Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists.
N-methyl-D-aspartate (NMDA) receptor antagonists can elicit symptoms in humans that resemble those seen in schizophrenic patients. Rodents manifest locomotor and stereotypic behaviors when treated with NMDA receptor antagonists such as phencyclidine (PCP) or dizocilpine maleate (MK-801); these behaviors are usually associated with an activated dopamine system. However, recent evidence suggests that increased glutamatergic transmission mediates the effects of these NMDA receptor antagonists. The role of dopamine in PCP- and MK-801-induced behavior (eg hyperlocomotion) remains unclear. We used dopamine-deficient (DD) mice in which tyrosine hydroxylase is selectively inactivated in dopaminergic neurons to determine whether dopamine is required for the locomotor and molecular effects of PCP and MK-801. DD mice showed a similar increase in locomotor activity and c-fos mRNA induction in the striatum in response to these NMDA receptor antagonists as control mice. Restoration of dopamine signaling in DD mice enhanced their locomotor response to PCP and MK-801. Administration of LY379268, a group II metabotropic glutamate receptor agonist that inhibits glutamate release, blocked PCP- and MK-801-induced hyperlocomotion in both DD and control mice. These results suggest that glutamate, rather than dopamine, is required for the locomotor and molecular effects of NMDA receptor antagonists, but that glutamate and dopamine can act cooperatively.
Chartoff
Elena H
EH
Department of Psychiatry, Harvard Medical School, McLean Hospital Belmont, MA, USA.
Heusner
Carrie L
CL
Palmiter
Richard D
RD
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000172:deficiency*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency
D001552:Benzazepines; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D016291:Dizocilpine Maleate; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D010622:Phencyclidine; D006220:Haloperidol; D004298:Dopamine