The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat

Rassnick, Stefanie; Stinus, Luis; Koob, George F.

doi:10.1016/0006-8993(93)90004-7

Cited by 185 publications

(113 citation statements)

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Section: Alcohol and Sedative Hypnoticsmentioning

confidence: 99%

“…Dopamine receptor antagonists have been shown to reduce lever-pressing for alcohol in nondeprived rats (Pfeffer and Samson 1988), and extracellular dopamine levels also have been shown to increase in nondependent rats orally selfadministering low doses of alcohol (Weiss et al 1992a). However, virtually complete 6-hydroxydopamine denervation of the nucleus accumbens failed to alter voluntary responding for alcohol (Rassnick et al 1993c) suggesting that dopamine-independent, neurochemical systems likely contribute critically to the mediation of alcohol's reinforcing actions.The sedative and anti-punishment (anxiolytic) effects of sedative-hypnotics are associated with facilitation of the GABA A receptor and/or inhibition of the NMDA glutamate receptor (Hoffman et al 1989;Lovinger et al 1989;Richards et al 1991). GABAergic antagonists also reverse many of the behavioral effects of alcohol that are associated with intoxication (Frye and Breese 1982;Liljequist and Engel 1982).…”

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confidence: 99%

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Drug Addiction, Dysregulation of Reward, and Allostasis

Koob

Moal

2001

Neuropsychopharmacology

2,561

1,962

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This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drugtaking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to BACKGROUNDDrug addiction is a chronically relapsing disorder that is defined by two major characteristics: a compulsion to take the drug with a narrowing of the behavioral repertoire toward excessive drug intake, and a loss of control in limiting intake (American Psychiatric Association 1994; World Health Organization 1992). An important challenge for neurobiological research is to understand the neuroadaptive differences between controlled drug use and loss of control, and by extension, the molecular, cellular and system processes that lead to addiction (Koob and Le Moal 1997).Animal models are critical for understanding the neuropharmacological mechanisms involved in the development of addiction. While there are no complete animal models of addiction, animal models do exist for many elements of the syndrome. These elements can be derived from symptoms or diagnostic criteria for addiction or conceptual frameworks such as different sources of reinforcement (American Psychiatric Association 1994; World Health Organization 1992). Linking neu- 24 , NO . 2 ropharmacological events to animal models can occur at multiple levels of analysis -molecular, cellular and system -and it will only be the integration of these changes across dimensions of analysis that will allow a full understanding of the neurobiology of drug addiction.Advances in neuroscience research are rapidly unr...

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Section: Alcohol and Sedative Hypnoticsmentioning

confidence: 99%

mentioning

confidence: 99%

Drug Addiction, Dysregulation of Reward, and Allostasis

Koob

Moal

2001

Neuropsychopharmacology

2,561

1,962

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“…Moreover, ethanol has a greater effect on NE turnover and release than on DA (Corrodi et al, 1966;Hunt and Majchrowicz, 1974). Both chemical lesioning of the NE system and blocking NE synthesis via DBH inhibitors reduce voluntary ethanol intake, whereas DA lesions do not Kiianmaa et al, 1979;Rassnick et al, 1993b).…”

Section: Ne and Ethanol Samentioning

confidence: 99%

“…However, inconsistencies similar to those obtained in examining the DA mediation of opiate reinforcement have plagued the field. For example, 6-OHDA lesions of the NAc do not alter ethanol SA in rats (Lyness and Smith, 1992;Rassnick et al, 1993b;Ikemoto et al, 1997, Koistinen et al, 2001. Further, there have been some conflicting results regarding the effects of pretreatment with dopaminergic agents (Goodwin et al, 1996;Silvestre et al, 1996).…”

Section: Ne and Ethanol Samentioning

confidence: 99%

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Neuropsychopharmacol

323

277

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Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine b-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.

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“…Instead, AAS appear to be another class of non-stimulant drugs, with at least some of their behavioral effects mediated by DA-independent pathways. Self-administration of opiates (Pettit et al, 1984), ethanol (EtOH; Rassnick et al, 1993), and phencyclidine (Carlezon and Wise, 1996) are not dependent on mesolimbic DA. In particular, although benzodiazepines reduce Acb DA (Finlay et al, 1992;Invernizzi et al, 1991;Zetterstrom and Fillenz, 1990), they are nonetheless self-administered (Naruse and Asami, 1987;Szostak et al, 1987) and produce CPP (File, 1986;Spyraki and Fibiger, 1988;Spyraki et al, 1985).…”

Section: Aas Is Another Drug Of Abuse With Da-independent Effectsmentioning

confidence: 98%

Testosterone and nucleus accumbens dopamine in the male Syrian hamster

Triemstra

Sato

Wood

2008

Psychoneuroendocrinology

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SummaryMost drugs of abuse increase dopamine (DA) in nucleus accumbens (Acb). However, the effects of anabolic androgenic steroids (AAS) on Acb DA have not been examined. We determined the effects of subcutaneous (sc) testosterone (T) on Acb DA in male hamsters. The effects of sc amphetamine were also examined for comparison. In addition, Acb DA was evaluated during intracerebroventricular (ICV) T infusion, designed to mimic T intake during ICV T selfadministration in drug-naïve and drug-preexposed animals. Acb DA was measured using in vivo microdialysis and HPLC-EC. T (7.5 or 37.5 mg/kg), amphetamine (1 or 5 mg/kg), or vehicle was injected sc and Acb DA monitored for 4 hrs. In the ICV experiment, T (1 or 2 μg/infusion) or vehicle was infused ICV every 6 min for 4 hrs and Acb DA monitored. ICV T preexposure was accomplished by repeating the same ICV T infusion (1 μg/infusion) daily for 14 days, and T infusion was accompanied by microdialysis on 15 th day. Neither sc nor ICV T administration increased Acb DA. At high dose (2 μg/infusion), ICV T decreased Acb DA. Likewise, daily ICV infusion of T for 15 days did not alter Acb DA. In contrast, sc amphetamine significantly increased Acb DA at both doses. Therefore, unlike many drugs of abuse, AAS does not increase Acb DA levels. The reduction in DA at high T doses is likely due to autonomic depressant effects of AAS. We suggest that AAS act via mechanism distinct from those of stimulants, but may share neural substrates with other drugs of abuse. Keywordsanabolic androgenic steroid; testosterone; amphetamine; hamster; nucleus accumbens; dopamine; microdialysis; HPLC-EC; intracerebroventricular; subcutaneous Androgenic anabolic steroid (AAS) use is widespread among athletes and non-athletes (Yesalis et al., 1993). Physical (Leshner, 2000) and psychological (Brower, 2002;Pope and Katz, 1994) effects of AAS use are of significant concern from a public health perspective. Brower (2002) has recently suggested that most AAS users initiate use for the anabolic properties, but many subsequently develop physical and psychological dependence. However, the addictive potential of AAS has received little attention so far. The results of studies using animal models of drug abuse indicate that AAS are reinforcing. For example, AAS induces conditioned place preference (CPP) in rats (Packard et al., 1997) and mice (Arnedo et al., 2000). In addition, AAS *Address all reprint requests and correspondence to: Ruth I. Wood, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, 1333 San Pablo St. BMT 401, Los Angeles, CA 90033, Telephone (323) 442-1980, Fax: (323) 442-3466, e-mail: riw@usc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during ...

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The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat

Cited by 185 publications

References 34 publications

Drug Addiction, Dysregulation of Reward, and Allostasis

Drug Addiction, Dysregulation of Reward, and Allostasis

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Testosterone and nucleus accumbens dopamine in the male Syrian hamster

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