Genetic approaches to the analysis of addiction processes

George, Frank R.; Goldberg, Steven R.

doi:10.1016/0165-6147(89)90083-7

Cited by 130 publications

(42 citation statements)

References 18 publications

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“…While data do not exist directly evaluating this hypothesis, relevant analogies can be made with other models of increased susceptibility of drug reinforcement. Similar to HR versus LR ), Lewis rats demonstrate increased susceptibility to psychostimulant, opioid, or ethanol reinforcement compared to Fischer rats (George and Goldberg, 1989;Guitart et al, 1992). Likewise, rats treated chronically with cocaine or amphetamine demonstrate a greater susceptibility for psychostimulant self-administration (Horger et al, 1990(Horger et al, , 1992Piazza et al, 1990).…”

Section: Discussionmentioning

confidence: 96%

Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs

et al. 1994

J. Neurosci.

146

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Rats that have a greater locomotor response to novelty (high responders, HR) have differences in measures of presynaptic dopamine transmission compared to low responders (LR) to a novel environment, including altered dopamine release and behavioral response to indirect dopamine agonists. This study examined the role of three dopamine terminal fields, the nucleus accumbens, striatum, and medial prefrontal cortex, in differences between HR and LR. In the first experiment, dopamine was infused directly into the nucleus accumbens (0, 3, 10, and 30 micrograms/side) or the striatum (0, 10, 30, and 100 micrograms/side). HR showed a greater behavioral response to both the 3 and 30 micrograms/side doses infused into the nucleus accumbens compared to LR. No differences between HR and LR were revealed by dopamine infusion into the striatum. In the second experiment, radioligand binding assays were performed to determine if differences exist between high and low responder rats in the Bmax and/or KD of radiolabeled antagonist ligands for the dopamine D1 and/or D2 receptors. There were fewer D2 binding sites in the nucleus accumbens and fewer sites in the striatum in HR compared to LR. High responders showed a greater Bmax for D1 binding sites in the nucleus accumbens than LR. No differences in number of binding sites for D1 receptors were observed between HR and LR in the striatum. No differences between HR and LR in D2 or D1 receptor binding were observed in the medial prefrontal cortex. There were no differences in KD for any of the dopamine receptors in the regions examined.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 96%

Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs

et al. 1994

J. Neurosci.

146

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“…Thus, shared genetic vulnerability may underlie several forms of reward-seeking behavior, and it is likely that there is a polygenetic basis (George and Goldberg, 1989;Kosten et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Higher locomotor response to cocaine in female (vs. male) rats selectively bred for high (HiS) and low (LoS) saccharin intake

Carroll

Anderson

Morgan

2007

Pharmacology Biochemistry and Behavior

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Rats selectively bred for high saccharin consumption (HiS) self-administer more oral ethanol and i.v. cocaine than those selectively bred for low saccharin consumption (LoS). Male and female drug-seeking-prone (HiS) and -resistant (LoS) rats were used in the present experiment to test the prediction that cocaine-induced locomotor activity and sensitization varied with sex and their selective breeding status (HiS and LoS). All rats were intermittently exposed over 2 weeks to pairs of sequential saline and cocaine injections, separated by 45 min. The first 5 pairs of injections, each separated by 2-3 days (10-12 days total), were given to examine the development of cocaineinduced locomotor activity and the development of locomotor sensitization, which was determined by comparing the effects of cocaine injection 1 with injection 6, which was given 2 weeks after the 5 pairs of intermittent injections. Results indicated that after the first injection pair (saline, cocaine) the HiS and LoS groups did not differ (saline vs. cocaine) in locomotor activity; however, after cocaine injections 1, 5 and 6, HiS females were more active than HiS males and LoS females. There were also significant phenotype differences (HiS > LoS) in locomotor activity after cocaine injections 5 and 6. There was only a weak sensitization effect in cocaine-induced locomotor activity in HiS females after cocaine injection 5 (compared to 1); however it was not present after injection 6 or in other groups. The lack of a strong sensitization effect under these temporal and dose conditions was inconsistent with previous reports. However, the results showing HiS > LoS and females > males on cocaine-induced activity measures are consistent with several measures of cocaine-seeking behavior (acquisition, maintenance, escalation, extinction, and reinstatement), and they suggest that cocaine-induced locomotor activity and sensitization are behavioral markers of drug-seeking phenotypes.

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“…More recently, research to find specific genes contributing to human vulnerability is being developed in parallel with studies in experimental animal models in order to define the limits of possible genetic and environmental factors in vulnerability (Cadoret et al 1986; Devor and Cloninger 1989;George and Goldberg 1989;Uhl et al 1995). From clinical and naturalistic approaches, it is generally agreed that preexisting intrinsic vulnerability does exist that leads from recreational use to abuse and dependence for a small percentage of users (Anthony et al 1994).…”

Section: Vulnerability To Addiction and Allostasis: Genetic Contributmentioning

confidence: 99%

Drug Addiction, Dysregulation of Reward, and Allostasis

Koob

Moal

2001

Neuropsychopharmacology

2,543

2,002

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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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Genetic approaches to the analysis of addiction processes

Cited by 130 publications

References 18 publications

Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs

Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs

Higher locomotor response to cocaine in female (vs. male) rats selectively bred for high (HiS) and low (LoS) saccharin intake

Drug Addiction, Dysregulation of Reward, and Allostasis

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