Role of NMDA receptor subtypes in the induction of catalepsy and increase in Fos protein expression after administration of haloperidol.
The increase of Fos expression in the striatum induced by haloperidol, an antagonist of the dopamine D2 receptor, might be related to the activation of glutamatergic neurotransmission, especially that of N-methyl-D-aspartate (NMDA) receptors. In this study, using behavioral and immunohistochemical techniques, we examined the effects of a noncompetitive NMDA antagonist, (+)-MK-801, and an NMDA receptor NR2B subunit antagonist, ifenprodil, on catalepsy, an extrapyramidal symptom; in this context, we also considered the expression of Fos protein in the forebrain after the administration of haloperidol. Catalepsy in mice, induced by the administration of haloperidol (1 mg/kg), was inhibited by pretreatment with (+)-MK-801 (0.2 mg/kg) or ifenprodil (10 mg/kg). Furthermore, pretreatment with (+)-MK-801 (0.2 mg/kg) significantly attenuated the induction of Fos-immunoreactive (IR) cells in the dorsomedial, dorsolateral, and ventrolateral striatum, but not in the shell region of the nucleus accumbens after the administration of haloperidol, whereas pretreatment with ifenprodil (10 mg/kg) significantly attenuated the induction of Fos-IR cells in all of these areas. It is known that ifenprodil binds sigma receptors and alpha-1 adrenergic receptors with high affinity. Pretreatment with the sigma receptor antagonist BD-1407 (3 mg/kg) or the alpha-1 adrenergic receptor antagonist prazosin (3 mg/kg) affected neither catalepsy nor the expression of Fos-IR cells after the administration of haloperidol. However, pretreatment with CP-101,606 (1 mg/kg), a selective antagonist for the NR2B subunit of the NMDA receptor, significantly attenuated catalepsy and the expression of Fos-IR cells in the forebrain after the administration of haloperidol. These results suggest that the NMDA receptor antagonists attenuated the induction of catalepsy and Fos-IR cells in forebrain after the administration of haloperidol. It was also suggested that haloperidol-induced expression of Fos-IR cells in the shell region of the nucleus accumbens might be differentially regulated by NMDA receptor subunits. Therefore, it appears that selective antagonists for the NR2B subunit of the NMDA receptor (e.g., CP-101,606) might be useful drugs for the treatment of extrapyramidal side effects (EPS) associated with the chronic use of typical antipsychotics such as haloperidol.
Yanahashi
Satoshi
S
Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan.
Hashimoto
Kenji
K
Hattori
Kotaro
K
Yuasa
Shigeki
S
Iyo
Masaomi
M
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism*; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D005029:Ethylenediamines / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010880:Piperidines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011930:Reaction Time; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D018492:Dopamine Antagonists; D005029:Ethylenediamines; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D016291:Dizocilpine Maleate; C095106:traxoprodil mesylate; D006220:Haloperidol; C010739:ifenprodil; D011224:Prazosin