion was confirmed using in situ hybridization. We aimed to untangle the possible contribution of M4 autoreceptors to the effects of the global M4 knockout by examining aspects of basal locomotion and dose-dependent reactivity to the psychostimulant and rewarding properties of cocaine, haloperidol-induced catalepsy, and examined both the anti-cataleptic and locomotion-inducing effects of the non-selective anticholinergic drug scopolamine.ResultsBasal phenotype assessment revealed no developmental deficits in knockout mice. Cocaine stimulated locomotion in both genotypes, with no differences observed at lower doses. However, at the highest cocaine dose tested, male knockout mice displayed significantly less activity compared to wild type littermates (p = 0.0084). Behavioral sensitization to cocaine was similar between knockout and wild type mice. Conditioned place preference tests indicated no differences in the rewarding effects of cocaine between genotypes. In food-reinforced operant tasks knockout and wild type mice successfully acquired the tasks with comparable performance results. M4 receptor depletion did not affect haloperidol-induced catalepsy and scopolamine reversal of catalepsy but attenuated scopolamine-induced locomotion in females (p = 0.04). Our results show that M4 receptor depletion attenuated the locomotor response to high doses of cocaine in males and scopolamine in females, suggesting sex-specific regulation of cholinergic activity.ConclusionDepletion of M4 receptors on cholinergic neurons does not significantly impact basal behavior or cocaine-induced hyperactivity but may modulate the response to high doses of cocaine in male mice and the response to scopolamine in female mice. Overall, our findings suggest that M4-dependent autoregulation plays a minor but delicate role in modulating specific behavioral responses to pharmacological challenges, possibly in a sex-dependent manner.

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Effects of muscarinic M₁ receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.

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Effects of muscarinic M<sub>1</sub> receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.

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Effects of muscarinic M1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.

Publications

Effects of muscarinic M<sub>1</sub> receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.

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OmicsDI is part of the ELIXIR infrastructure

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Effects of muscarinic M₁ receptor stimulation on reinforcing and neurochemical effects of cocaine in rats.