Sex differences in cocaine self‐administration behaviour under long access versus intermittent access conditions

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.

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Incentive and dopamine sensitization produced by intermittent but not long access cocaine self-administration

10.1101/499475 ◽

2018 ◽

Cited By ~ 2

Author(s):

Alex B. Kawa ◽

Alec C. Valenta ◽

Robert T. Kennedy ◽

Terry E. Robinson

Keyword(s):

Nucleus Accumbens ◽

Drug Use ◽

In Vivo Microdialysis ◽

Group Differences ◽

Self Administration ◽

The Core ◽

Intermittent Access ◽

High Motivation ◽

Long Access

Recent studies suggest that the temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self-administered cocaine to produce addiction-like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of Long Access (LgA) cocaine self-administration, which is widely used to model the transition to addiction, with Intermittent Access (IntA), which is thought to better reflect the pattern of drug use in humans, on the ability of self-administered cocaine to increase dopamine (DA) overflow in the core of the nucleus accumbens (using in vivo microdialysis), and to produce addiction-like behavior. IntA experience was more effective than LgA in producing addiction-like behavior- a drug experience-dependent increase in motivation for cocaine assessed using behavioral economic procedures, and cue-induced reinstatement, despite much less total drug consumption. There were no group differences in basal levels of DA in dialysate, but a single self-administered IV injection of cocaine increased DA in the core of the nucleus accumbens to a greater extent in rats with prior IntA experience than those with LgA or Short Access (ShA) experience, and the latter two groups did not differ. Furthermore, high motivation for cocaine was associated with a high DA response. Thus, IntA, but not LgA, produced both incentive and DA sensitization. This is consistent with the notion that a hyper-responsive dopaminergic system may contribute to the transition from casual patterns of drug use to the problematic patterns that define addiction.

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

10.1101/2020.04.22.055715 ◽

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.

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Intermittent access cocaine self-administration produces psychomotor sensitization: effects of withdrawal, sex and cross-sensitization

10.1101/859520 ◽

2019 ◽

Cited By ~ 1

Author(s):

Crystal C. Carr ◽

Carrie R. Ferrario ◽

Terry E. Robinson

Keyword(s):

Behavioral Plasticity ◽

Cocaine Addiction ◽

Preclinical Model ◽

Self Administration ◽

Stimulant Drug ◽

Incentive Sensitization ◽

Intermittent Access ◽

Psychomotor Sensitization ◽

Long Access ◽

Addiction Drug

AbstractThe psychomotor activating effects of drugs such as cocaine or amphetamine can change in very different ways – showing sensitization or tolerance – depending on whether they are administered more or less intermittently. This behavioral plasticity is thought to reflect, at least in part, changes in dopamine (DA) neurotransmission, and therefore, may provide insights into how repeated drug use promotes the development of substance use disorders. Indeed, the most widely used preclinical model of cocaine addiction, which involves Long Access (LgA) self-administration procedures, is reported to produce tolerance to cocaine’s psychomotor activating effects and effects on DA activity. This is cited as evidence in support of the view that in addiction, drug-seeking and-taking is motivated to overcome this DA deficiency and associated anhedonia. In contrast, Intermittent Access (IntA) cocaine self-administration is more effective than LgA in producing addiction-like behavior, but sensitizes DA neurotransmission. There is, however, very little information concerning the effects of IntA experience on the psychomotor activating effects of cocaine. The purpose of the studies reported here, therefore, was to determine whether IntA experience produces psychomotor sensitization with similar characteristics to that produced by the intermittent, noncontingent administration of cocaine. It did. The psychomotor sensitization produced by IntA experience with cocaine: (1) was greater after a long (30 days) vs short (1 day) period of withdrawal; (2) was greater in females than males; and (3) resulted in cross-sensitization to another psychomotor stimulant drug, amphetamine. This pattern of cocaine experience-dependent plasticity favors an incentive-sensitization view of addiction.

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Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system

10.1101/2020.04.23.055848 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jennifer E. Fragale ◽

Morgan H. James ◽

Gary Aston-Jones

Keyword(s):

Behavioral Economics ◽

Receptor Antagonist ◽

Critical Role ◽

Opioid Addiction ◽

Male Rats ◽

Self Administration ◽

Drug Seeking ◽

Intermittent Access ◽

Long Access

AbstractThe orexin (hypocretin) system plays a critical role in motivated drug-taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1h (short access; ShA), or 6h periods (long access, LgA), or IntA (5min of access separated by 25min of no-access) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and cued-induced reinstatement compared to rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin-expressing neurons. Together, results indicate that the IntA model is a useful tool in the study of opioid addiction, and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self-administration of fentanyl.

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Incubation of Cocaine Craving After Intermittent-Access Self-administration: Sex Differences and Estrous Cycle

Biological Psychiatry ◽

10.1016/j.biopsych.2019.01.015 ◽

2019 ◽

Vol 85 (11) ◽

pp. 915-924 ◽

Cited By ~ 22

Author(s):

Céline Nicolas ◽

Trinity I. Russell ◽

Anne F. Pierce ◽

Steeve Maldera ◽

Amanda Holley ◽

...

Keyword(s):

Sex Differences ◽

Estrous Cycle ◽

Self Administration ◽

Intermittent Access ◽

Cocaine Craving

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Sex differences in incentive-sensitization produced by intermittent access cocaine self-administration

Psychopharmacology ◽

10.1007/s00213-018-5091-5 ◽

2018 ◽

Vol 236 (2) ◽

pp. 625-639 ◽

Cited By ~ 15

Author(s):

Alex B. Kawa ◽

Terry E. Robinson

Keyword(s):

Sex Differences ◽

Self Administration ◽

Incentive Sensitization ◽

Intermittent Access

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

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz050 ◽

2019 ◽

Vol 22 (11) ◽

pp. 710-723 ◽

Cited By ~ 8

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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