Acquisition Of Alcohol Drinking Behavior Research Articles

Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats

Sigma-1 receptor (Sig-1R) has been proposed as a novel therapeutic target for drug and alcohol addiction. We have shown previously that Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while Sig-1R antagonists on the other hand block excessive drinking in genetic and environmental models of alcoholism, without affecting intake in outbred non-dependent rats. Even though significant progress has been made in understanding the function of Sig-1R in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. Administration of the selective Sig-1R antagonist BD-1063 dramatically reduced the acquisition of alcohol drinking behavior as well as the preference for alcohol in genetically selected TSRI Sardinian alcohol preferring (Scr:sP) rats; the treatment had instead no effect on total fluid intake, food intake or body weight gain, proving selectivity of action. Furthermore, BD-1063 dose-dependently decreased alcohol-seeking behavior in rats trained under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a conditioned reinforcer. Finally, an innate elevation in Sig-1R protein levels was found in the nucleus accumbens of alcohol-preferring Scr:sP rats, compared to outbred Wistar rats, alteration which was normalized by chronic, voluntary alcohol drinking. Taken together these findings demonstrate that Sig-1R blockade reduces the propensity to both acquire alcohol drinking and to seek alcohol, and point to the nucleus accumbens as a potential key region for the effects observed. Our data suggest that Sig-1R antagonists may have therapeutic potential in multiple stages of alcohol addiction.

Reducing effect of the positive allosteric modulators of the GABA B receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats

The γ-aminobutyric acid B (GABA B) receptor full agonists, baclofen and CGP44532, have been found to suppress different aspects of alcohol drinking behavior, including acquisition and maintenance, in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to assess whether this capability extends to the recently synthesized, positive allosteric modulators of the GABA B receptor, 2,6-Di- tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N, N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783). In the “acquisition” experiments, CGP7930 (0, 25, 50 and 100 mg/kg; i.g.) and GS39783 (0, 6.25, 12.5 and 25 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-naive sP rats. In the “maintenance” experiments, (0, 50 and 100 mg/kg; i.g.) and GS39783 (0, 50 and 100 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-experienced sP rats. Alcohol intake was evaluated under the standard, homecage 2-bottle “alcohol (10%, v / v) vs water” regimen with unlimited access for 24 h/day. Both CGP7930 and GS39783 dose-dependently suppressed the acquisition of alcohol drinking behavior. In the “maintenance” experiments, CGP7930 and GS39783 reduced daily alcohol intake by 30–40% only at the highest dose when compared to vehicle-treated rats; this effect tended to vanish on continuing treatment. The results of the present study suggest that positive allosteric modulation of the GABA B receptor produced an effect on alcohol drinking behavior similar to that produced by GABA B receptor full agonists. These data also suggest that positive allosteric modulation of the GABA B receptor may constitute a potential strategy for developing new drugs for treating alcohol dependence.

Voluntary alcohol intake in two rat lines selectively bred for learned helpless and non-helpless behavior

A high comorbidity between depression and alcoholism has been reported in several studies, but the mechanisms underlying this relationship remain unknown. We tested whether learned helplessness in rats as a model for depression is associated with enhanced alcohol intake and relapse behavior. Congenital learned helplessness (cLH) and congenital non-learned helplessness (cNLH) rats were selectively bred for differences in an escape paradigm. Sucrose preference was tested at the first hour of the dark phase. In order to study an association with alcohol drinking behavior, rats underwent a free-choice procedure with access to water, and 5% and 20% alcohol solutions for 6 weeks. After acquisition of alcohol drinking behavior, the alcohol deprivation effect (ADE) was assessed. Sensitivity to the sedative-hypnotic effect of alcohol was measured by loss of the righting reflex. cLH rats showed significantly lower preference for sucrose solutions during the second half hour of the dark phase than cNLH rats. Alcohol intake of male cLH rats was not significantly different from that of male cNLH rats. In contrast, cLH female rats consumed higher amounts of alcohol than female cNLH rats. The ADE was more pronounced in female animals, although the magnitude of the ADE was similar in both cNLH and cLH female rats. The time to regain the righting reflex was significantly higher in both male and female cLH rats than in cNLH rats. In summary, these data suggest that an inborn depressive-like behavior in female rats is associated with enhanced alcohol intake.

