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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