Adolescent ethanol exposure and differential rearing environment affect taste reactivity to ethanol in rats.

The identification and characterization of variables that influence "liking" and enhance vulnerability to repeated alcohol use are vital to understanding and treating alcohol use disorders. In the current study, we explore the influence of rearing environment and experimenter-administered adolescent ethanol on the hedonic value of ethanol, sucrose, and quinine. Male and female rats were reared for 30 days starting at postnatal day (PND) 21 in either an enriched, isolated, or standard condition and received 1.5 g/kg (intraperitoneally [i.p.]) 20% (w/v) ethanol or saline every other day for 12 days starting at PND 28. Thereafter, all rats had indwelling intraoral fistulae implanted and their taste reactivities to water, ethanol (5, 10, 20, 30, 40% v/v), sucrose (0.1, 0.25, 0.5 M), and quinine (0.1, 0.5 mM) were recorded and analyzed. Results indicated that enrichment elevated hedonic responding to sucrose compared to isolation, and induced a stronger negative relationship between hedonic responding and ethanol concentration compared to standard conditions. Enrichment also elevated aversive responding to ethanol and quinine compared to both isolated and standard condition rats. Adolescent ethanol injections marginally reduced aversive responding to quinine. These results replicate previous findings that environmental enrichment enhances both "liking" and aversion. In addition, the current findings suggest that, while adolescent ethanol injections may blunt aversive responses to quinine, they have no effect on aversive or hedonic responding to ethanol or sucrose. Together with existing literature, our results may suggest that experience with the taste of ethanol is necessary for alterations to ethanol "liking" and aversion.

Differential rearing alters taste reactivity to ethanol, sucrose, and quinine.

RATIONALE: Early-life environment influences reinforcer and drug motivation in adulthood; however, the impact on specific components of motivation, including hedonic value ("liking"), remains unknown. OBJECTIVES: The current study determined whether differential rearing alters liking and aversive responding to ethanol, sucrose, and quinine in an ethanol-naïve rat model. METHODS: Male and female rats were reared for 30 days starting at postnatal day 21 in either an enriched (EC), isolated (IC), or standard condition (SC). Thereafter, all rats had indwelling intraoral fistulae implanted and their taste reactivity to water, ethanol (5, 10, 20, 30, 40% v/v), sucrose (0.1, 0.25, 0.5 M), and quinine (0.1, 0.5 mM) was recorded and analyzed. RESULTS: EC rats had higher amounts of liking responses to ethanol, sucrose, and quinine and higher amounts of aversive responses to ethanol and quinine compared to IC rats. While EC and IC rats' responses were different from each other, they both tended to be similar to SCs, who fell in between the EC and IC groups. CONCLUSIONS: These results suggest that environmental enrichment may enhance sensitivity to a variety of tastants, thereby enhancing liking, while isolation may dull sensitivity, thereby dulling liking. Altogether, the evidence suggests that isolated rats have a shift in the allostatic set-point which may, in part, drive increased responding for a variety of rewards including ethanol and sucrose. Enriched rats have enhanced liking of both sucrose and ethanol suggesting that enrichment may offer a unique phenotype with divergent preferences for incentive motivation.

Voluntary ethanol consumption during early social isolation and responding for ethanol in adulthood.

Little is known about the influence of rearing environments concurrent with voluntary intermittent access to ethanol on subsequent adult ethanol-related behaviors. Previous research has shown that adult rats reared in post-weaning, social isolation conditions (IC) respond more for operant ethanol compared to laboratory standard conditions (SC). Ethanol-exposed adolescents tend to consume more ethanol in adulthood than rats exposed as adults. The current study examined voluntary ethanol consumption during adolescence between IC and SC rats, subsequent operant responding for ethanol, and extinction of responding in the same rats as adults. Differences in ethanol metabolism may alter the amount of reward value per unit of ethanol consumed. Therefore, the current study also examined blood ethanol concentrations (BEC) between IC rats and SC rats. Ethanol-naïve Long-Evans rats arrived in the lab at postnatal day (PND) 21 and were separated into either IC or SC where they remained for the duration of the experiments. On PND 27, rats received intermittent access to 20% ethanol (3 days/week) for 4 or 6 weeks. Rats in the 6-week cohort were then trained to lever press for 20% ethanol in 30-min sessions followed by extinction. A separate cohort was reared in IC or SC, injected with 1.5 or 3.0 g/kg of ethanol (intraperitoneally [i.p.]), followed by BEC measurement. Overall, IC rats had higher ethanol preference and consumption during adolescence/early adulthood. IC and SC rats did not differ in their rates of operant responding for ethanol, and SC rats responded more than IC rats during extinction. There were no differences in BEC between IC and SC rats. These findings highlight the importance of the environment during rat adolescent development with isolation conditions increasing binge-like drinking and ethanol preference after 3-4 weeks without differences in metabolism as a potential factor. Additionally, the findings indicate that intermittent adolescent access to ethanol may change typical differences in operant responding patterns between IC and SC rats in adulthood.

Dopamine D(3) receptor antagonist SB-277011A inhibits methamphetamine self-administration and methamphetamine-induced reinstatement of drug-seeking in rats.