Effect of the combination of naltrexone and baclofen, on acquisition of alcohol drinking behavior in alcohol-preferring rats

Recent surveys suggest that positive outcomes in the pharmacotherapy of alcoholism may be obtained through drug combinations. The present study evaluated the effect of the combination of the opioid receptor antagonist, naltrexone, with the GABA B receptor agonist, baclofen, on the acquisition of alcohol drinking behavior in Sardinian alcohol-preferring (sP) rats. Rats were treated with either saline, 0.5 mg/kg naltrexone, 1 mg/kg baclofen, or 0.5 mg/kg naltrexone plus 1 mg/kg baclofen once a day for 10 days. Alcohol was offered immediately after the first drug injection under the 2-bottle regimen. Alcohol intake in saline-treated rats rose to 5–6 g/kg/day within a few days, indicative of a rapid acquisition of alcohol drinking behavior. Neither naltrexone nor baclofen, when given alone, affected alcohol drinking behavior. In contrast, the drug combination resulted in a significant reduction in daily alcohol intake and retardation in the acquisition of alcohol drinking behavior. These results suggest that combination of naltrexone plus baclofen may result in a synergistic reduction in alcohol intake in sP rats. These results are discussed in terms of naltrexone and baclofen exerting a concomitant and reciprocally potentiating inhibitory action on alcohol-induced activation of mesolimbic dopamine transmission.

IDN 5082, a standardized extract of Salvia miltiorrhiza, delays acquisition of alcohol drinking behavior in rats

Recent research demonstrated that extracts from the dried roots of Salvia miltiorrhiza, a valued folk medicine in China, are effective in reducing voluntary alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats. These studies were conducted in alcohol-experienced sP rats, i.e. rats which had the opportunity to consume alcohol for several weeks before the test with Salvia miltiorrhiza extracts, reproducing the human “active drinking” phase. In contrast, the present study investigated the effect of IDN 5082, a standardized extract of S. miltiorrhiza, on the acquisition of alcohol drinking behavior in sP rats that had never experienced alcohol before the study. Consistently, the first administration of IDN 5082 (0, 25, 50 and 100 mg/kg; i.g.) occurred immediately before alcohol presentation. Alcohol was offered under the two-bottle free-choice regimen with unlimited access for 24 h per day. Treatment with IDN 5082 was repeated once daily for 10 consecutive days. IDN 5082 dose-dependently delayed acquisition of alcohol drinking behavior; IDN 5082-induced reduction in alcohol intake was compensated by an increase in water intake. These results add further support to the preclinical anti-alcohol profile of S. miltiorrhiza extracts.

The cannabinoid receptor antagonist SR 141716 prevents acquisition of drinking behavior in alcohol-preferring rats

The cannabinoid CB 1 receptor antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide) (SR 141716); 0.3–3 mg/kg, i.p., twice daily for 10 days), prevented the acquisition of alcohol drinking behavior in rats genetically selected for alcohol preference (Sardinian alcohol-preferring (sP) rats), having the free choice between alcohol (10%, v/v) and water. The results suggest that activation of cannabinoid CB 1 receptors is essential for the acquisition of alcohol drinking behavior in animals with a genetically determined alcohol preference.

Effect of vasopressin-like peptides on consumption of ethanol by the rat

Rats were trained to accept ethanol in their drinking water, by succesive small increments or decrements in alcohol concentration in response to the individual consumption of each rat. Those injected with desglycinamide 9-lysine 8-vasopressin (DGLVP), 1–4 μg SC every second day, attained almost twice as high a final acceptance concentration (FAC) and mean daily ethanol intake (g/kg) as vehicle-treated controls. Hypophysectomized animals initially accepted the same alcohol concentrations as intact rats, but drank much larger volumes and correspondingly higher daily g/kg intakes. However, this was rapidly succeeded by rejection of all but very low concentrations, which was unaffected by DGLVP. During a subsequent free-choice period (water vs. ethanol at individual FACs), the groups maintained their relative positions with respect to ethanol intake. This was not altered by injection of vasopressin in the hypophysectomized rats, but was overcome by raising the alcohol concentration. The results suggest that vasopressin-like peptides facilitate acquisition of alcohol drinking behavior.