Effects of monoamine reuptake inhibitors on cocaine self-administration in rats

Tella, Srihari R.

doi:10.1016/0091-3057(94)00438-o

Cited by 93 publications

(61 citation statements)

References 46 publications

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“…If these rewarding and aversive features normally balanced each other to produce little net reward or aversion with SERT blockade, fluoxetine or other selective serotonin reuptake inhibitors would display minimal aversion and also little abuse liability in humans, as has been observed. [73][74][75] The fluoxetine reward acquired by DAT and by NET knockout mice is consistent with the idea that each of these knockouts shifts the balance between rewarding and aversive serotonergic components, although not necessarily in identical ways.…”

Section: Cocaine Reward and Aversion: Rich Patterns Of Multitransporsupporting

confidence: 53%

Cocaine, reward, movement and monoamine transporters

Uhl¹,

Hall²,

Sora³

2002

Mol Psychiatry

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Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities. Cocaine is a prototypical psychomotor stimulant that increases locomotor activity and elevates mood with rewarding euphoria.1 It also produces fearful and jittery aversive effects in many who take it.2,3 Cocaine blocks monoamine uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET), and can also block ligand-and voltage-gated channels with somewhat lower potencies. 4 Understanding the relationships between cocaine's molecular actions and its psychomotor stimulant and aversive properties has remained surprisingly incomplete. This review focuses on recent advances in our understanding of the complex relationships between cocaine's molecular actions and its locomotor stimulant, rewarding and aversive properties.The 'DAT-is-it' hypothesis drove thinking about cocaine reward for at least a decade, ideas widely linked to Kuhar, Spealman and their colleagues 4-8 who gathered evidence from structure-activity relationships of transporter-blocking compounds with differential potencies at DAT, SERT and NET. They examined relationships between potencies of these compounds in tests of reward and binding affinities at each of the monoamine transporters. They each identified the best correlations for the rewarding effects of cocaine with DAT blockade. These authors also cited prior work from lesion studies 9-12 and electrical brain stimulation studies [13][14][15][16][17] This 'DAT-is-it' hypothesis was a major motivation for work that resulted in cloning DAT cDNAs, genes and gene variants in our laboratory and others. [23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29,31-53 and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains. [56][57][58][59] These studies revealed an exquisite DAT-dependence of cocaine's locomotor stimulation. By contrast, they also produced surprising results that refuted the strong 'DAT-is-it' hypothesis of cocaine reward. Cocaine-induced locomotion: DAT is itDAT variation in humans and mice links robustly with variation in both baseline locomotion and/or psychostimulant-induced locomotor activities. Three strains of DAT knockout ...

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Section: Cocaine Reward and Aversion: Rich Patterns Of Multitransporsupporting

confidence: 53%

Cocaine, reward, movement and monoamine transporters

Uhl¹,

Hall²,

Sora³

2002

Mol Psychiatry

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“…Although 6-OHDA lesions of DA produce a long-lasting reduction in SA of cocaine, lesions of both the dorsal and VNBs fail to alter responding (Roberts et al, 1977). Furthermore, while selective DA reuptake inhibitors themselves are readily self-administered and alter psychostimulant SA, selective NET inhibitors possess neither property (Woolverton, 1987;Howell and Byrd, 1991;Skjoldager et al, 1993;Tella, 1995;Wee et al, 2006). The only noradrenergic drug that appears to have reinforcing properties is clonidine, an a2-adrenergic receptor (a2AR) agonist that is self-administered by both rats and nonhuman primates (Shearman et al, 1981;Woolverton et al, 1982).…”

Section: Ne and Psychostimulant 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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“…Modulation of the NET has a minimal effect on cocaine discriminative stimulus studies, while modulation of the DAT and SERT have potent effects in this model [61]. Inhibitors of the NET also have minimal effect on cocaine self-administration [62]. Finally, there is no relationship between affinity of cocaine analogues for the NET and their lethality [63].…”

Section: Post-receptor Effects Of Cocainementioning

confidence: 99%

Mechanisms of Acute Cocaine Toxicity

Heard¹,

Palmer²,

Zahniser³

2008

TOPHARMJ

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Abstract:Patients with acute cocaine poisoning present with life-threatening symptoms involving several organ systems. While the effects of cocaine are myriad, they are the result of a limited number of cocaine-protein interactions, including monoamine transporter, neurotransmitter receptor and voltage-gated ion channels. These primary interactions trigger a cascade of events that ultimately produce the clinical effects. The purpose of this article is to review the primary interactions of cocaine and the effects that these interactions trigger. We also describe the progression of symptoms observed in cocaine poisoning as they relate to serum cocaine concentrations.

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Effects of monoamine reuptake inhibitors on cocaine self-administration in rats

Cited by 93 publications

References 46 publications

Cocaine, reward, movement and monoamine transporters

Cocaine, reward, movement and monoamine transporters

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

Mechanisms of Acute Cocaine Toxicity

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