L-TYPE CA 2+ CHANNEL ACTIVITY DETERMINES MODULATION OF GABA RELEASE BY DOPAMINE IN THE SUBSTANTIA NIGRA RETICULATA AND THE GLOBUS PALLIDUS OF THE RAT S. RECILLAS-MORALES, c L. SA ´ NCHEZ-VEGA, a N. OCHOA-SA ´ NCHEZ, a I. CABALLERO-FLORA ´ N, a F. PAZ-BERMU ´ DEZ, a I. SILVA, d J. ACEVES, a D. ERLIJ b AND B. FLORA ´ N a * a Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico b Department of Physiology, SUNY Downstate Medical Center, NY, USA c Department of Pharmacology, CINVESTAV-IPN, Mexico d Facultad de Ciencias Naturales, Universidad Auto ´noma de Quere ´taro, Qro, Mexico Abstract—Modulation of L-type Ca 2+ -channel function by dopamine is a major determinant of the rate of action potential firing by striatal medium spiny neurons. However, the role of these channels in modulating GABA release by nerve termi- nals in the basal ganglia is unknown. We found that depolar- ization-induced [ 3 H]GABA release in both the substantia nigra reticulata and the external globus pallidus (GPe), was depressed by about 50% by either the selective L-channel dihydropyridine blocker nifedipine or the P/Q channel blocker x-agatoxin TK. The effects of these blockers were additive and together eliminated about 90% of depolarization-induced [ 3 H]GABA release. In addition, in the substantia nigra reticula- ta, dihydropyridines prevented both the stimulation of [ 3 H]GABA release produced by dopamine D1 receptor activa- tion and the inhibition caused by D4 receptor activation. In the GP nifedipine blocked the effects of D2 and A2 A receptor coactivation as well as the effects of activating adenylyl cyclase with forskolin. x-Agatoxin TK did not interfere with the action of these modulatory agents. The L-type Ca 2+ -channel agonist BAYK 8644 stimulated GABA release in both substantia nigra reticulata and GP. Because dihydropyridine sensitivity is a key criterion to identify L-type Ca 2+ -channel activity, our results imply that these channels are determinant of GABA release modulation by dopamine in striatonigral, striatopallidal and pallidonigral terminals. Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: basal ganglia, L-type Ca 2+ channel, dihydropyridines, P/Q-type Ca 2+ channel, presynaptic dopamine receptors. INTRODUCTION Loss of dopamine in the basal ganglia leads to Parkinson’s disease. The largest structure in the basal ganglia is the striatum. Dopamine release by projections of the substantia nigra pars compacta (SNc) modulates excitability of the neurons in the striatum and controls transmitter release by their projections. More than 90% of the nerve cells in this structure are GABAergic medium spiny neurons (MSNs) (Parent and Hazrati, 1995a). These neurons form two populations that are distinguished by the separate targets of their efferents and by different mechanisms of dopamine signaling. One population projects to the output structures of the basal ganglia substantia nigra pars reticulata (SNr) and internal globus pallidus (GPi) and expresses dopamine D1 (D1Rs), D3 receptors (D3Rs) and substance P (SP + ). The other, projects to the external GP (GPe) and expresses dopamine D2 receptors (D2Rs) and enkephalin (Enk + )(Surmeier et al., 1996). Dopamine modulates striatal cell body excitability via changes in the L-Ca 2+ channel function (Herna´ndez- Lo´pez et al., 1997, 2000). However, it is not known whether L-Ca 2+ channels are involved in the modulation of GABA release by dopamine in striatal cell terminals. In striatonigral projections activation of D1Rs stimulates GABA release (Floran et al., 1990; Radnikow and Misgeld, 1998; Nava-Asbell et al., 2007; Acosta-Garcia et al., 2009). In striatopallidal terminals dopamine activates D2Rs that depress GABA release (Floran et al., 1997; Cooper and Stanford, 2001). In addition in the SNr, dopamine inhibits GABA release by activating D4Rs present in pallidonigral projections (Acosta-Garcia et al., 2009; Aceves et al., 2011; Cruz-Trujillo et al., 2013). The role of L-Ca 2+ channel in dopamine action in the basal ganglia function may also be relevant to the understanding of the physiopathology and therapy of Parkinson’s disease because recent studies show that blockade of L-Ca 2+ channels appears to be beneficial in the management of the disease (Schuster et al., 2009; Ritz et al., 2010). EXPERIMENTAL PROCEDURES Animals Male Wistar rats (180–200 g) housed together (five per cage) with water and food available ad libitum and kept under a natural light cycle were used throughout. All the procedures were carried out in accordance with the 0306-4522/13 $36.00 Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuroscience.2013.10.037 * Corresponding author. Tel: +52-55-5747-3800x5137; fax: +52-55- 7473754. E-mail addresses: bfloran@fisio.cinvestav.mx, bfloran@live.com.mx (B. Flora´n). Abbreviations: A 2A Rs, adenosine A 2A receptors; ACSF, artificial cerebrospinal fluid; D1Rs, dopamine D1 receptors; Enk + , enkephaline; GP, globus pallidus; GPe, external GP; MSNs, medium spiny neurons; SNr, substantia nigra pars reticulata. Neuroscience 256 (2014) 292–301 292