Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice.
OBJECTIVE
The effects of sigma receptor antagonists on methamphetamine (METH)-induced stereotypy have not been examined. We examined the effects of sigma antagonists on METH-induced stereotypy in mice.


RESULTS
The administration of METH (10 mg/kg) to male ddY mice induced stereotyped behavior consisting of biting (90.1%), sniffing (4.2%), head bobbing (4.1%), and circling (1.7%) during an observation period of 1 h. Pretreatment of the mice with BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol; 1, 5, and 10 mg/kg), a non-specific sigma receptor antagonist, significantly increased METH-induced sniffing (19.2%, 30.5%, and 43.8% of total stereotypical behavior) but decreased biting (76.6%, 66.9%, and 49.3% of total stereotypical behavior) in a dose-dependent manner. This response was completely abolished by (+)-SKF 10,047 ([2S-(2alpha,6alpha,11R)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol; 4 and 10 mg/kg), a putative sigma(1) receptor agonist, and partially by PB 28 (1-cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalen-1-yl)-n-propyl]piperazine; 1 and 10 mg/kg), a putative sigma(2) receptor agonist. The BMY 14802 action on METH-induced stereotypy was mimicked by BD 1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine; 10 mg/kg), a putative sigma(1) receptor antagonist, but not by SM-21 ((+/-)-tropanyl 2-(4-chlorophenoxy)butanoate; 1 mg/kg), a putative sigma(2) receptor antagonist. The BD 1047 effect on METH-induced stereotypy was also abolished completely by (+)-SKF 10,047 and partially by PB 28. The overall frequency of METH-induced stereotypical behavior was unchanged with these sigma receptor ligands, despite the alteration in particular behavioral patterns. The BMY 14802 action on METH-induced stereotypy was unaffected by pretreatment with centrally acting histamine H(1) receptor antagonists (pyrilamine or ketotifen, 10 mg/kg), suggesting that these effects are independent of histamine H(1) receptor signaling systems.


CONCLUSIONS
In summary, modulation of central sigma(1) receptors alters the pattern of METH-induced stereotypy, producing a shift from stereotypical biting to stereotypical sniffing, without affecting the overall frequency of stereotypical behavior.
Kitanaka
J
J
Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. kitanaka-hyg@umin.net
Kitanaka
N
N
Tatsuta
T
T
Hall
F S
FS
Uhl
G R
GR
Tanaka
K
K
Nishiyama
N
N
Morita
Y
Y
Takemura
M
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005029:Ethylenediamines / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007665:Ketotifen / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors*; D013239:Stereotyped Behavior / Q000187:drug effects*; D014326:Tropanes / Q000494:pharmacology
C505382:1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-propyl)-piperazine; D002087:Butyrates; D000697:Central Nervous System Stimulants; D005029:Ethylenediamines; D006634:Histamine H1 Antagonists; D009281:Naphthalenes; D010879:Piperazines; D011743:Pyrimidines; D017480:Receptors, sigma; D014326:Tropanes; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; C107044:SM 21; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D008694:Methamphetamine; C012134:SK&F 10047; D011738:Pyrilamine; D010620:Phenazocine; D007665:Ketotifen