Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin

Dalley, Jeffrey W.; Lääne, Kristjan; Peña, Yolanda; Theobald, David E. H.; Everitt, Barry J.; Robbins, Trevor W.

doi:10.1007/s00213-005-0107-3

Cited by 117 publications

(94 citation statements)

References 42 publications

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“…Indeed, accumulating evidence suggests that extended access to cocaine has a greater likelihood of producing a number of symptoms of addiction, relative to limited access, one of which is the tendency to escalate drug intake (Ahmed and Koob, 1998;Paterson and Markou, 2003;Deroche-Gamonet et al, 2004;Vanderschuren and Everitt, 2004;Ferrario et al, 2005). However, in one previous study, rats were allowed to selfadminister a maximum of 150 injections of cocaine over 8 h, and these animals achieved a level of intake comparable to that of the LgA group here, but did not show persistent deficits on a five-choice serial reaction time task (Dalley et al, 2005a). There are at least two possible reasons for this.…”

Section: Percent Of Controlmentioning

confidence: 50%

Persistent Alterations in Cognitive Function and Prefrontal Dopamine D2 Receptors Following Extended, but Not Limited, Access to Self-Administered Cocaine

Briand

Flagel²,

García-Fuster³

et al. 2008

Neuropsychopharmacol

123

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Drug addicts have deficits in frontocortical function and cognition even long after the discontinuation of drug use. It is not clear, however, whether the cognitive deficits are a consequence of drug use, or are present prior to drug use, and thus are a potential predisposing factor for addiction. To determine if self-administration of cocaine is capable of producing long-lasting alterations in cognition, rats were allowed access to cocaine for either 1 h/day (short access, ShA) or 6 h/day (long access, LgA) for 3 weeks. Between 1 and 30 days after the last self-administration session, we examined performance on a cognitively demanding test of sustained attention that requires an intact medial prefrontal cortex. The expression levels of dopamine D1 and D2 receptor mRNA and D2 protein in the prefrontal cortex were also examined. Early after discontinuation of drug use, LgA (but not ShA) animals were markedly impaired on the sustained attention task. Although the LgA animals improved over time, they continued to show a persistent pattern of performance deficits indicative of a disruption of cognitive flexibility up to 30 days after the discontinuation of drug use. This was accompanied by a significant decrease in DA D2 (but not D1) mRNA in the medial and orbital prefrontal cortex, and D2 receptor protein in the medial prefrontal cortex of LgA (but not ShA) animals. These findings establish that repeated cocaine use is capable of producing persistent alterations in the prefrontal cortex and in cognitive function, and illustrate the usefulness of extended access self-administration procedures for studying the neurobiology of addiction.

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Section: Percent Of Controlmentioning

confidence: 50%

Persistent Alterations in Cognitive Function and Prefrontal Dopamine D2 Receptors Following Extended, but Not Limited, Access to Self-Administered Cocaine

Briand

Flagel²,

García-Fuster³

et al. 2008

Neuropsychopharmacol

123

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“…Most studies that have examined differential access regimens have focused on cocaine i.v. intake, with reports of escalated increases (Ahmed and Koob 1998;Mantsch et al 2004;Morgan et al 2002) or no changes (Dalley et al 2005;Kippin et al 2006;Roth and Carroll 2004b) over time. In addition to cumulative changes in drug intake, it has been argued that increased intake seen during the first hour of daily long-access self-administration of cocaine or heroin reflects allostatic decreases in reward function (Ahmed and Koob 2005).…”

