scholarly journals Effects of acute and repeated administration of the selective M4 PAM VU0152099 on cocaine vs. food choice in male rats

2021 ◽  
Author(s):  
Morgane H Thomsen ◽  
Jill R Crittenden ◽  
Craig W. Lindsley ◽  
Ann M. Graybiel
Keyword(s):  
Acetylcholine Receptors ◽  
Repeated Administration ◽  
Muscarinic Acetylcholine Receptors ◽  
Male Rats ◽  
Contrast Effects ◽  
Self Administration ◽  
Cocaine Use ◽  
Dopamine Receptor Antagonists ◽  
Cocaine Seeking ◽  
Term Administration

Ligands that stimulate muscarinic acetylcholine receptors 1 and 4 (M1, M4) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M4 stimulation, as well as long-lasting, delayed, reductions in cocaine taking and cocaine seeking with combined M1/M4 receptor stimulation or with M1 stimulation alone. M4 stimulation opposes dopaminergic signaling acutely, but direct dopamine receptor antagonists have proved unhelpful in managing cocaine use disorder because they lose efficacy with long-term administration. It is therefore critical to determine whether M4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer, to obtain quantitative measurement of whether M4 stimulation could produce delayed and lasting reduction in cocaine taking. VU0152099 produced progressively augmenting suppression of cocaine choice and cocaine intake, but produced neither rebound nor lasting effects after treatment ended. To compare and contrast effects of M1 vs. M4 stimulation, we tested whether the M4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signaling factor, required for M1- mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M4- mediated suppression of cocaine self-administration. These findings support the potential usefulness of M4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M1-selective ligands, and show that M1 and M4 stimulation modulate cocaine-taking behavior by distinct mechanisms.

scholarly journals Lateral habenula M2 muscarinic receptor control of neuronal activity and cocaine seeking behavior

2021 ◽  
Author(s):  
Clara I.C. Wolfe ◽  
Eun-Kyung Hwang ◽  
Agustin Zapata ◽  
Alexander F Hoffman ◽  
Carl R. Lupica
Keyword(s):  
Acetylcholine Receptors ◽  
Behavioral Control ◽  
Control Point ◽  
Muscarinic Acetylcholine Receptors ◽  
Self Administration ◽  
Cellular Mechanisms ◽  
Lateral Habenula ◽  
Selective Blockade ◽  
Cocaine Seeking

The lateral habenula (LHb) plays a central role in balancing reward and aversion by opposing the contributions of brain reward nuclei. Using a rat cocaine self-administration model, we previously found that LHb inhibition or non-selective blockade of LHb muscarinic acetylcholine receptors (mAChRs) led to persistent cocaine seeking despite its signaled unavailability. As understanding roles for the LHb and cholinergic signaling in behavioral control is important to psychiatric illness and addiction, we examine how mAChRs act on LHb neurons using in vitro electrophysiology. We find that different groups of LHb neurons are depolarized or hyperpolarized by the cholinergic agonist carbachol (CCh), and that CCh could inhibit GABAergic and glutamatergic synaptic inputs to these cells. Presynaptic CCh effects were reversed by the M2 mAChR (M2R) antagonist AFDX-116, but not by pirenzepine, an M1R antagonist. Contemporaneous measurement of CCh effects on synaptic inhibition and excitation in LHb neurons showed a smaller effect on inhibition, suggesting a net shift in synaptic integration toward greater inhibition by mAChRs. Synaptic currents elicited by light-activation of ventral tegmental area (VTA) axons in the LHb, following channelrhodopsin-2 transfection of VTA, were also inhibited by M2Rs, suggesting the VTA as at least one M2R-sensitive LHb afferent. Finally, Go-NoGo cocaine seeking studies showed that blockade of LHb M2Rs, and not M1Rs, triggered continued cocaine seeking. These data identify LHb M2Rs as a potential control point of LHb function that enables withholding responses for cocaine and define cellular mechanisms through which mAChRs modulate LHb activity.

