TY - JOUR
T1 - Levetiracetam-mediated emotional behavior in heterozygous rolling Nagoya CaV2.1 channel mutant mice
AU - Takahashi, Eiki
AU - Niimi, Kimie
AU - Itakura, Chitoshi
N1 - Funding Information:
All procedures involving animals were approved by the Animal Experiments Committee of RIKEN. All animals were cared for humanely in accordance with institutional guidelines for animal experimentation. The rolling Nagoya mouse strain, which was found among descendants of a cross between strains SIII and C57BL/6 ( Oda, 1973 ), was provided by the RIKEN BioResource Center with support from the National BioResource Project of the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Male +/+ and rol/+ F1 progeny were derived from a cross between +/+ and rol/+ mice and genotyped by PCR using tail DNA ( Takahashi et al., 2009a ). The mice were given free access to water and food pellets (CRF-1; Oriental Yeast Co., Ltd., Tokyo, Japan) and were housed under a 12-h/12-h light/dark cycle (lights on from 08:00 to 20:00) at 23 ± 1 °C and 55 ± 5% humidity. All behavioral analyses were conducted between 09:00 and 16:00 by a well-trained experimenter who was blinded to the mouse strains. Anxious behavior was studied using the elevated plus maze ( Pellow et al., 1985 ) and light–dark exploration ( Crawley, 1981 ) behavioral tests. Depressive behavior was studied using the forced swimming ( Porsolt et al., 1978 ) and tail suspension ( Steru et al., 1985 ) tests. The mice were moved into the behavioral testing room at least 1 h before testing. We examined the levels of TPH and TPH phosphorylated at serine-58 (p-TPH) by Western blot analysis and used high-performance liquid chromatography (HPLC) to examine the monoamine concentrations. Separate groups of two-month-old male mice were used for the behavior, expression, and monoamine concentration tests.
PY - 2010/9
Y1 - 2010/9
N2 - CaV2.1, which is highly expressed in the nervous system, plays an essential role in presynaptic neurotransmitter release. Although recent data suggest that the antiepileptic drug levetiracetam (LEV) inhibits presynaptic CaV2.1 activity, the precise physiological role of CaV2.1/LEV-regulated emotional performance has not been elucidated. We examined whether CaV2.1/LEV mediates emotional behavior using a combined pharmacologic and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the CaV2.1α1 mutation demonstrated normal emotional behavior. Exposure to 75mg/kg LEV, which had no effect in wild-type controls, reduced anxiety in elevated plus maze and light-dark exploration tests and reduced depression in forced swimming and tail suspension behavioral tests in rol/+ mice. Similar behavioral patterns in motor activity were noted in wild-type and rol/+ mice injected with 0-150mg/kg LEV. The phosphorylation of tryptophan hydroxylase at serine-58 and serotonin concentration were increased in the brainstems of rol/+ mice injected with 75mg/kg LEV but not in those of wild-type controls. These results indicate that CaV2.1/LEV mediates serotonin signaling leading to alterations in emotion. Our results also indicate that a combination of subthreshold pharmacologic and genetic approaches can be used to study functional signaling pathways in neuronal circuits.
AB - CaV2.1, which is highly expressed in the nervous system, plays an essential role in presynaptic neurotransmitter release. Although recent data suggest that the antiepileptic drug levetiracetam (LEV) inhibits presynaptic CaV2.1 activity, the precise physiological role of CaV2.1/LEV-regulated emotional performance has not been elucidated. We examined whether CaV2.1/LEV mediates emotional behavior using a combined pharmacologic and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the CaV2.1α1 mutation demonstrated normal emotional behavior. Exposure to 75mg/kg LEV, which had no effect in wild-type controls, reduced anxiety in elevated plus maze and light-dark exploration tests and reduced depression in forced swimming and tail suspension behavioral tests in rol/+ mice. Similar behavioral patterns in motor activity were noted in wild-type and rol/+ mice injected with 0-150mg/kg LEV. The phosphorylation of tryptophan hydroxylase at serine-58 and serotonin concentration were increased in the brainstems of rol/+ mice injected with 75mg/kg LEV but not in those of wild-type controls. These results indicate that CaV2.1/LEV mediates serotonin signaling leading to alterations in emotion. Our results also indicate that a combination of subthreshold pharmacologic and genetic approaches can be used to study functional signaling pathways in neuronal circuits.
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U2 - 10.1016/j.pbb.2010.05.020
DO - 10.1016/j.pbb.2010.05.020
M3 - Article
C2 - 20570694
AN - SCOPUS:77954819590
SN - 0091-3057
VL - 96
SP - 294
EP - 300
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
IS - 3
ER -