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 Amphetamine Maintenance Therapy During Intermittent Cocaine Self-Administration in Rats: Reduction of Addiction-like Behavior is Associated with Attenuation of Psychomotor and Dopamine Sensitization

2020 ◽  
Author(s):  
Florence Allain ◽  
Benoît Delignat-Lavaud ◽  
Marie-Pierre Beaudoin ◽  
Vincent Jacquemet ◽  
Terry E. Robinson ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Ex Vivo ◽  
Progressive Ratio ◽  
Male Rats ◽  
Ratio Schedule ◽  
Self Administration ◽  
Nucleus Accumbens Core ◽  
Fast Scan Cyclic Voltammetry ◽  
Cocaine Use ◽  
Psychomotor Sensitization

ABSTRACTBackgroundD-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine’s effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine’s potency at the DAT.MethodsMale rats self-administered cocaine intermittently (5 minutes ON, 25 minutes OFF x 10) for 14 sessions, with or without concomitant D-amphetamine (5 mg/kg/day via s.c. osmotic minipump). In Experiment 1, psychomotor sensitization, responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed relapse were assessed. In Experiment 2, rats self-administered cocaine or saline intermittently, with or without D-amphetamine, and the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core was assessed using fast scan cyclic voltammetry ex vivo.ResultsIntA cocaine self-administration produced psychomotor sensitization, strong motivation to take and seek cocaine, and it increased cocaine’s potency at the DAT. The co-administration of D-amphetamine suppressed both the psychomotor sensitization and high motivation for cocaine produced by IntA experience, and also reversed sensitization of cocaine’s actions at the DAT, leaving baseline DAT function unchanged.ConclusionsTreatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

scholarly journals Sex differences in cocaine self-administration behaviour under Long Access versus Intermittent Access conditions

2018 ◽  
Author(s):  
Hajer Algallal ◽  
Florence Allain ◽  
Ndeye Aissatou Ndiaye ◽  
Anne-Noel Samaha
Keyword(s):  
Sex Differences ◽  
Progressive Ratio ◽  
Incentive Motivation ◽  
Cocaine Addiction ◽  
Male Rats ◽  
Locomotor Sensitization ◽  
Self Administration ◽  
Cocaine Use ◽  
Intermittent Access ◽  
Long Access

A widely accepted rodent model to study cocaine addiction involves allowing animals continuous access to drug during long self-administration sessions (Long-access or LgA). This produces continuously high brain concentrations of drug during each session. This might not model the pharmacokinetics of cocaine use in experienced human users, which are thought to involve intermittently spiking brain cocaine concentrations within and between bouts of use. Intermittent-access (IntA) cocaine self-administration models this spiking pattern in rats. IntA is also particularly effective in increasing incentive motivation for drug. Most IntA studies have been conducted in male rats. Both humans and non-human animals can show sex differences in all phases of the addiction process. We compared cocaine use in female and male rats that self-administered the drug (0.25 mg/kg/injection, i.v.) during 10 daily, 6-h LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. However, only IntA rats (both sexes) developed locomotor sensitization to self-administered cocaine and sensitization was greatest in the females. Five and 25 days after the last self-administration session, we quantified incentive motivation for cocaine by measuring breakpoints for the drug (0.083-0.75 mg/kg/injection) under progressive ratio. Breakpoints were similar in IntA and LgA rats. There were no sex differences in breakpoints under LgA. However, under IntA, females reached higher breakpoints for cocaine than males. Thus, LgA might be best suited to study sex differences in cocaine intake, while IntA might be best suited to study sex differences in incentive motivational processes in cocaine addiction.

scholarly journals Taking rapid and intermittent cocaine infusions enhances both incentive motivation for the drug and cocaine-induced gene regulation in corticostriatal regions

2020 ◽  
Author(s):  
Ellie-Anna Minogianis ◽  
Anne-Noël Samaha
Keyword(s):  
Gene Regulation ◽  
Mrna Expression ◽  
Progressive Ratio ◽  
Incentive Motivation ◽  
Male Rats ◽  
Behavioural Plasticity ◽  
Self Administration ◽  
Drug Induced ◽  
Intermittent Access ◽  
Long Access

