Molecular Neurobiology of Drug Addiction

Nestler, Eric J.

doi:10.1038/npp.1994.37

Cited by 94 publications

(37 citation statements)

References 16 publications

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“…As a means of counteracting this perturbation or insult, the nervous system responds by producing stable neurochemical alterations in the brain, particularly within dopamine responsive neurons. These long-lived changes in brain neurochemistry occur through alterations in gene expression and are maintained to ultimately underlie the behavioral abnormalities, which characterize addiction (Nestler, 1994(Nestler, , 2001). The earliest event in gene regulation involves the activation of transcription factors, nuclear proteins, which regulate gene transcription.…”

Section: Sensitization and D 1 Receptor-mediated Neuronal Signaling Tmentioning

confidence: 99%

D₁ dopamine receptor: A putative neurochemical and behavioral link to cocaine action

Hummel

Unterwald

2002

Journal Cellular Physiology

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Cocaine is one of the most abused psychostimulants known to man and as such, researchers have been steadfast in their attempts to understand the neurobiological mechanisms responsible for its abuse. Cocaine undoubtedly wreaks havoc on a number of mammalian neuronal neurotransmitter systems, and it is maintained that this dysregulatory effect supports cocaine abuse. Cocaine's mechanism of action has been well described. Cocaine binds differentially to the dopamine, serotonin, and norepinephrine transport proteins and directly prevents the reuptake of dopamine, serotonin, and norepinephrine into pre-synaptic neurons (Heikkila et al., 1975, Biochem Pharmacol 24(8):847±852;Reith et al., 1986, Biochem Pharmacol 35(7):1123±1129; Ritz et al., 1987, Science 237:1219± 1223. Inhibition of re-uptake subsequently elevates the synaptic concentrations of each of these neurotransmitters. In addition to this direct effect, cocaine also produces a number of indirect actions, which alter other neuromodulatory systems (i.e., opioidergic, glutamatergic, and GABAergic systems). Many of these effects are just beginning to be elucidated, but nonetheless contribute to this agent's diverse pharmacological pro®le. Interestingly, it is the indirect actions of this melli¯uous molecule, which mediate most of its sought and unsought effects. The intricacy with which cocaine produces neuronal alterations beyond its direct effects on neurotransmitter re-uptake appear to be most relevant to cocaine abuse, and hence the phenomenon of addiction. In light of cocaine's multifarious effects on numerous neuronal systems, its effect on dopaminergic neurotransmission has attracted the most attention, particularly because of the implicated role of dopamine in brain reward. Pharmacologically, the psychostimulant effects of cocaine appear to be mediated by its ability to enhance dopaminergic activity within the mesocorticolimbic circuit (Roberts et al., 1977, Pharmacol Biochem Behav 6(6):615±620). Additionally, it is the intensity with which cocaine produces alterations in dopaminergic circuitry that have enabled this drug to prevail as one of the most addictive substances known to man. This review will summarize ®ndings relevant to cocaine-induced alterations in dopaminemediated signal transduction. Speci®cally, it will concentrate on the D 1 dopamine receptor and intracellular signaling mediated by this receptor subtype. It will describe cocaine-induced cellular and behavioral alterations relevant to this pathway and how these changes potentially effect gene transcription and protein expression. This article too will review a common behavioral manifestation associated with repeated cocaine exposure, sensitization, and why the D 1 dopamine receptor and its associated signaling pathway have been implicated in this phenomenon. Lastly, this article will discuss how targeting the D 1 dopamine receptor and its signaling pathway may offer some insight into understanding cocaine addiction, a somewhat elusive brain disease.

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Section: Sensitization and D 1 Receptor-mediated Neuronal Signaling Tmentioning

confidence: 99%

D₁ dopamine receptor: A putative neurochemical and behavioral link to cocaine action

Hummel

Unterwald

2002

Journal Cellular Physiology

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“…The nucleus accumbens and its dopaminergic innervation are known to be involved in reward processes (e.g., Everitt and Robbins 1992;Koob 1992;LeMoal and Simon 1991;Nestler 1994), and conditioned reinforcement, in particular Robbins 1984, 1986). Notably, reductions in cortical dopamine function can lead to increased nucleus accumbens dopamine transmission (Deutch et al 1990;Deutch 1992).…”

Section: Implications For Motivated Behavior and Affective Dysfunctionmentioning

confidence: 99%

Impaired Inhibition of Conditioned Responses Produced by Subchronic Administration of Phencyclidine to Rats

