Biophysical and Pharmacological Characterization of Voltage- Dependent Ca Channels in Neurons Isolated From Rat Nucleus Accumbens

Churchill, Dennis and Brian A. MacVicar. Biophysical and phar(Berridge and Dupont 1994; Snutch and Reiner 1992; Tsien macological characterization of voltage-dependent Ca channels et al. 1988, 1991). in neurons isolated from rat nucleus accumbens. J. Neurophysiol. Ca currents have been classified into low-threshold 79: 635–647, 1998. The nucleus accumbens (NA) has an integ(Akaike 1991; Huguenard 1996), and high-threshold susrative role in behavior and may mediate addictive and psychotheratained and inactivating currents (Bean 1989; Carbone and peutic drug action. Whole cell recording techniques were used Swandulla 1989; Kostyuk 1989; Tsien et al. 1988). More to characterize electrophysiologically and pharmacologically highrecently, high-threshold Ca currents have been grouped and low-threshold voltage-dependent Ca currents in isolated NA into L, N, and P/Q types using biophysical and pharmaconeurons. High-threshold Ca currents, which were found in all logical tools; the latter includes peptide toxins found in inneurons studied and include both sustained and inactivating compovertebrate venom in addition to dihydropyridines (DHPs) nents, activated at potentials greater than 050 mV and reached maximal activation at Ç0 mV. In contrast, low-threshold Ca that have been well-characterized (Tsien et al. 1991). It has currents activated at voltages greater than 064 mV with maximal been demonstrated in many neurons that DHPs primarily activation occurring at 030 mV. These were observed in 42% of block L-type, v-conotoxin-GVIA blocks N-type, v-agaacutely isolated neurons. Further pharmacological characterization toxin-IVA blocks P/Q-type, and v-conotoxin-MVIIC blocks of high-threshold Ca currents was attempted using nimodipine N/P/Q-type Ca currents (Hillyard et al. 1992; Mintz et (Nim), v-conotoxin-GVIA (v-CgTx) and v-agatoxin-IVA al. 1992b; Sher and Clementi 1991; Tsien et al. 1991). An (vAga), which are thought to identify the L, N, and P/Q subtypes additional class of neuronal high-threshold Ca current has of Ca currents, respectively. Nim (5–10 mM) blocked 18%, been named the R-type current by some investigators due vCgTx (1–2 mM) blocked 25%, and vAga (200 nM) blocked to its resistance to block by the available toxins (Brown et al. 17% of total Ca current. Nim primarily blocked a sustained high1994; Eliot and Johnston 1994; Magee and Johnston 1995; threshold Ca current in a partially reversible manner. In contrast, Randall and Tsien 1995). vCgTx irreversibly blocked both sustained and inactivating components. vAga irreversibly blocked only a sustained component. The nucleus accumbens (NA), as an interface between In all three of these Ca channel blockers, plus 5 mM v-conotoxinthe limbic and extrapyramidal system, has an integrative role MVIIC to eliminate a small unblocked Q-type Ca current (7%), in behavior. It functions in selective attention, secondary a toxin-resistant high-threshold Ca current remained that was reinforcement, and reward (Carlsson and Carlsson 1990a; 32% of total Ca current. This current inactivated much more Pennartz et al. 1994). Interestingly, it may mediate the reinrapidly than the other high-threshold Ca currents, was depressed forcing effects of addictive drugs (Koob 1992) and possibly in 50 mM Ni and reached maximal activation 5–10 mV negative is involved in the pathogenesis and pharmacotherapy of to the toxin-sensitive high-threshold Ca currents. Thus NA neuschizophrenia (Andreasen 1994; Carlsson and Carlsson rons have multiple types of high-threshold Ca currents with a 1990b; Meltzer 1991). Both the NA and the related striatum large component being the toxin-resistant ‘‘R’’ component. ( involved in motor integration) are composed of GABAergic medium-spiny neurons and receive cortical excitatory input