ARC and BDNF expression after cocaine self-administration or cue-induced reinstatement of cocaine seeking in adolescent and adult male rats

2018 ◽  
Vol 23 (6) ◽  
pp. 1233-1241 ◽  
Author(s):  
Chen Li ◽  
Alexandria C. White ◽  
Terri Schochet ◽  
Jacqueline F. McGinty ◽  
Kyle J. Frantz
Keyword(s):  
Adult Male ◽  
Male Rats ◽  
Self Administration ◽  
Bdnf Expression ◽  
Cocaine Seeking

Effects of an acute cannabidiol treatment on cocaine self-administration and cue-induced cocaine seeking in male rats

2016 ◽  
Vol 31 (1) ◽  
pp. 96-104 ◽  
Author(s):  
Ashraf Mahmud ◽  
Stephanie Gallant ◽  
Firas Sedki ◽  
Tracey D’Cunha ◽  
Uri Shalev
Keyword(s):  
Elevated Plus Maze ◽  
Anxiolytic Effect ◽  
Progressive Ratio ◽  
Male Rats ◽  
Self Administration ◽  
Schedule Of Reinforcement ◽  
Cocaine Seeking ◽  
Therapeutic Value ◽  
Plus Maze ◽  
Wide Range

Cannabidiol is a non-psychoactive compound that is the second most abundant component of cannabis. It has been shown to have a potential therapeutic value for a wide range of disorders, including anxiety, psychosis, and depression. Recently, it was suggested that cannabidiol might be a potential treatment for heroin craving and relapse. Here we investigated the effects of an acute treatment with cannabidiol on cocaine self-administration and cue-induced cocaine seeking in rats. Rats were trained to press a lever to self-administer cocaine (0.5 mg/kg/infusion), first under a fixed interval 20 s (FI-20 s) and then under a progressive ratio (PR) schedule of reinforcement. Cocaine self-administration under a PR schedule of reinforcement was not attenuated by cannabidiol injections (5.0 mg/kg and 10.0 mg/kg; i.p.) when tested 30 min and 24 h after treatment. Cannabidiol treatment (5.0 mg/kg or 10.0 mg/kg) also did not attenuate cue-induced cocaine seeking in rats after a withdrawal period of 14 days. In contrast, treatment with cannabidiol (10.0 mg/kg; i.p.) resulted in a statistically significant anxiolytic effect in the elevated plus-maze. Our findings suggest that, under the conditions described here, an acute cannabidiol treatment has a minimal effect on a rat model of cocaine intake and relapse.

scholarly journals Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors

2021 ◽  
Author(s):  
Zhi-Bing You ◽  
Ewa Galaj ◽  
Francisco Alén ◽  
Bin Wang ◽  
Guo-Hua Bi ◽  
...  
Keyword(s):  
Research Effort ◽  
Critical Role ◽  
Dopamine Neurons ◽  
Brain Stimulation Reward ◽  
Mrna Levels ◽  
Self Administration ◽  
Conditioned Stimuli ◽  
Cocaine Use ◽  
Ghrelin Receptor ◽  
Cocaine Seeking

AbstractCocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.

scholarly journals D-amphetamine maintenance therapy reduces cocaine use in female rats

2021 ◽  
Author(s):  
Ndeye Aissatou Ndiaye ◽  
Florence Allain ◽  
Anne-Noel Samaha
Keyword(s):  
Maintenance Therapy ◽  
Progressive Ratio ◽  
Cocaine Addiction ◽  
Female Rats ◽  
Male Rats ◽  
Ratio Schedule ◽  
Self Administration ◽  
Cocaine Use ◽  
Intermittent Access ◽  
Amphetamine Treatment

Currently, there are no approved medications to treat cocaine addiction. In this context, d-amphetamine maintenance therapy is a promising pharmacological strategy to reduce cocaine use. In both male rats and human cocaine users, d-amphetamine treatment reduces cocaine taking and seeking. However, this has not been examined systematically in female animals, even though cocaine addiction afflicts both women and men, and the sexes can differ in their response to cocaine. Here, we determined how d-amphetamine maintenance therapy during cocaine self-administration influences cocaine use in female rats. In experiment 1, two groups of female rats received 14 intermittent access (IntA) cocaine self-administration sessions. One group received concomitant d-amphetamine maintenance treatment (COC + A rats; 5 mg/kg/day, via minipump), the other group did not (COC rats) After discontinuing d-amphetamine treatment, we measured responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. In experiment 2, we assessed the effects of d-amphetamine maintenance on these measures in already cocaine-experienced rats. To this end, rats first received 14 IntA cocaine self-administration sessions without d-amphetamine. They then received 14 more sessions now either with (COC/COC + A rats) or without (COC/COC rats) concomitant d-amphetamine treatment. In both experiments, d-amphetamine-treated rats showed reduced motivation to take and seek cocaine, responding less for cocaine both under progressive ratio and extinction conditions. In contrast, d-amphetamine treatment did not influence cocaine-primed reinstatement of cocaine seeking. Thus, d-amphetamine treatment reduces both the development and expression of addiction-relevant patterns of cocaine use in female animals.

