Biochemical and behavioral evidence for an interaction between ethanol and calcium channel antagonists

Abstract

In the present series of experiments we have studied the effects of the dihydropyridine calcium channel antagonist nifedipine on ethanol-induced changes in behavior and dopamine (DA) release and metabolism. The locomotor-stimulatory effect of low doses of ethanol (2.5 g/kg) was antagonized by nifedipine, whereas ethanol-induced sedation observed after higher doses (4.5 g/kg) was potentiated. Biochemical studies indicated that ethanol enhanced the metabolism and release of DA in the striatum and the DA-rich limbic regions measured by post mortem analyses of DA-metabolites by HPLC with electrochemical detection and by in vivo voltammetry in anaesthetized rats, respectively. Pretreatment with nifedipine antagonized the stimulatory effects of ethanol on the DA-system. Nifedipine reduced the preference for ethanol, estimated by the relative intake of ethanol (6% v/v) and water in a free-choice situation, suggesting an influence of nifedipine not only on the stimulatory but also on the positive reinforcing effects of ethanol. The present results suggest that the locomotor-stimulatory and positive reinforcing effects of ethanol as well as its enhancing effect on dopaminergic activity may involve an enhancement of calcium mediated mechanisms.

The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice

“…Moreover, the alcohol-induced locomotor stimulation observed in wild type mice was significantly lower in ghrelin knockout mice. Alcohol-induced locomotor stimulation is regulated, at least in part, by its ability to enhance dopamine in the nucleus accumbens (Engel et al, 1988;Imperato and DiChiara, 1986;Wise and Bozarth, 1987). Thus whereas accumbal dopamine release provides a direct measure of activation of the mesolimbic dopamine system by alcohol, the locomotor stimulatory response provides a more indirect yet supportive measure of this activation.…”

“…We measured alcohol-induced locomotor activity as most drugs of abuse (including alcohol) cause locomotor stimulation, an effect mediated, at least in part, by their ability to enhance the extracellular concentration of accumbal dopamine (Engel et al, 1988;Imperato and DiChiara, 1986;Wise and Bozarth, 1987). It should however be emphasized that other neurotransmitters mediate alcohol-induced locomotor stimulation (Engel et al, 1992).…”

The role of the central ghrelin system in reward from food and chemical drugs

“…However, ghrelin may also enhance non-homeostatic feeding by interacting with key reward systems Perello et al 2010;Skibicka et al 2011a;Skibicka et al 2011b). The reward system, specifically the mesolimbic dopamine system, mediates a state of well-being of natural and chemical reinforcers; it enhances motivation behaviours such as food-seeking and is involved in the development of addiction to drugs of abuse (Engel et al 1988;Hansen et al 1991;Schultz et al 1997). When consumed in excess and over time food can cause the same brain neuroadaptations as drug abuse (Grigson 2002).…”

“…Interestingly, administration of a GHS-R1A antagonist into the VTA blocks the ability of ghrelin to increase food intake (Abizaid et al 2006) and to release dopamine in the N.Acc suggesting that ghrelin activates GHS-R1A expressed on dopaminergic cell bodies in the VTA. Given that accumbal dopamine release appears to mediate the rewarding properties of incentives (eg food and alcohol) (Engel et al 1988;Robinson and Berridge 1993;Wise and Bozarth 1987), the collective data showing that ghrelin targets this dopamine system implicates GHS-R1A directly in the reward mechanism.…”

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

“…Thus, LCCBs block development of conditioned place preference (CPP) (Suzuki et al, 1992;Biala and Langwinski, 1996;Shibasaki et al, 2010; but see MartinIverson et al, 1997), where CPP is thought to develop because the acute rewarding properties of abused drugs becomes paired with a particular environment. In addition, drug self-administration is likely maintained, at least in part, by the acute reinforcing effects of abused drugs (Everitt and Robbins, 2005;Sanchis-Segura and Spanagel, 2006), and LCCBs reduce self-administration of alcohol (Engel et al, 1988;Rezvani and Janowsky, 1990;Pucilowski et al, 1992;De Beun et al, 1996;Gardell et al, 1997;Cramer et al, 1998), cocaine (Kuzmin et al, 1992;Martellotta et al, 1994), and morphine (Kuzmin et al, 1992). LCCBs also reduce intake of sucrose (Calcagnetti and Schechter, 1992), saccharin (Pucilowski et al, 1992), and food (De Beun et al, 1996), suggesting that LCCBs might reduce reward more generally or perhaps have nonspecific effects on motor activity.…”