D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat

Maldonado, Rafaël; Robledo, Patricia; Chover, A.J.; Caine, S. Barak; Koob, George F.

doi:10.1016/0091-3057(93)90112-7

Cited by 141 publications

(85 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The VTA also sends DA terminals to the NAcc where it is involved in cocaine reinforcing effects (Maldonado et al, 1993;McGregor and Roberts, 1993;Phillips et al, 2003). It is conceivable that blockade of VTA iGLU receptors decreases cocaine-primed reinstatement by interfering with DA in the NAcc.…”

Section: Discussionmentioning

confidence: 99%

Ionotropic Glutamate Receptors in the Ventral Tegmental Area Regulate Cocaine-Seeking Behavior in Rats

Sun

Akins

Mattingly

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

Drug addiction is characterized by compulsive drug-seeking and drug-taking behavior and by a high rate of relapse even after long periods of abstinence. Although the mesocorticolimbic dopamine (DA) pathway is thought to play a critical role in drug craving and relapse, recent evidence also implicates glutamate, an amino acid known to activate DA neurons in the ventral tegmental area (VTA) via ionotropic receptors. To assess whether increased glutamate transmission in the VTA is involved in cocaine-primed drug-seeking behavior, we tested rats in a between-session reinstatement model. They were trained to press a lever for cocaine infusions (0.25 mg/ infusion) accompanied by compound stimuli (light and tone) under a modified fixed-ratio 5 reinforcement schedule. Cocaine-primed reinstatement was conducted after lever pressing was extinguished in the absence of the conditioned stimuli. Blockade of ionotropic glutamate receptors in the VTA by local application of kynurenate (0.0, 1.0, 3.2, and 5.6 mg/side) dose-dependently decreased cocaineprimed reinstatement, whereas sucrose-primed reinstatement of sucrose-seeking behavior was unaffected. In addition, the minimum effective dose for decreasing cocaine-primed reinstatement was ineffective in the substantia nigra. Together, these data indicate that glutamatergic activation of the VTA is critical for cocaine-primed reinstatement. Because such activation can increase impulse flow in DA neurons and thus DA release in mesocorticolimbic targets, this glutamate-DA interaction in the VTA may underlie cocaine-primed relapse to cocaine-seeking behavior.

show abstract

Section: Discussionmentioning

confidence: 99%

Ionotropic Glutamate Receptors in the Ventral Tegmental Area Regulate Cocaine-Seeking Behavior in Rats

Sun

Akins

Mattingly

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Reinforcement paradigms employing dopamine receptor antagonists have demonstrated increases, decreases, or no change in cocaine selfadministration following dopamine receptor antagonist pretreatment (Maldonado et al, 1993;Caine and Koob, 1994;Campbell et al, 1999). Many of the disparate ®ndings can be attributed to differences in experimental design such as schedule of reinforcement (Caine and Koob, 1994).…”

Section: Receptors Mediate Cocaine-induced Behaviorsmentioning

confidence: 99%

“…Many of the disparate ®ndings can be attributed to differences in experimental design such as schedule of reinforcement (Caine and Koob, 1994). Until recently, D 1 antagonist studies were directed at understanding the role of D 1 receptors in cocaine reinforcement at mesocorticolimbic dopamine terminal sites (Maldonado et al, 1993;Roberts, 1993, 1995). Recent evidence, however, suggests that D 1 receptors in the VTA may mediate cocaine reinforcement.…”

Section: Receptors Mediate Cocaine-induced Behaviorsmentioning

confidence: 99%

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

Hummel

Unterwald

2002

Journal Cellular Physiology

View full text Add to dashboard Cite

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.

show abstract

“…In turn, discrete lesions of DA terminals by 6-OHDA point to the nucleus accumbens (NAc) as the DA projection area responsible for cocaine reinforcement (Pettit et al, 1984;Roberts et al, 1980). Studies on the effect of systemic and local intracerebral infusion of selective D1 antagonists (Caine et al, 1995;Koob et al, 1987;Maldonado et al, 1993) on i.v. cocaine SA indicate a specific role of NAc DA D1 receptors.…”

Section: Introductionmentioning

confidence: 99%

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

et al. 2015

View full text Add to dashboard Cite

Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of cFos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement.

show abstract

D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat

Cited by 141 publications

References 12 publications

Ionotropic Glutamate Receptors in the Ventral Tegmental Area Regulate Cocaine-Seeking Behavior in Rats

Ionotropic Glutamate Receptors in the Ventral Tegmental Area Regulate Cocaine-Seeking Behavior in Rats

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

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

Contact Info

Product

Resources

About

D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat

Cited by 141 publications

References 12 publications

Ionotropic Glutamate Receptors in the Ventral Tegmental Area Regulate Cocaine-Seeking Behavior in Rats

Ionotropic Glutamate Receptors in the Ventral Tegmental Area Regulate Cocaine-Seeking Behavior in Rats

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

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

Contact Info

Product

Resources

About

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