Alcohol, Cocaine, and Brain Stimulation‐Reward in C57Bl6/J and DBA2/J Mice

Abstract

Background Pleasure and reward are critical features of alcohol drinking that are difficult to measure in animal studies. Intracranial self-stimulation (ICSS) is a behavioral method for studying the effects of drugs directly on the neural circuitry that underlies brain reward. These experiments had 2 objectives: first, to establish the effects of alcohol on ICSS responding in the C57Bl6/J (C57) and DBA2/J (DBA) mouse strains; and second, to compare these effects to those of the psychostimulant cocaine. Methods Male C57 and DBA mice were implanted with unipolar stimulating electrodes in the lateral hypothalamus and conditioned to spin a wheel for reinforcement by the delivery of rewarding electrical stimulation (i.e., brain stimulation-reward or BSR). Using the curve-shift method, the BSR threshold (θ0) was determined immediately before and after oral gavage with alcohol (0.3, 0.6, 1.0, 1.7 g/kg) or water. Blood alcohol concentration (BAC) was measured to determine the influence of alcohol metabolism on BSR threshold. Separately, mice were administered cocaine (1.0, 3.0, 10.0, 30.0 mg/kg) or saline intraperitoneally. Results In C57 mice, the 0.6 g/kg dose of alcohol lowered BSR thresholds by about 20%, during the rising (up to 40 mg/dl), but not falling, phase of BAC. When given to the DBA mice, alcohol lowered BSR thresholds over the entire dose range; the largest reduction was by about 50%. Cocaine lowered BSR thresholds in both strains. However, cocaine was more potent in DBA mice than in C57 mice as revealed by a leftward shift in the cocaine dose–response curve. For both alcohol and cocaine, effects on BSR threshold were dissociable from effects on operant response rates. Conclusions In C57 and DBA mice, reductions in BSR threshold reflect the ability of alcohol to potentiate the neural mechanisms of brain reward. The DBA mice are more sensitive to the reward-potentiating effects of both alcohol and cocaine, suggesting that there are mouse strain differences in the neural mechanisms of brain reward that can be measured with the ICSS technique.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…C57BL/6 (Cazala et al, 1974). More recent comparisons of C57BL/6J and DBA/2J mice using hybrid frequency-rate procedures found no strain differences in ICSS thresholds, although maximal ICSS rates were greater in C57BL/6 mice (Elmer et al, 2010;Fish et al, 2010). In rats responding under a frequencyrate procedure, ICSS thresholds did not differ between Lewis, Fischer 344, and Sprague-Dawley rats, and in this study, maximal response rates also did not differ across strain (Lepore et al, 1996).…”

“…Effects of ethanol were examined in C57BL/6J and DBA/2J mice using a hybrid frequency-rate procedure. Administration of ethanol resulted in ICSS facilitation in each strain and did so across a broader range of doses and pretreatment times in DBA/2J mice compared with C57BL/6J mice (Fish et al, 2010). The ability of ethanol to facilitate ICSS in Abuse Potential Testing ICSS in C57BL/6J mice is consistent with its ability to maintain self-administration in this strain, but the effect in DBA/2J mice is inconsistent with data showing that ethanol does not maintain self-administration in this strain (Risinger et al, 1998).…”

“…With regard to strain differences on drug effects, amphetamine and cocaine produce abuse-related reductions in ICSS thresholds to similar degrees in both C57BL/6J and DBA/2J mice (Elmer et al, 2010;Fish et al, 2010). A study examining these strains along with BALB/c mice provided some evidence of potency differences for amphetamine effects on ICSS across these strains (BALB/c .…”

Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome

“…ICSS was performed as detailed previously (54). Briefly, mice (26 WT and 27 Ube3a m-/p+ mice) were anesthetized (120 mg/kg ketamine, 9 mg/kg xylazine; Hospira), and 0.25% bupivacaine (Hospira) was applied to the scalp incision site.…”

Different Contributions of Dopamine D1 and D2 Receptor Activity to Alcohol Potentiation of Brain Stimulation Reward in C57BL/6J and DBA/2J Mice

“…Both strains had similar BSR thresholds (Elmer et al, 2010;Fish et al, 2010) and no strain difference was found in amphetamine potency (Elmer et al, 2010); however, DBA mice were more sensitive to the threshold lowering effects of cocaine (Fish et al, 2010). Additionally, the two strains were differentially sensitive to morphine and alcohol.…”