Delta-opioid and 5-HT3 receptor antagonist effects on ethanol reward and discrimination in C57BL/6 mice.

The effects of the receptor antagonists MDL 72222 (MDL, 5-HT3) and naltrindole (delta-opioid) on ethanol reward and its discrimination were examined in ethanol-preferring C57BL/6 (C57) mice. MDL attenuated lever responding for 12% ethanol delivered on a fixed-ratio 8 reinforcement schedule at a dose that did not influence responding for water reward, thus confirming a previous report that ICS 205-930 reduced ethanol reward for Long-Evans rats. Our study in combination with the reduced ethanol consumption reported for C57 mice injected with odansetron indicates that 5-HT3 receptor systems are involved in mediating behavior directed toward obtaining ethanol as well as its consumption. By attenuating the rewarding effects of ethanol or of ethanol conditioned cues (e.g., the operant environment), 5-HT3 antagonists may be useful in the treatment of alcohol abuse. The 5-HT3 antagonist effects in this study are comparable with the effects of naltrexone on ethanol reward in C57 mice, although higher doses were required to reduce operant responding for ethanol reward. In contrast to the 5-HT3 antagonist and naltrexone effects, naltrindole, an antagonist with greater specificity for the delta-opioid receptor, was without effect on ethanol reward. This result and recent reports for rats and monkeys suggests that the general antagonists might be more efficacious in attenuating ethanol reward. Both MDL and naltrindole produced only slight reductions in the ethanol discriminative cue, suggesting that the rewarding and discriminative effects of ethanol are not likely mediated by identical neural mechanisms as previously suggested.

Naltrexone effects on ethanol reward and discrimination in C57BL/6 mice.

The effects of the opioid antagonist, naltrexone, on operant responding for oral ethanol reward delivered on a fixed-ratio schedule, and on the discriminative stimulus properties of intraperitoneally injected ethanol, was examined in two separate experiments. The ages, food/water motivational conditions, and naltrexone doses for the two experiments were similar to allow a direct comparison of naltrexone effects on the two measures. Male food-deprived C57BL/6 mice responded for ethanol during either preprandial (low thirst, high hunger motivation) or postprandial (high thirst, low hunger motivation tests). The reinforcing value of ethanol relative to water was greater during the preprandial tests; however, the amounts of ethanol consumed was greater during the postprandial tests, with some mice becoming unconscious during the 15-min test session. Naltrexone produced dose-responsive reductions in responding for ethanol under either testing condition. During postprandial tests, naltrexone reduced responding for ethanol reward at a dose (1.25 mg/kg) that had little effect on responding for water reward, suggesting some selectivity for ethanol reward. In addition, doses of naltrexone that reduced responding for ethanol rewards did not alter the discrimination of ethanol (g/kg) in an operant discrimination task, but did reduce the total number of responses made during these tests. Thus, under similar motivational and dosing conditions, the opiate antagonist attenuated the reinforcing, but not the discriminative properties of ethanol, suggesting that the latter is mediated by either different or additional neural mechanisms in C57BL/6 mice.

Cocaine discrimination: relationship to local anesthetics and monoamine uptake inhibitors in C57BL/6 mice.

Although the discriminative properties of cocaine have been examined extensively in rats, and to a lesser extent in other species, there are currently no reports on cocaine discrimination by mice. In one of our experiments, C57BL/6 (C57) mice acquired cocaine discrimination (10 mg/kg training dose) and exhibited dose responsive generalization to lower doses of the drug, which was similar to previous reports using rats. In addition, mazindol, a general monoamine uptake inhibitor similar to cocaine, and nomifensine, which is relatively specific for the dopamine transporter, substituted completely for cocaine, as described for rats. In contrast, there was little substitution evidenced by monoamine uptake inhibitors relatively specific for the norepinephrine transporter (nisoxetine) or for the serotonin transporter (fluoxetine), or by the local anesthetics procaine or lidocaine. In our second experiment, neither cocaine nor mazindol substituted for procaine in animals trained to discriminate the local anesthetic (100 mg/kg) although lidocaine substituted completely for the procaine cue. These experiments emphasize the importance of the dopamine transporter in mediating the discriminative stimulus effects of cocaine in C57 mice. The lack of cross generalization between cocaine and procaine suggests that the anesthetic properties of cocaine contribute little toward its discrimination by this mouse strain.

Long-term intracranial cannula stabilization in mice with light cured resin composites.

A simple and rapid method is described for the introduction and stabilization of chronic indwelling cannulae in mice. Materials and adhesive bonding techniques commonly used in restorative dentistry were used to stabilize the cannulae. The effectiveness of this method was evaluated by shear strength testing across time and histological evaluation of coronal brain sections. Shear strength increased during the first week post surgery and remained stable for up to 60 days. The force required to dislodge the cannulae from skulls ranged from 0.70 to 2.45 kg. Histological evaluation revealed no significant infection or inflammatory response due to the materials used. Cannulae stabilization by this technique appears to be suitable for most experimental conditions.

Prenatal cocaine exposure increases the reinforcing strength of oral ethanol in C57 mice.

Pregnant C57BL/6J mice received daily injections of 10 mg/kg cocaine or saline during gestation days 12-18. Although a previous report indicated that this dose of cocaine did not alter maternal weight gain, birth weight, growth, or adult weight, the present study indicates that it did increase the reinforcing efficacy of ethanol in fully mature male and female offspring. Food-deprived subjects responded on fixed ratio-8 (FR-8) and progressive ratio-2 (PR-2) schedules of reinforcement for 10-, 5-, or 3-s access to various ethanol concentrations. The male prenatal cocaine-exposed mice tended to have higher response totals under the FR-8 schedule and higher breaking-points during some PR-2 tests, with the greatest difference between groups occurring at the highest ethanol concentration. The female prenatal cocaine-exposed mice consumed more ethanol than controls during most of the tests, and had higher breaking-points compared to controls during the more demanding PR-2 tests. Thus, it appears that a dose of cocaine that has no observable effect on many maternal and perinatal outcome measures can alter systems mediating ethanol reward.

The discrimination and durability of an ethanol cue in young and mid-aged female mice.

Young adult (6 months) and mid-aged (12 months) C57BL/6 mice both learned to discriminate ethanol (ETOH, 1.0 g/kg) although criterion performance occurred later for mid-aged mice. ETOH discrimination improved with increasing dose (0.25-1.0 g/kg) and the dose-response function was unaffected by age. The ETOH cue had declined by 40 min postinjection for young mice not unlike a previous report for young rats. In contrast, the ETOH cue remained discriminable at 40 min for mid-aged mice, an effect perhaps due to their slower rate of ETOH metabolism and accountable for the previously reported reduction in ethanol consumption by mid-aged mice. Retention tests and reacquisition training both indicated that the ETOH cue can be retained by both age groups for at least 60 days without discrimination training or food deprivation. The present study suggests that the ethanol discriminative cue in mid-aged mice does not differ from that in young adult mice in potency but is more long lasting, the latter perhaps being related to their reduced ethanol consumption. Of significance from a therapeutic perspective, is that the ETOH cue remained discriminable for 2 months in both age groups (i.e., approximately 1/12 of their total life span).