Cocaine- and Amphetamine-Regulated Transcript Peptide Modulation of Voltage-Gated Ca²⁺Signaling in Hippocampal Neurons

Abstract

Administration of cocaine and amphetamine increases cocaine- and amphetamine-regulated transcript (CART) expression in the rat striatum (Douglass et al., 1995). CART mRNA is highly expressed in different parts of the human and rat brain, including hippocampus (Douglass et al., 1995; Couceyro et al., 1997; Kuhar and Yoho, 1999; Hurd and Fagergren, 2000). The presence of CART peptide 55-102 immunoreactivity in dense core vesicles of axon terminals suggests that the peptide may be released and may act as a neuromodulator (Smith et al., 1997) to induce neurophysiological and behavioral effects. Little is known, however, about CART peptide-responsive cells, receptor(s), or intracellular signaling mechanisms that mediate CART peptide action. Here we show that CART peptide 55-102 inhibits voltage-dependent intracellular Ca(2+) signaling and attenuates cocaine enhancement of depolarization-induced Ca(2+) influx in rat hippocampal neurons. The inhibitory effect of CART peptide 55-102 on Ca(2+) signaling is likely mediated by an inhibition of L-type voltage-gated Ca(2+) channel activity via a G-protein-dependent pathway. These results indicate that voltage-gated Ca(2+) channels in hippocampal neurons are targets for CART peptide 55-102 and suggest that CART peptides may be important in physiology and behavior mediated by the hippocampus, such as certain forms of learning and memory.

Injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens reduces cocaine self-administration in rats

“…A CART receptor has been revealed by CART's induction of signaling. An inhibition of L-type voltage-gated calcium channels by CART peptide has been reported in cultured rat hippocampal neurons [ 40 ]. Specific CART peptide receptor binding has been identified in AtT20 cells [ 36 ], PC12 cells [ 27 ], HepG2 cells, hypothalamic dissociated cells [ 20 ], and in primary cultures of NAcc neurons [ 19 ].…”

“…Rats were then switched to a progressive ratio (PR) schedule of reinforcement. Under this schedule, response requirements for each successive presentation of a reinforcer increased progressively in the following series: 1, 2, 4,6,9,12,15,20,25,32,40,50,62,77,95,118,145,178,219,268,328,402,492,603,737,901. Break point (BP) was determined in the cocaine experiment as the last ration achieved before 1 hr had lapsed without reinforcement with a maximum session length of 5 hr.…”

Acid-Sensing Ion Channels Contribute to the Effect of Acidosis on the Function of Dendritic Cells

“…The procedure for whole-cell patch-clamp recording was performed as described in our previous studies (28,29), with minor modification. The bath solution for recording ASIC currents contained NaCl 150 mM, KCl 5 mM, MgCl 2 1 mM, CaCl 2 2 mM, HEPES 10 mM, and glucose 10 mM; pH was adjusted to 7.4 with NaOH.…”

Cocaine Increases Dopamine Release by Mobilization of a Synapsin-Dependent Reserve Pool

“…Cocaine is known to increase dopamine release from striatal terminals even when isolated from their cell bodies (Lee et al, 2001), meaning that cocaine must act locally within the presynaptic terminal. In some cells, cocaine can enhance presynaptic Ca 2ϩ influx (Premkumar, 1999;Yermolaieva et al, 2001), and chronic administration of cocaine increases the sensitivity of released dopamine to Ca 2ϩ channel blockers (Pierce and Kalivas, 1997). It is thought that Ca 2ϩ -dependent phosphorylation of synapsins is required for mobilization of vesicles from the reserve pool during electrical stimulation (Greengard et al, 1993).…”