Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers

Abstract

Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective. Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. Flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.

Cocaine‐induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese‐enhanced MRI

“…Aberrant Ca 2+ channel activity in neurons of the reward circuitry is well established as a mechanism of cocaine action in the animal literature (41)(42)(43)(44), and genes involved in Ca 2+ regulation play a role in the pathophysiology of cocaine addiction (19). For example, in animals, Ca 2+ channel blockers decrease behavioral sensitization to cocaine and reduce cocaine-mediated synaptosomal Ca 2+ transport in the NAC (45). Cocaine-induced reward and psychological dependence behavior, as measured in the conditioned place preference paradigm, is blocked by intracerebroventricular administration of the LTCC blocker nifedipine, with this effect also reported for morphine-and methamphetamine-induced reward behavior (46).…”

CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease

“…Repeated micro-injections of LTCC dihydropyridine agonist BayK 8644 in the VTA of rats resulted in an increased behavioral response to cocaine (Licata et al, 2000), and BayK 8644-induced stimulation of LTCCs in the caudate putamen increases extracelluar dopamine levels as measured by microdialysis (Okita et al, 2000). Additionally, it has been shown that peripheral administration of dihydropyridine antagonists attenuates sensitization to stimulants (Biala and Weglinska, 2004; Mills et al, 2007). Some data suggest that Ca v 1.2 channels are important for the behavioral expression of sensitization, but not the development of sensitization (Giordano et al, 2010; Schierberl et al, 2011).…”

L‐type calcium channels and psychiatric disorders: A brief review

“…The majority of studies in animals, with a few exceptions [Schindler et al, 1995], underscored the possible role of systemic administration of LTCC antagonists in attenuating cocaineinduced rewarding effects, inhibiting cocaine-self-administration, and reducing cocaine-induced behavioral effects such as locomotor and stereotypic activity [Pani et al, 1991;Kuzmin et al, 1992;Schechter, 1993;Martellotta et al, 1994;Reimer and MartinIverson, 1994;Calcagnetti et al, 1995;Martin-Iverson et al, 1997;Mills et al, 2007]. Furthermore, Anderson et al [2008] have provided evidence that the pathophysiology of cocaine addiction could be, in part, explained by a D1 receptor-mediated activation of LTCCs in the nucleus accumbens.…”