Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice

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Abstract

A large body of evidence supports the hypothesis that the reinforcing effects of cocaine depend on its ability to block the dopamine transporter (DAT), thereby increasing dopamine extracellular concentration within the mesocorticolimbic system. However, the fact that cocaine similarly binds to the serotonin and norepinephrine transporters (SERT and NET, respectively), raises the possibility that modulation of mesocorticolimbic dopaminergic transmission might be achieved through alternate pathways. The successful disruption of the genes coding for the DAT, the SERT and the NET offered ideal tools to determine the extent of the participation of these transporters and respective monoaminergic systems in the reinforcing effects of cocaine. Studies of cocaine-induced motor activation and maintenance of intravenous (i.v.) self-administration in DAT- and in NET-knockout (KO) mice are reviewed here, and discussed in light of new observations obtained from double monoamine transporters KO mice (i.e., DAT-KO/SERT-KO, NET-KO/SERT-KO). The reinforcing potency of cocaine is maintained in the absence of the DAT but decreased in the absence of the NET; its motivational rewarding effect is observed in the absence of the SERT, but not when both DAT and SERT are lacking. Moreover, a dichotomy between cocaine motor activating and reinforcing effects is reported. Such dichotomy is suggestive of independent mechanisms underlying the psychomotor stimulant and reinforcing effects of cocaine. Overall, these studies provide evidence that cocaine dynamically acts at multiple sites through pathways that might be exchangeable under certain circumstances.

Introduction

Cocaine abuse remains a critical challenge for society. One million Americans aged 12 years or older were estimated to be dependent on cocaine in 2000, when 361,000 new users were reported (2001 National Household Survey on Drug Abuse, NHSDA/SAMHSA/Department of Health and Human Services, Bethesda, MD). Economic burden, social order and public health consequences of such scenario are severe, but no specific treatment has yet been approved for cocaine addiction. The reduction of such treatment gap demands, in great part, a better understanding of the neuropathways and mechanisms implicated in the effects of cocaine.

Innovative research in cocaine abuse has been aggressively pursued and has flourished in the last decade, in particular, due to the rapid advance in genetics and the successful generation of mice lacking specific genes. Noteworthy was the generation of mice lacking one or two of the molecular targets of cocaine Giros et al., 1996, Xu et al., 2000, Sora et al., 1998, Sora et al., 2001, Hall et al., 2002, which are the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SERT). These are responsible, respectively, for the uptake of dopamine, norepinephrine and serotonin (5-HT), from the synapses into nerve terminals. The overall behavioral analysis and neurochemical evaluation of the DAT-, NET- and SERT-knockout (KO) mice, which are reviewed elsewhere Gainetdinov and Caron, 2003, Stephens et al., 2002, Uhl et al., 2002 as well as in other articles of this issue, has been extremely valued in expanding the knowledge of cocaine's molecular actions.

The present review centers on reports assessing the psychomotor stimulant and reinforcing effects of cocaine in some of these mutants, and more specifically, in data obtained from experiments describing cocaine-induced motor activation and self-administration.

Section snippets

Motor behavior

As a psychostimulant drug, cocaine, characteristically, elicits a dose-dependent increase in motor ambulatory activity in rodents Snoddy and Tessel, 1985, Nielsen and Scheel-Kruger, 1988. This hyperactivity is more prominent at low doses, and decreases at higher doses where stereotyped repetitive behavior appears (Tyler and Tessel, 1979). At very high doses, gradual loss of righting reflexes occurs which is rapidly followed by clonic seizures and death Benowitz, 1993, Matsumoto et al., 1997.

Psychomotor and reinforcing effects of cocaine in DAT-KO mice

First described by Giros et al. (1996), the DAT-KO mouse attracted foremost interest particularly because of its accepted major role in mediating cocaine's reinforcing effects Ritz et al., 1987a, Ritz et al., 1987b. A comprehensive research on these mice significantly clarified the cellular, neurochemical, and physiological role of the DAT in dopaminergic transmission, and gave rise to innovative concepts on the biology of the dopaminergic system (for review, see Gainetdinov and Caron, 2003).

Psychomotor and reinforcing effects of cocaine in NET-KO mice

Neurochemical observations in NET-KO mice were analogous to the observations in DAT-KO mice. A prolonged synaptic lifetime of norepinephrine resulted in increase of extracellular concentration of norepinephrine, depletion of norepinephrine intraneuronal stores, and decreased α1-adrenoceptor binding in the hippocampus (Xu et al., 2000).

Behavioral evaluation of these mutants described them with decreased immobility in the tail suspension test, greater locomotor stimulation and conditioned place

Conclusion

The KO mouse technology represents and remains a powerful genetic tool for the study of addiction, in spite of its limitations. We revisited here studies of cocaine-induced motor activation, behavioral sensitization and maintenance of i.v. self-administration in particular, in DAT-KO and NET-KO mice. While the exact mechanism(s) underlying such cocaine effects has not yet been fully determined, these studies brought together evidence that cocaine acts through diverse and not exclusive

Acknowledgments

I thank Dr. Andy Mead for his comments.

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