scholarly journals Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats

2021 ◽  
Author(s):  
Lieselot Leen G Carrette ◽  
Cristina Corral ◽  
Caitlin Crook ◽  
Brent Boomhower ◽  
Molly Brennan ◽  
...  
Keyword(s):  
Individual Differences ◽  
Weight Control ◽  
Protective Factor ◽  
Causal Effect ◽  
Small Sample ◽  
Cocaine Addiction ◽  
Self Administration ◽  
Cocaine Use ◽  
Cocaine Seeking ◽  
Using Data

In addition to its pleasurable effects, weight control is a significant contributor to initiation, maintenance and relapse of cocaine use. This suggests that individual differences in bodyweight control and feeding hormones, such as leptin may contribute to the vulnerability to cocaine use disorder. While pre-clinical studies have shown a mutually inhibitory relationship between leptin and cocaine, they have used small sample sizes and did not investigate individual differences in a large heterogeneous population. Here, we tested if individual differences in bodyweight and blood leptin level is associated with high or low vulnerability to addiction-like behaviors using data from 500 heterogenous stock rats and 160 blood samples from the Cocaine Biobank, using a model of extended access to intravenous self-administration of cocaine. Finally, we tested a separate cohort to evaluate the causal effect of exogenous leptin administration on cocaine seeking. Bodyweight, while changing due to cocaine self-administration in males, was not related to the vulnerability to addiction-like behavior. Blood leptin levels after ~6 weeks of cocaine self-administration did not correlate with addiction-like behaviors, however, baseline blood leptin levels before any access to cocaine negatively predicted addiction-like behavior. Finally, administration of leptin reduced cocaine intake after acute withdrawal and cocaine seeking after 6 weeks of protracted abstinence. These results demonstrate that high blood leptin level before access to cocaine may be a protective factor against the development of cocaine addiction-like behavior, that exogenous leptin reduces the motivation to take and seek cocaine, but that blood leptin level and bodyweight changes in current users are not good biomarkers for addiction-like behaviors.

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

2021 ◽  
pp. 026988112110192
Author(s):  
Samantha N Scott ◽  
Raul Garcia ◽  
Gregory L Powell ◽  
Sophia M Doyle ◽  
Brielle Ruscitti ◽  
...  
Keyword(s):  
Cue Reactivity ◽  
Fixed Ratio ◽  
Test Session ◽  
Female Rats ◽  
Male Rats ◽  
Inhibitory Effects ◽  
Self Administration ◽  
Training Dose ◽  
Male And Female Rats ◽  
Cocaine Seeking

Background: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. Aims: We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. Methods: Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21–60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions). Results: Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion. Conclusions: CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT1BR agonists may have clinical efficacy as anti-relapse medications for cocaine use disorders.

scholarly journals Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cued cocaine relapse

2020 ◽  
Author(s):  
Allison R. Bechard ◽  
Carly N. Logan ◽  
Javier Mesa ◽  
Yasmin Padovan Hernandez ◽  
Harrison Blount ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Basolateral Amygdala ◽  
Male Rats ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Cocaine Seeking ◽  
Context Cues ◽  
Glutamate Efflux

AbstractCeftriaxone is an antibiotic that reliably attenuates the reinstatement of cocaine-seeking after extinction while preventing the nucleus accumbens (NA) core glutamate efflux that drives reinstatement. However, when rats undergo abstinence without extinction, ceftriaxone attenuates context-primed relapse but NA core glutamate efflux still increases. Here we sought to determine if the same would occur when relapse is prompted by both context and discrete cues (context+cues) after cocaine abstinence. Male rats self-administered intravenous cocaine for 2 hr/day for 2 weeks. Cocaine delivery was accompanied by drug-associated cues (light+tone). Rats were then placed into abstinence with daily handling but no extinction training for two weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a context+cue relapse test, microdialysis procedures were conducted. Rats were perfused at the end of the test for later Fos analysis. A separate cohort of rats was infused with the retrograde tracer cholera toxin B in the NA core and underwent the same self-administration and relapse procedures. Ceftriaxone increased baseline glutamate and attenuated both context+cue-primed relapse and NA core glutamate efflux during this test. Ceftriaxone reduced Fos expression in regions sending projections to the NA core (prefrontal cortex, basolateral amygdala, ventral tegmental area) and specifically reduced Fos in prelimbic cortex and not infralimbic cortex neurons projecting to the NA core. Thus, when relapse is primed by drug-associated cues and context, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core-projecting neurons.

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