Calcium channel agonist, (^ )-Bay K8644, causes a transient increase in striatal monoamine oxidase activity in Balb/c mice Supriti Samantaray, Goutam Chandra, Kochupurackal P. Mohanakumar * Division of Neurosciences, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Calcutta 700 032, India Received 15 October 2002; received in revised form 12 February 2003; accepted 14 February 2003 Abstract We investigated in vivo effects of the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl] pyridine-3-carboxylic acid ((^ )-Bay K8644) on mitochondrial monoamine oxidase (MAO) activity and striatal dopamine (DA) content employing fluorimetric and HPLC-electrochemical procedures, respectively. (^ )-Bay K8644 administration resulted in visible behavioral dysfunctions in mice. A reversible dose-independent inhibition of striatal DA levels and a significant increase in the brain mitochondrial MAO-A and -B activities were observed in animals treated with the calcium agonist. A positive relationship between the rise in the enzyme activity and decrease in DA content in (^ )-Bay K8644 treated animals indicates a direct, but transient effect of this channel activator on DA metabolism, which may be related to acute behavioral syndromes exhibited following administration of the drug. Moreover, a direct involvement of L-type dihydropyridine sensitive calcium channels is indicated in this action, since nicardipine could effectively attenuate (^ )-Bay K8644-induced behavioral aberrations, or block the striatal DA depletion and the increase in MAO activity. The present results have far-reaching implications in neuropharmacological research, where co-treatment of calcium channel drugs and MAO inhibitors are warranted. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Dopamine metabolism; Calcium channels; Behaviors; Nicardipine; Mitochondria; Striatum An L-type calcium channel agonist, 1,4-dihydro-2,6- dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl] pyridine-3- carboxylic acid ((^ )-Bay K8644), has been extensively used for characterizing calcium channel involvement in neurophysiological processes. (^ )-Bay K8644 triggers subtle or overt behaviors following systemic or intrastriatal administration [1,13,17]. A profound effect of (^ )-Bay K8644 on dopamine (DA) release in vitro from striatal slices [7] and synaptosomes [14,18] or in vivo from the nucleus caudatus putamen (NCP) [13,17] has been reported. Ca 2þ -dependent DA release from striatal synaptosomes but not from the brain stem indicated the presence of calcium channels in the rat striatum [18]. In the rat, (^ )-Bay K8644 caused an increase in the rhythmic and bursting activity of dopaminergic cells [10] and potentiated slow excitatory synaptic transmission [3]. The agonist when administered with m-hydroxybenzylhydrazine or nifedipine alters the levels of DA metabolites in caudate nucleus [2,5]. These reports suggest that (^ )-Bay K8644 has a profound effect on the striatal dopaminergic system. We investigated the effect of (^ )-Bay K8644 on monoamine oxidase (MAO) activity in vitro and in vivo to examine the status of this enzyme in acutely regulating the levels of DA in the striatum. Adult Balb/c mice were used in the study. The Institute’s animal ethics committee approved the experimental proto- col, which met the national guidelines (Indian National Science Academy, 2000). (^ )-Bay K8644 was adminis- tered i.p. (0.1, 0.3, 1, 2, 3 and 10 mg/kg, RBI-Sigma). Nicardipine (10 mg/kg, i.p., Sigma, St. Louis, MO) was administered 45 min prior to (^ )-Bay K8644 injections. (^ )-Bay K8644 (1–10 mg/kg) caused behavioral aberra- tions in mice within 5 min. Behavioral manifestations such as convulsion, tremor, forelimb and hindlimb extension, forepaw treading, back peddling, vocalization, Straub tail, hyperactivity and self-mutilation were ranked as not present, mild or severe by two independent observers for 1 h, who are trained in evaluating animal behaviors. 0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00238-6 Neuroscience Letters 342 (2003) 73–76 www.elsevier.com/locate/neulet * Corresponding author. Tel.: þ91-33-2413-3223; fax: þ 91-33-2473- 5197/2472-3967. E-mail address: mohankumar@iicb.res.in (K.P. Mohanakumar).