Jentsch

Taylor

2001

Neuropsychopharmacology

103

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Several recent investigations have suggested that an important function of the frontostriatal system is inhibitory response control, and we previously reported that subchronic exposure to phencyclidine (PCP) produced deficits in inhibitory control in monkeys. The current studies were designed to examine whether subchronic administration of PCP to rats would subsequently affect the ability to inhibit conditioned responses when relationships between rewardOne of the proposed functions of the prefrontal cortex and its projection sites within the striatal complex is inhibitory response control (Milner 1963;Mishkin 1964;Robbins 1996). Studies in non-human primates have suggested that subjects with lesions within the ventral regions of frontal cortex exhibit impaired ability to withhold responses in Go/No-go or operant extinction tests. Moreover, monkeys with lesions of the frontal cortex exhibit abnormal control of behavior by previously-reinforced stimuli in discrimination reversal tasks and show deficits in object retrieval/detour paradigms where animals have to retrieve a reward from a transparent box by making a reaching detour while inhibiting reaching directly at the reward (Butter 1968;Iversen and Mishkin 1970;Rosenkilde 1975;Diamond 1988;Dias et al. 1996a Dias et al. ,b, 1997Wallis et al. 1997). Likewise, frontal cortical lesions in rats can produce reversal-learning deficits (Divac 1971;Kolb et al. 1974;Bussey et al. 1997).In each of these tasks, the performance impairments can be described as increased control of behavior by "pre-potent" stimuli (i.e., stimuli with previous motiva- Inhibitory Deficits after PCP 67 tional significance). These pre-potent stimuli can be unconditioned reinforcers or can acquire motivational significance by contingent association with primary reward, thus becoming second-order, conditioned reinforcers. The Go/No-go and extinction deficits may reflect an inability to inhibit the conditioned, pre-potent tendency to respond, per se , while deficits on the object retrieval/detour task may result from "enhanced appetitive effects of reward over behavior" (Dias et al. 1996b, page 884). Moreover, in reversal tasks, the originally reinforced stimulus likely acquires conditioned-reinforcing properties by contingent association with reward. These deficits in monkeys are analogous to those observed in humans with damage within the ventral frontal cortex. Lesions to the orbitofrontal cortex in humans results in the preference for immediate, inefficient rewards, over delayed but more advantageous rewards, as measured by "option-outcome" procedures (Damasio 1996). Likewise, lesions to more dorsal regions of the prefrontal cortex impair performance of Stroop and Wisconsin Card Sorting tests, both of which require intact "inhibitory control" (Milner 1963).An elegant method for evaluating the incentive qualities of stimuli and the control of behavior by conditioned stimuli is the "acquisition of a new response" (Hill 1970;Robbins 1975Robbins , 1976Mackintosh 1974;Taylor and Robbins 1984). In th...

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“…The nucleus accumbens, as part of the mesolimbic dopamine system, is thought to be important in psychomotor stimulant-induced locomotor activity (Kelly and Iversen, 1976;Mogenson and Nielsen, 1984;Clarke et al, 1988;Delfs et al, 1990) and in the reinforcing effects of cocaine (Nestler, 1994). The striatum, part of the nigrostriatal system, is thought to have a role in motor activity, such as stereotypy (Alexander and Crutcher, 1990;Cote and Crutcher, 1991) but also in rewarded "habit" learning (Everitt and Wolf, 2002;Kelley and Berridge, 2002).…”

Section: Discussionmentioning

confidence: 99%

Withdrawal from Repeated Cocaine Alters Dopamine Transporter Protein Turnover in the Rat Striatum

Kimmel¹,

Carroll²,

Kuhar³

2003

J Pharmacol Exp Ther

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Several studies have shown that repeated cocaine administration, followed by withdrawal, alters dopamine transporter (DAT) levels in the rat. These changes must arise from changes in either transporter protein production or degradation, or both. Previously, our laboratory developed an approach to measure the synthesis rate, degradation rate constant, and half-life of DAT in the rat striatum and nucleus accumbens after administration of the irreversible dopamine transporter ligand, RTI-76. These initial studies showed that: 1) the half-life of the transporter was between 2 and 3 days in these two brain regions; 2) pretreatment with dopamine D1 and D2 receptor agonists and antagonists over several days differentially altered DAT half-lives in the striatum and nucleus accumbens; and 3) pretreatment with cocaine for several days increased the half-life of DAT by decreasing the degradation rate constant in both brain regions. In the present study, we determined that repeated pretreatment (10 days) with 20 mg/kg cocaine (i.p.) and a subsequent withdrawal period (10 days) alters the dopamine transporter turnover in the rat striatum, but not in the nucleus accumbens. Cocaine pretreatment and withdrawal reduced the half-life of the transporter protein from 2.1 days to 0.94 day in the striatum, but did not alter the half-life of 2.2 days in the nucleus accumbens. The results indicate the complex and long-lasting effects of cocaine administration on cellular processes. The mechanism(s) of these effects remains to be elucidated.

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Molecular Neurobiology of Drug Addiction

Cited by 94 publications

References 16 publications

D₁ dopamine receptor: A putative neurochemical and behavioral link to cocaine action

D₁ dopamine receptor: A putative neurochemical and behavioral link to cocaine action

Impaired Inhibition of Conditioned Responses Produced by Subchronic Administration of Phencyclidine to Rats

Withdrawal from Repeated Cocaine Alters Dopamine Transporter Protein Turnover in the Rat Striatum

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Molecular Neurobiology of Drug Addiction

Cited by 94 publications

References 16 publications

D1 dopamine receptor: A putative neurochemical and behavioral link to cocaine action

D1 dopamine receptor: A putative neurochemical and behavioral link to cocaine action

Impaired Inhibition of Conditioned Responses Produced by Subchronic Administration of Phencyclidine to Rats

Withdrawal from Repeated Cocaine Alters Dopamine Transporter Protein Turnover in the Rat Striatum

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D₁ dopamine receptor: A putative neurochemical and behavioral link to cocaine action

D₁ dopamine receptor: A putative neurochemical and behavioral link to cocaine action