The dopamine transporter: a crucial component regulating dopamine transmission.
The dopamine system is implicated in the control of locomotion, cognition, and endocrine function. The relative contribution of the various dopamine-related components is not well established mainly because drugs that target the dopaminergic system often lack selectivity. The in vivo gene inactivation procedure, or knockout, enables the creation of new strains of mice lacking a specific gene. This technique has been applied recently to inactivate the expression of the plasma membrane dopamine transporter. Here we summarize the main findings obtained with these transgenic mice carrying this "genetic defect," leading to a better understanding of the relative contribution of the dopamine transporter regarding locomotor activity, regulation of the expression of peptides under the control of dopaminergic activity, and responses to various drugs targeting the dopamine system. Our results establish not only the central importance of the transporter as the key element controlling dopamine levels in the brain, but also its role as an obligatory target for the behavioral and biochemical action of amphetamine and cocaine. In addition, the genetically altered mice offer a unique model to test the specificity and selectivity of dopamine transporter-acting drugs and may provide important new concepts related to the clinical and social implications of conditions such as Parkinson's disease, schizophrenia, and drug addiction.
Jaber
M
M
Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Jones
S
S
Giros
B
B
Caron
M G
MG
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D018628:Gene Dosage; D005838:Genotype; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D010300:Parkinson Disease / Q000503:physiopathology; D010641:Phenotype; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000503:physiopathology
D000662:Amphetamines; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D003042:Cocaine; D004298:Dopamine