ABSTRACTA goal in addiction research is to distinguish forms of neuroplasticity that are involved in the transition to addiction from those involved in mere drug taking. Animal models of drug self-administration are essential in this context. Here, we compared in male rats two cocaine self-administration procedures that differ in the extent to which they evoke addiction-like behaviours. We measured both incentive motivation for cocaine using progressive ratio procedures, and cocaine-induced c-fos mRNA expression, a marker of neuronal activity. Rats self-administered intravenous cocaine (0.25 mg/kg/infusion) for seven daily 6-hour sessions. One group had intermittent access (IntA; 6 minutes ON, 26 minutes OFF x 12) to rapid infusions (delivered over 5 seconds). This models the temporal kinetics of human cocaine use and produces robust addiction-like behaviour. The other group had Long access (LgA) to slower infusions (90 seconds). This produces high levels of intake without promoting robust addiction-like behaviour. LgA-90s rats took twice as much cocaine as IntA-5s rats did, but IntA-5s rats showed greater incentive motivation for the drug. Following a final self-administration session, we quantified c-fos mRNA expression in corticostriatal regions. Compared to LgA-90s rats, IntA-5s rats had more cocaine-induced c-fos mRNA in the orbitofrontal and prelimbic cortices and the caudate-putamen. Thus, a cocaine self-administration procedure (intermittent intake of rapid infusions) that promotes increased incentive motivation for the drug also enhances cocaine-induced gene regulation in corticostriatal regions. This suggests that increased drug-induced recruitment of these regions could contribute to the neural and behavioural plasticity underlying the transition to addiction.

scholarly journals Activation of G-protein Coupled Estradiol Receptor 1 in the Dorsolateral Striatum Enhances Motivation for Cocaine and Drug-Induced Reinstatement in Female Rats

2021 ◽  
Author(s):  
Jacqueline Quigley ◽  
Molly K. Logsdon ◽  
Brianna C. Graham ◽  
Kendra G. Beaudoin ◽  
Jill B Becker
Keyword(s):  
G Protein ◽  
Progressive Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Ratio Schedule ◽  
Drug Induced ◽  
Drug Seeking ◽  
Schedule Of Reinforcement ◽  
Estradiol Receptor ◽  
G Protein Coupled

Abstract BackgroundEstradiol potentiates drug-taking behaviors, including motivation to self-administer cocaine and reinstatement of drug-seeking after extinction in females, but not males. The dorsolateral stratum (DLS) is a region of the brain implicated in mediating drug-seeking behaviors and more specifically, is a target brain area to study how estradiol regulates these behaviors. The estradiol receptors α, β, and G-protein coupled estradiol receptor 1 (GPER1) are all present in the DLS. In this study the effects of activating GPER1 in the DLS on drug-seeking are investigated. MethodsGonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on an fixed-ratio 1 schedule of reinforcement. For four weeks, animals underwent testing on a progressive ratio schedule of reinforcement to determine their motivation to attain cocaine. Halfway through progressive ratio testing, a selective agonist targeting GPER1 (G1) was administered intra-DLS to determine the contribution of GPER1 activation on motivation for cocaine. The effects of intra-GPER1 activation on drug-induced reinstatement after extinction was subsequently determined. ResultsActivation of GPER1, via G1 administration intra-DLS potentiated females’ motivation to self-administer cocaine. There was no effect of prior G1 treatment on extinction of cocaine-taking in females, however, G1 treatment resulted in greater drug-induced reinstatement (10 mg/kg cocaine, i.p.). There were no effects of intra-DLS GPER1 activation observed on motivation for cocaine or cocaine-induced reinstatement of responding in males. Conclusions These results support the conclusion that activation of GPER1 in the DLS enhances cocaine seeking behaviors for female, but not male rats.

scholarly journals 7,8-Dihydroxyflavone Enhances Cue-Conditioned Alcohol Reinstatement in Rats

2020 ◽  
Vol 10 (5) ◽  
pp. 270 ◽  
Author(s):  
Samuel J. Hogarth ◽  
Elvan Djouma ◽  
Maarten van den Buuse
Keyword(s):  
Body Weight ◽  
Progressive Ratio ◽  
Ethanol Exposure ◽  
Ethanol Solution ◽  
Female Rats ◽  
Male Rats ◽  
Sprague Dawley ◽  
Self Administration ◽  
Bdnf Expression ◽  
Sprague Dawley Rats

