Deletion of N-Type Calcium Channels Alters Ethanol Reward and Reduces Ethanol Consumption in Mice

Abstract

N-type calcium channels are modulated by acute and chronic ethanol exposure in vitro at concentrations known to affect humans, but it is not known whether N-type channels are important for behavioral responses to ethanol in vivo. Here, we show that in mice lacking functional N-type calcium channels, voluntary ethanol consumption is reduced and place preference is developed only at a low dose of ethanol. The hypnotic effects of ethanol are also substantially diminished, whereas ethanol-induced ataxia is mildly increased. These results demonstrate that N-type calcium channels modulate acute responses to ethanol and are important mediators of ethanol reward and preference.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…In contrast with Ca V 2.1 null mice, Ca V 2.2 deficiency leads to only mild consequences, which include reduced pain hypersensitivity in models of inflammatory and neuropathic pain (Hatakeyama et al, 2001;Kim et al, 2001a;Saegusa et al, 2001), hyperactivity (Beuckmann et al, 2003), reduced anxiety (Saegusa et al, 2001), a reduction of voluntary alcohol intake (Newton et al, 2004), and problems with blood pressure control . The effects of Ca V 2.2 channel deletion on pain are consistent with the notion that Ca V 2.2 channels are critical for neurotransmitter release from afferent terminals in the spinal dorsal horn (for review, see Bourinet et al, 2014), and these findings validate Ca V 2.2 channels as potential targets for analgesics.…”

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…The NVDCC blocker ziconotide is a powerful analgesic drug approved for the treatment of severe chronic pain in humans (McGivern 2007), and other NVDCC blockers are being developed for use in humans to treat stroke and pain (Giordanetto et al, 2011). Such blockers might also help treat addiction, since rodent studies have shown that NVDCCs promote alcohol intake (Newton et al, 2004) and that NDVCC blockers are antinociceptive, potentiate morphine analgesia, and attenuate morphine tolerance and physical dependence and withdrawal (Meng et al, 2008). Also, NP078585, a blocker of NVDCCs and TVDCCs in human trials for chronic pain, reduces the intoxicating and reinforcing effects of ethanol and abolishes stressinduced reinstatement for alcohol in rats (Newton et al, 2008).…”

Developmentally Regulated Actions of Alcohol on Hippocampal Glutamatergic Transmission

“…Through their modulation, ethanol inhibits dopamine release from rat striatal synaptosomes (Woodward et al, 1990), vasopressin release from rat neurohypophysial nerve terminals (Wang et al, 1991), and depolarization-induced rises in [Ca 2ϩ ] i in PC12 cells (Solem et al, 1997). Importantly, mice lacking N-type channels display reduced voluntary ethanol consumption, decreased sensitivity to its hypnotic effects, and a mild increase in ethanolinduced ataxia (Newton et al, 2004).…”