Section: Discussionmentioning

confidence: 99%

Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

2008

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Rationale-Methamphetamine is a highly addictive psychostimulant, and chronic methamphetamine users show high rates of relapse. Furthermore, prolonged methamphetamine abuse can lead to psychiatric symptoms and has been associated with various cognitive dysfunctions. However, the impact of self-administered methamphetamine on cognitive dysfunction and relapse has not been concurrently examined in an animal model.Objectives-The present study determined the effects of short-vs. long-access contingent methamphetamine on self-administration, extinction responding, reinstatement of methamphetamine seeking, and cognitive performance on an object exploration task.Materials and methods-Long-Evans rats self-administered methamphetamine i.v. (0.02 mg/ infusion) or received saline during daily sessions (1 or 2 h) for 10 days, followed by either maintained short-(1 or 2 h) or long-access (6 h) self-administration for 14 days. Lever responding was extinguished prior to reinstatement, which consisted of presentation of drug-paired cues or a priming injection of methamphetamine (1.0 mg/kg). Animals were also tested on an object exploration task prior to self-administration and at 10−12 days after cessation of self-administration, thus providing a comparison of pre-methamphetamine exposure with post-methamphetamine exposure.Results-Long-access methamphetamine self-administration resulted in escalation of daily intake. Furthermore, animals in both short-and long-access groups showed robust conditioned-cued and drug-primed reinstatement, with long access resulting in enhanced methamphetamine-primed reinstatement. Methamphetamine self-administration also led to access-dependent impairments on novel object recognition but failed to impair recognition of spatial reconfiguration.Conclusions-Extended methamphetamine self-administration enhances drug-primed reinstatement and decreases novel object recognition, indicating that prolonged contingent methamphetamine increases motivation for drug seeking following withdrawal while increasing cognitive deficits.

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“…Indeed, extended access to cocaine self-administration in rats does not induce long-lasting impairments of cognitive function known to depend on the prefrontal cortex, such as response inhibition and sustained attention (Dalley et al, 2005(Dalley et al, , 2007, whereas trait impulsivity precedes the onset of drug use and facilitates the progression to drug addiction (Dalley et al, 2007). However, our results demonstrate that independent of any premorbid condition (because rats were randomly assigned to the three groups), extended access to cocaine self-administration by itself may cause severe working memory impairments associated with prefrontal cortex damage, suggesting that a significant contribution to prefrontal cortex dysfunction also may be a consequence of chronic drug use.…”

Section: Discussionmentioning

confidence: 99%

“…Despite accumulating evidence that limited drug exposure induces neuronal changes in the prefrontal cortex (Ben-Shahar et al, 2007;Bowers et al, 2004;Crespo et al, 2002), there is little evidence to date of long-lasting neuronal adaptations of the prefrontal cortex after escalation in cocaine intake with extended access (Ben-Shahar et al, 2007;Ferrario et al, 2005;Seiwell et al, 2007). Moreover, recent reports demonstrated that extended access to cocaine self-administration did not induce long-lasting impairment of prefrontal cortex cognitive function, such as response inhibition and sustained attention (Dalley et al, 2005(Dalley et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments

George

Mandyam

Wee

et al. 2007

Neuropsychopharmacol

155

127

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Humans with drug addiction exhibit compulsive drug-seeking associated with impairment of prefrontal cortex cognitive function. Whether prefrontal cortex dysfunction is a consequence of chronic drug exposure, or mediates the transition from drug use to drug dependence, is unknown. The current study investigates whether a history of escalated vs controlled cocaine intake is associated with specific working memory impairments, and long-lasting alterations of the dorsomedial prefrontal cortex and orbitofrontal cortex in rats. Working memory was assessed in rats with a history of extended (6 h per session) or limited (1 h per session) access to cocaine (0.5 mg/kg per injection), 3-17 days after the last self-administration session, using a delayed nonmatching-to-sample task. The density of neurons, oligodendrocytes, and astrocytes was quantified in the dorsomedial prefrontal cortex and orbitofrontal prefrontal cortex 2 months after the last self-administration session. Working memory impairments were observed after a history of chronic and escalated cocaine intake, but not after repeated limited access to cocaine. Moreover, working memory impairments were correlated with a decreased density of neurons and oligodendrocytes but not astrocytes in the dorsomedial prefrontal cortex, and with a decreased density of oligodendrocytes in the orbitofrontal cortex. Considering the role of the prefrontal cortex in goal-directed behavior, the prefrontal cortex dysfunctions observed here may exacerbate the loss of control associated with increased drug use and facilitate the progression to drug addiction.

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Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin

Abstract: These data, together with recent findings of attentional dysfunction during the withdrawal of intravenous self-administration of amphetamine, suggest that generically different drugs of abuse produce similar disturbances in visual attentional performance during the early withdrawal period.

Cited by 117 publications

References 42 publications

Persistent Alterations in Cognitive Function and Prefrontal Dopamine D2 Receptors Following Extended, but Not Limited, Access to Self-Administered Cocaine

Persistent Alterations in Cognitive Function and Prefrontal Dopamine D2 Receptors Following Extended, but Not Limited, Access to Self-Administered Cocaine

Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments

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