Alcohol use disorder (AUD) is a detrimental disease that develops through chronic ethanol exposure. Reduced brain-derived neurotrophic factor (BDNF) expression has been associated with AUD and alcohol addiction, however the effects of activation of BDNF signalling in the brain on voluntary alcohol intake reinstatement and relapse are unknown. We therefore trained male and female Sprague Dawley rats in operant chambers to self-administer a 10% ethanol solution. Following baseline acquisition and progressive ratio (PR) analysis, rats were split into drug and vehicle groups during alcohol lever extinction. The animals received two weeks of daily IP injection of either the BDNF receptor, TrkB, agonist, 7,8-dihydroxyflavone (7,8-DHF), or vehicle. During acquisition of alcohol self-administration, males had significantly higher absolute numbers of alcohol-paired lever presses and a higher PR breakpoint. However, after adjusting for body weight, the amount of ethanol was not different between the sexes and the PR breakpoint was higher in females than males. Following extinction, alcohol-primed reinstatement in male rats was not altered by pretreatment with 7,8-DHF when adjusted for body weight. In contrast, in female rats, the weight-adjusted potential amount of ethanol, but not absolute numbers of active lever presses, was significantly enhanced by 7,8-DHF treatment during reinstatement. Analysis of spontaneous locomotor activity in automated photocell cages suggested that the effect of 7,8-DHF was not associated with hyperactivity. These results suggest that stimulation of the TrkB receptor may contribute to reward craving and relapse in AUD, particularly in females.

scholarly journals Activation of G protein-coupled estradiol receptor 1 in the dorsolateral striatum enhances motivation for cocaine and drug-induced reinstatement in female but not male rats

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jacqueline A. Quigley ◽  
Molly K. Logsdon ◽  
Brianna C. Graham ◽  
Kendra G. Beaudoin ◽  
Jill B. Becker
Keyword(s):  
G Protein ◽  
Progressive Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Ratio Schedule ◽  
Drug Induced ◽  
Drug Seeking ◽  
Schedule Of Reinforcement ◽  
Estradiol Receptor ◽  
G Protein Coupled

Abstract Background Estradiol potentiates drug-taking behaviors, including motivation to self-administer cocaine and reinstatement of drug-seeking after extinction in females, but not males. The dorsolateral stratum (DLS) is a region of the brain implicated in mediating drug-seeking behaviors and, more specifically, is a target brain area to study how estradiol regulates these behaviors. The estradiol receptors α, β, and G protein-coupled estradiol receptor 1 (GPER1) are all present in the DLS. In this study, the effects of activating GPER1 in the DLS on drug-seeking are investigated. Methods Gonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on a fixed-ratio 1 schedule of reinforcement. For 4 weeks, animals underwent testing on a progressive ratio schedule of reinforcement to determine their motivation to attain cocaine. Halfway through progressive ratio testing, a selective agonist targeting GPER1 (G1) was administered intra-DLS to determine the contribution of GPER1 activation on motivation for cocaine. The effects of intra-DLS GPER1 activation on drug-induced reinstatement after extinction were subsequently determined. Results Activation of GPER1, via intra-DLS G1 administration, potentiated females’ motivation to self-administer cocaine. There was no effect of prior G1 treatment on extinction of cocaine-taking in females; however, G1 treatment resulted in greater drug-induced reinstatement (10 mg/kg cocaine, i.p.). There were no effects of intra-DLS GPER1 activation observed on motivation for cocaine or cocaine-induced reinstatement of responding in males. Conclusions These results support the conclusion that activation of GPER1 in the DLS enhances cocaine-seeking behaviors for female, but not male rats.

scholarly journals Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

2019 ◽  
Vol 22 (11) ◽  
pp. 710-723 ◽  
Author(s):  
Atul P Daiwile ◽  
Subramaniam Jayanthi ◽  
Bruce Ladenheim ◽  
Michael T McCoy ◽  
Christie Brannock ◽  
...  
Keyword(s):  
Sex Differences ◽  
Nucleus Accumbens ◽  
Fixed Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Self Administration ◽  
Male And Female ◽  
Orexin Receptors ◽  
Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

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