α1-Noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access

Wee, Sunmee; Mandyam, Chitra D.; Lekic, Dusan; Koob, George F.

doi:10.1016/j.euroneuro.2007.08.003

Cited by 138 publications

(135 citation statements)

References 57 publications

(53 reference statements)

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“…Consistent with the notion that escalation of drug intake is an important step in the development of compulsive drug use, it has been shown that, after escalated cocaine or alcohol self-administration, other behavioral characteristics of addictive behavior can also be observed. These include increased motivation for the drug (Paterson and Markou, 2003;Liu et al, 2005;Lenoir and Ahmed, 2008;Wee et al, 2008;Orio et al, 2009), increased sensitivity for reinstatement of drug seeking after extinction (Mantsch et al, 2004;Ahmed and Cador, 2006;Kippin et al, 2006;Knackstedt and Kalivas, 2007) and reduced sensitivity to punishment (Wolffgramm, 1991;Wolffgramm andHeyne, 1991, 1995;H ö lter et al, 1998;Spanagel and H ö lter, 1999;Vanderschuren and Everitt, 2004;Lesscher et al, 2010;Ahmed, 2012).…”

Section: Escalation Of Drug Usementioning

confidence: 99%

Compulsive drug use and its neural substrates

Lesscher

Vanderschuren²

2012

Reviews in the Neurosciences

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Drug addiction is a chronic relapsing brain disease, characterized by compulsive drug use. Despite the fact that drug addiction affects millions of people worldwide, treatments for this disorder are limited in number and efficacy. In our opinion, understanding the neural underpinnings of drug addiction would open new avenues for the development of innovative treatments for this disorder. Based on an awareness that drug use and drug reward do not equal drug addiction, there has been increasing interest in developing animal models of addiction that mimick the loss of control over drug use more closely than existing models aimed at studying drug reward. The present review provides an overview of animal studies of compulsive drug use and the neural mechanisms involved. First, the employed models are summarized, with a particular emphasis on models of escalation of drug use and resistance to punishment. Next, we discuss mechanisms within the (ventral and dorsal) striatum and (central) amygdala that have recently been implicated in the compulsive seeking and taking of alcohol and cocaine. The studies discussed here provide a promising line of research that will advance our knowledge of the neural circuits involved in the self-destructive behavior that characterizes drug addiction.

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Section: Escalation Of Drug Usementioning

confidence: 99%

Compulsive drug use and its neural substrates

Lesscher

Vanderschuren²

2012

Reviews in the Neurosciences

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“…Sessions were run 6-7 days per week. The LgA and ShA rats were used in a previous study examining the effect of the noradrenergic receptor ligands prazosin, UK14304, and betaxolol on the escalated rate of cocaine selfadministration in rats (Wee et al, 2007). None of these compounds changed baseline cocaine intake in LgA and ShA rats, and rats were rebaselined for 19 days prior to beginning the present study (see Supplementary Materials and Methods for details).…”

Section: Cocaine Self-administrationmentioning

confidence: 99%

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

George

Mandyam

Wee

et al. 2007

Neuropsychopharmacol

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150

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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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“…Animals in this paradigm reliably show increases in intake of 30-40% over the course of 2 weeks (Ahmed and Koob, 1998). In most cases, this procedure has resulted in an increase in motivational measures such as PR breakpoints (Paterson and Markou, 2003;Wee et al, 2008; but see Liu et al, 2005a;Quadros and Miczek, 2009) and drug-induced reinstatement responding (Mantsch et al, 2008). The effect of LgA on Pmax appears to depend on procedural variables.…”

Section: Figurementioning

confidence: 99%

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

Zimmer

Oleson

Roberts

2012

Neuropsychopharmacol

133

196

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Recent attempts to model the addiction process in rodents have focused on cocaine self-administration procedures that provide extended daily access. Such procedures produce a characteristic loading phase during which blood levels rapidly rise and then are maintained within an elevated range for the duration of the session. The present experiments tested the hypothesis that multiple fastrising spikes in cocaine levels contribute to the addiction process more robustly than constant, maintained drug levels. Here, we compared the effects of various cocaine self-administration procedures that produced very different patterns of drug intake and drug dynamics on Pmax, a behavioral economic measure of the motivation to self-administer drug. Two groups received intermittent access (IntA) to cocaine during daily 6-h sessions. Access was limited to twelve 5-min trials that alternated with 25-min timeout periods, using either a hold-down procedure or a fixed ratio 1 (FR1). Cocaine levels could not be maintained with this procedure; instead the animals experienced 12 fast-rising spikes in cocaine levels each day. The IntA groups were compared with groups given 6-h FR1 long access and 2-h short access sessions and two other control groups. Here, we report that cocaine self-administration procedures resulting in repeatedly spiking drug levels produce more robust increases in Pmax than procedures resulting in maintained high levels of cocaine. These results suggest that rapid spiking of brain-cocaine levels is sufficient to increase the motivation to self-administer cocaine.

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α1-Noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access

Cited by 138 publications

References 57 publications

Compulsive drug use and its neural substrates

Compulsive drug use and its neural substrates

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

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

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