Taking Rapid and Intermittent Cocaine Infusions Enhances Both Incentive Motivation for the Drug and Cocaine-induced Gene Regulation in Corticostriatal Regions

Minogianis, Ellie-Anna; Samaha, Anne‐Noël

doi:10.1016/j.neuroscience.2020.05.058

Cited by 11 publications

(4 citation statements)

References 68 publications

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“…Though we have previously reported that 'high-responder" rats will earn significantly more infusions of MDPV under both FR and progressive ratio schedules of reinforcement, we did not evaluate responding under a progressive ratio schedule of reinforcement or use behavioral economics. Other studies find that rats with a history of long-or intermittent-access find cocaine and other reinforcers more reinforcing than rats with a history of short-access self-administration [14,18,72,75,[77][78][79][80][81][82], but see [83].…”

Section: Discussionmentioning

confidence: 99%

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

Doyle,

Beltran,

Bushnell

et al. 2024

Preprint

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Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long- and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT 2A, or 5-HT2C receptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.

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Section: Discussionmentioning

confidence: 99%

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

Doyle,

Beltran,

Bushnell

et al. 2024

Preprint

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“…Previous microinjection studies in rats show that LY379268 significantly reduces drug-seeking behaviour across 3-h test sessions, suggesting that the compound is effective for at least 3 h (Bossert et al, 2006). Thus, we used 0.125 mg/kg/infusion cocaine for our PR tests here, because rats typically reach break-point at this dose in around 3 h (Minogianis & Samaha, 2020). Rats received at least one day off between PR test sessions.…”

Section: Methodsmentioning

confidence: 99%

“…Several previous studies have implicated the dorsal striatum in incentive motivation for cocaine after a history of IntA cocaine use. IntA cocaine-taking experience increases cocaine-induced gene regulation in the dorsal striatum (Minogianis & Samaha, 2020). This is not just a correlational effect, because after IntA cocaine self-administration, temporary, pharmacological inhibition of the dorsal striatum with baclofen and muscimol microinjection reduces responding for cocaine in progressive ratio (PR) tests (Minogianis et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Metabotropic glutamate group II receptor activation in the dorsal striatum suppresses the motivation for cocaine in rats

Khoo

Uhrig

2022

Preprint

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After a history of intermittent cocaine intake, rats develop patterns of drug use characteristic of addiction. The dorsal striatum is involved in the increased pursuit of cocaine after intermittent drug self-administration experience. Within the dorsal striatum, chronic cocaine use changes metabotropic glutamate type II receptor (mGlu2/3) density and function. We examined the extent to which activity at these receptors mediates responding for cocaine after intermittent cocaine use. In Experiment 1, male Wistar rats (n = 11) self-administered 0.25 mg/kg/infusion cocaine during 10 daily intermittent access (IntA) sessions (5 min ON/25 min OFF, for 5 h/session). We then examined the effects of intra-dorsal striatum infusions of the mGlu2/3 receptor agonist LY379268 (0, 1, and 3 μg/hemisphere) on cocaine self-administration under a progressive ratio schedule of reinforcement. We observed a non-significant tendency for LY379268 to reduce responding for cocaine. In Experiment 2, we used a larger sample of male (n = 11) and female (n = 10) rats. Across 10 IntA sessions, the sexes showed similar levels of cocaine intake. Across the sexes, locomotion significantly increased over sessions, suggesting that rats developed psychomotor sensitization to self-administered cocaine. After 10 IntA sessions, intra-dorsal striatum LY379268 significantly reduced breakpoints achieved for cocaine, active lever presses, and cocaine infusions earned under progressive ratio. LY379268 had no effects on locomotion or inactive lever presses, indicating no motor effects. These results suggest that mGlu2/3 receptor activation in the dorsal striatum suppresses incentive motivation for cocaine, and this holds promise for anti-addiction therapeutics.

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“…Although it has been theorized that compulsive drug seeking arises from an over-reliance on habitual behavior compared to goal-directed drug seeking, the effects of IntA on habit formation or reliance on dopamine in the dorsolateral striatum (DLS), a structure important for habit initiation, have not been evaluated (Everitt, 2014; Ostlund and Balleine, 2008). One study showed that compared to LgA, IntA increased cocaine-induced c-fos expression in the dorsal striatum, including the DLS, but not the nucleus accumbens, suggesting IntA may impact habit circuitry, but its behavioral effects on habits are unknown (Minogianis and Samaha, 2020).…”

Section: Introductionmentioning

confidence: 99%

Intermittent cocaine self-administration has sex-specific effects on addiction-like behaviors in rats

Bender

Torregrossa

2022

Preprint

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Intermittent access (IntA) models of cocaine self-administration were developed to better model in rodents how cocaine is used by human drug users. Compared to traditional continuous access (ContA) models, IntA has been shown to enhance several pharmacological and behavioral effects of cocaine, but few studies have examined sex differences in IntA. Moreover, no one has examined the efficacy of cue extinction to reduce cocaine seeking in the IntA model, which has previously shown to be ineffective in other models that promote habit-like cocaine seeking. Therefore, rats were implanted with jugular vein catheters and dorsolateral striatum (DLS) cannulae and trained to self-administer cocaine paired with an audiovisual cue with ContA or IntA. In subsets of rats, we evaluated: the ability of Pavlovian cue extinction to reduce cue-induced drug seeking; motivation for cocaine using a progressive ratio procedure; compulsive cocaine taking by pairing cocaine infusions with footshocks; and dependence of drug-seeking on DLS dopamine (a measure of habit-like behavior) with the dopamine antagonist cis-flupenthixol. Overall, cue extinction reduced cue-induced drug seeking after ContA or IntA. Compared to ContA, IntA resulted in increased motivation for cocaine exclusively in females, but IntA facilitated more compulsive cocaine taking exclusively in males. After 10 days of IntA training, but not fewer, drug-seeking was dependent on DLS dopamine most notably in males. Our results suggest that IntA may be valuable for identifying sex differences in the early stages of drug use and provide a foundation for the investigation of the mechanisms involved.

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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

Cited by 11 publications

References 68 publications

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

Metabotropic glutamate group II receptor activation in the dorsal striatum suppresses the motivation for cocaine in rats

Intermittent cocaine self-administration has sex-specific effects on addiction-like behaviors in rats

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