Ketamine induces hyperactivity in rats and hypersensitivity to nicotine in rat striatal slices.
The symptoms of schizophrenia can be modeled in rats through blockade of ionotropic glutamate receptors, which induces changes in central dopamine circuits. These circuits also contain nicotinic acetylcholine receptors that are activated by nicotine. A role for nicotine in the etiology of schizophrenia is supported by clinical observations of high tobacco use rates in individuals experiencing the psychopathology. The present study investigated the effect of the ionotropic glutamate receptor antagonist ketamine on the function of striatal nicotinic acetylcholine receptors to understand better the potential role of these receptors in schizophrenia. Ketamine (0.1-300 microM) was ineffective to evoke [3H] overflow from rat striatal slices preloaded with [3H]dopamine. Application of psychotomimetic ketamine concentrations (1-10 microM) to striatal slices augmented nicotine-evoked [3H] overflow. Finally, rats received ketamine (30-50 mg/kg) injections for 30 days, to model the development of the disorder, and hyperactivity was observed, although repeated ketamine treatment did not significantly alter nicotine-evoked [3H]dopamine overflow. These data indicate that the function of nicotinic acetylcholine receptors that mediate dopamine release are altered by ketamine, and support a role for nicotinic acetylcholine receptors in schizophrenia pathology.
Rodvelt
Kelli R
KR
Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA.
Kracke
George R
GR
Schachtman
Todd R
TR
Miller
Dennis K
DK
D000818:Animals; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006948:Hyperkinesis / Q000139:chemically induced* / Q000523:psychology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D009538:Nicotine; D004298:Dopamine