Shifts in the neurobiological mechanisms motivating cocaine use with the development of an addiction-like phenotype in male rats

Lynch, Wendy J.; Bakhti-Suroosh, Anousheh; Abel, Jean M.; Davis, Camilla

doi:10.1007/s00213-020-05732-4

Cited by 7 publications

(12 citation statements)

References 81 publications

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“…All the compounds that reduced drug-taking in rats with well-regulated behavior also reduced drug-taking in rats with a more robust stimulant use disorder-like phenotype. Others have employed similar strategies to evaluate candidate medications, such as comparing short-or extended-access procedures, where the latter procedure was used to model a more robust stimulant use disorder-like phenotype (e.g., Ramôa et al 2014;Lynch et al 2021). Another strategy is to evaluate candidate medications is a choice procedure, where drug and an alternative reinforcer (e.g., food, social partner) are available simultaneously to provide a more real-world scenario that is sensitive to selective reductions in drug-taking while also allowing for detection of a general rate decreasing effect (for review, see Banks and Negus, 2017).…”

Section: Discussionmentioning

confidence: 99%

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder

Doyle

Peng

Cao

et al. 2023

J Pharmacol Exp Ther

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Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, though preclinical reductions in stimulant self-administration have not translated to meaningful reductions in stimulant use in humans. One possible reason for this discordance is that most preclinical studies evaluate candidate medications under conditions that promote predictable, and wellregulated patterns of drug-taking rather than the dysregulated and/or compulsive patterns of drug-taking characteristic of a stimulant use disorder. A subset of rats ("high-responders") that self-administer 3,4-methelyendioxypyrovalerone (MDPV), a monoamine uptake inhibitor, develop high levels of dysregulated drug-taking consistent with behaviors related to stimulant use disorders. Because MDPV acts on dopamine, serotonin (5-HT), and sigma receptor systems, the current studies compared the potency and effectiveness of a dopamine D 3 receptor partial agonist (VK4-40) or antagonist (VK4-116), a sigma receptor antagonist (BD1063), a dopamine D 2 /D 3 /sigma receptor antagonist (haloperidol), and a 5-HT 2C receptor agonist (CP-809,101) to reduce MDPV (0.0032-0.1 mg/kg/infusion) self-administration in highand low-responding rats as well as rats self-administering cocaine (0.032-1 mg/kg/infusion). haloperidol,101 were equipotent and effective at reducing drugtaking in all three groups of rats, including the high-responders, however, VK4-116 and CP-809,101 were less potent at reducing drug-taking in female compared to male rats. Together, these studies suggest that drugs targeting dopamine D 3 or 5-HT 2C receptors can effectively reduce dysregulated patterns of stimulant use, highlighting their potential utility for treating stimulant use disorders.

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Section: Discussionmentioning

confidence: 99%

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder

Doyle

Peng

Cao

et al. 2023

J Pharmacol Exp Ther

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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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“…Sexually mature male ( N = 39) and female ( N = 36) Sprague-Dawley rats (Charles River Laboratories, ME) were used as subjects. Behavioral data from a subset of the male rats (N = 28) has previously published ( Lynch et al, 2021 ) and was included here for comparison to the female behavioral data. The male and female subjects included in the present study were run contemporaneously.…”

Section: Methodsmentioning

confidence: 99%

“…If a right catheter failed, a new catheter was implanted into the left jugular vein with testing resuming after 2-day of recovery. Rats were also implanted with a bilateral infusion cannula aimed at the NAc core (+1.2 mm anterior-posterior, ± 1.5 mm mediolateral, -5.7 mm dorsoventral) during the time of jugular catheterization or the second half of the abstinence period ( Doyle et al, 2014 ; Ramôa et al, 2014 ; Lynch et al, 2021 ). This region was targeted because it is known to integrate dopamine and glutamate signaling and to mediate the reinforcing and motivational properties of addictive drugs ( Kalivas and McFarland, 2003 ; Doyle et al, 2014 ; Ramôa et al, 2014 ; Lynch et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…The development of an enhanced motivation for cocaine also corresponds to the development of other addiction-like features, including compulsive cocaine use despite negative consequences ( Towers et al, 2021 ) and enhanced cocaine-seeking (e.g., Peterson et al, 2014 ; Towers et al, 2023 ). Furthermore, we showed that in males the development of an enhanced motivation for cocaine is accompanied by a decreased sensitivity to NAc D2 receptor antagonism (relative to ShA controls), indicating that the role of D2 receptor signaling in motivating cocaine use becomes diminished with the development of addiction ( Lynch et al, 2021 ).…”

Section: Introductionmentioning

confidence: 92%

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Role of nucleus accumbens dopamine 2 receptors in motivating cocaine use in male and female rats prior to and following the development of an addiction-like phenotype

et al. 2023

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A hallmark of cocaine use disorder (CUD) is dysfunction of dopamine signaling in the mesolimbic pathway, including impaired dopamine 2 (D2) receptor signaling. One of the most replicated findings in human imagining studies is decreased striatal D2 receptor binding in individuals with a substance use disorder relative to healthy controls; however, the vast majority of the data is from males, and findings in smokers suggest this molecular shift may not translate to females. The goal of this study was to determine whether there are sex differences in the role of D2 receptors in motivating cocaine use prior to and following the development of an addiction-like phenotype (defined by an enhanced motivation for cocaine relative to the short-access, ShA, group). Here, male and female rats were given ShA (20 infusions/day, 3 days) or extended-access (ExA; 24h/day, 96 infusions/day, 10 days) to cocaine self-administration and then following 14 days of withdrawal, were tested under a progressive-ratio schedule to assess motivation for cocaine use. Once a stable level of motivation was established, the effect of NAc-infusions of the D2 receptor antagonist eticlopride (0–3.0 µg/side) were examined. We found that in males, eticlopride was less effective at decreasing motivation for cocaine following ExA versus ShA self-administration, particularly at low eticlopride doses. In contrast, in females, there were no differences in the effectiveness of eticlopride between ExA and ShA. These findings indicate that males, but not females, become less sensitive to NAc-D2 receptor antagonism with the development of an addiction-like phenotype.

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Shifts in the neurobiological mechanisms motivating cocaine use with the development of an addiction-like phenotype in male rats

Cited by 7 publications

References 81 publications

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder

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

Role of nucleus accumbens dopamine 2 receptors in motivating cocaine use in male and female rats prior to and following the development of an addiction-like phenotype

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