Intravenous cocaine induced-activity and behavioural sensitization in norepinephrine-, but not dopamine-transporter knockout mice.
Previously, it was reported that both norepinephrine transporter (NET) and dopamine transporter (DAT) knockout (KO) mice were sensitive to the reinforcing effects of cocaine. However, assessing the locomotor-stimulant effects of cocaine in these subjects has proven difficult due to significant differences in their baseline activity compared to wild-type controls. The present studies were designed to clarify the role of NET and DAT in the stimulant effects of acute and repeated cocaine utilizing these knockout mice, and thereby assess the role of these substrates in the locomotor stimulant effects of cocaine. Mice were habituated to the test environment for sufficient time to ensure equal baselines at the time of cocaine administration. Mice then received cocaine (3-25 mg/kg) intravenously according to a within-session cumulative dose-response design. Cocaine dosing was repeated at 48-h intervals for four sessions to assess behavioural sensitization. NET-KO mice exhibited a reduced response to acute cocaine administration compared to wild-type (WT) controls. However, comparable sensitization developed in NET-KO and WT mice. The DAT-KO and DAT-heterozygote (HT) mice displayed no locomotor activation following either acute or repeated cocaine administration. These data suggest a role for the NET in the acute response to cocaine, but no involvement in sensitization to cocaine. In contrast, DAT appears to be necessary for both the acute locomotor response to cocaine and the subsequent development of sensitization. In addition to existing data concerning the reinforcing effects of cocaine in DAT-KO mice, these data suggest a dissociation between the reinforcing and locomotor stimulant effects of cocaine.
Mead
Andy N
AN
Behavioural Neuroscience Branch, National Institute of Drug Abuse-Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. andym@biols.susx.ac.uk
Rocha
Beatriz A
BA
Donovan
David M
DM
Katz
Jonathan L
JL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004780:Environment, Controlled; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D007275:Injections, Intravenous; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters / Q000172:deficiency* / Q000235:genetics
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493215:Slc6a3 protein, mouse; D027981:Symporters; D003042:Cocaine