We have previously reported that selective blockade of brain dopamine D(3) receptors by SB-277011A significantly attenuates cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. In the present study, we investigated whether SB-277011A similarly inhibits methamphetamine self-administration and methamphetamine-induced reinstatement to drug-seeking behavior. Male Long-Evans rats were allowed to intravenously self-administer methamphetamine (0.05 mg/kg/infusion) under fixed-ratio 2 (FR2) or progressive-ratio (PR) reinforcement conditions, and some rats were tested for methamphetamine-induced reinstatement of drug-seeking behavior after extinction of self-administration. The effects of SB-277011A on each of these methamphetamine-supported behaviors were then tested. Acute intraperitoneal (i.p.) administration of SB-277011A failed to alter methamphetamine self-administration under FR2 reinforcement, but significantly lowered the break-point for methamphetamine self-administration under PR reinforcement. SB-277011A also significantly inhibited methamphetamine-triggered reinstatement of extinguished drug-seeking behavior. Overall, these data show that blockade of dopamine D(3) receptors by SB-277011A attenuates the rewarding and incentive motivational effects of methamphetamine in rats, supporting the development of selective dopamine D(3) antagonists for the treatment of methamphetamine addiction.

Differential rearing conditions and alcohol-preferring rats: consumption of and operant responding for ethanol.

Exposing rats to differential rearing conditions during early postweaning development has been shown to produce changes in a number of behaviors displayed during adulthood. The purpose of the present studies was to investigate whether rearing alcohol-preferring (P) and nonpreferring (NP) rats in an environmental enrichment condition (EC), a social condition (SC), or an impoverished condition (IC) would differentially affect self-administration of 10% ethanol. In Experiment 1, rats were tested for consumption of 10% ethanol in limited- and free-access tests. For Experiment 2, rats were trained to respond in an operant chamber for ethanol and then provided concurrent access to 10% ethanol and water. Each solution was presented in a separate liquid dipper after meeting the schedule of reinforcement on distinct levers. After concurrent access tests, the water lever/dipper was inactivated and a progressive ratio (PR) schedule was initiated. Three successive solutions (10% ethanol, 15% ethanol, and 10% sucrose) were tested under the PR. For P rats, rearing in an EC reduced ethanol consumption, preference, and motivation to obtain ethanol, relative to P rats reared in an IC. Thus, exposure to a novel environment immediately after weaning acted to decrease the reinforcing properties of ethanol in an animal model for alcoholism.

PG01037, a novel dopamine D3 receptor antagonist, inhibits the effects of methamphetamine in rats.

Our previous studies have shown that the selective dopamine D(3) receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine- or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D(3) receptor antagonist PG01037 on methamphetamine self-administration, methamphetamine-associated cue-induced reinstatement of drug seeking and methamphetamine-enhanced brain stimulation reward. Rats were allowed to intravenously self-administer methamphetamine under fixed-ratio 2 and progressive-ratio reinforcement conditions, and then the effects of PG01037 on methamphetamine self-administration and cue-induced reinstatement were assessed. Additional groups of rats were trained for intracranial electrical brain stimulation reward and the effects of PG01037 and methamphetamine on brain stimulation reward were assessed. Acute intraperitoneal administration of PG01037 (3, 10, 30 mg/kg) failed to alter methamphetamine or sucrose self-administration under fixed-ratio 2 reinforcement, but significantly lowered the break-point levels for methamphetamine or sucrose self-administration under progressive-ratio reinforcement. In addition, PG01037 significantly inhibited methamphetamine-associated cue-triggered reinstatement of drug-seeking behavior and methamphetamine-enhanced brain stimulation reward. These data suggest that the novel D(3) antagonist PG01037 significantly attenuates the rewarding effects as assessed by progressive-ratio self-administration and brain stimulation reward, and inhibits methamphetamine-associated cue-induced reinstatement of drug-seeking behavior These findings support the potential use of PG01037 or other selective D(3) antagonists in the treatment of methamphetamine addiction.

Chronic naltrexone treatment and ethanol responsivity in outbred rats.

BACKGROUND: Acute naltrexone treatment in rats produces significant alterations in ethanol palatability (increase in the aversiveness of the solution) and ethanol consumption during tests of restricted access (decrease in consumption). The effects of chronic naltrexone exposure, accomplished by implantation of osmotic mini-pumps, were examined in the present study. METHODS: Rats were surgically implanted with intraoral fistulae for taste reactivity testing. The animals were given 2 bottles (distilled water and 10% ethanol, v/v) for 3, 2-week phases: Pre-Drug, Drug, and Post-Drug. After the Pre-Drug phase, rats were assigned to groups (counterbalanced based on ethanol intake) and implanted with a mini-pump containing saline, 7.5 mg/kg/d naltrexone, or 15 mg/kg/d naltrexone. The pumps were removed 2 weeks later. During each 2-week phase, taste reactivity tests with 10% ethanol were conducted at 1, 7, and 14 days (a total of 9 reactivity tests). RESULTS: The 7.5 mg/kg/d dose produced only minor effects on 10% ethanol reactivity and consumption during the Drug phase. The 15 mg/kg/d naltrexone dose generally shifted taste reactivity responding to 10% ethanol in a negative direction and produced a transient decrease in ethanol consumption. The 15 mg/kg/d group significantly increased ethanol consumption beyond the level of consumption by the Saline group when the pumps were removed, although the increase was delayed 48 hours. By the end of the Post-Drug period, this naltrexone group returned to control levels of ethanol consumption. CONCLUSIONS: Chronic naltrexone treatment at 15 mg/kg/d significantly decreased the palatability of a 10% ethanol solution, an effect seen even after drug withdrawal. Naltrexone had a minor effect on ethanol consumption during treatment but did decrease overall levels of fluid consumption. The significant increase in ethanol consumption postdrug by the high-dose naltrexone group, presumably due to receptor up-regulation during treatment, is important and understanding this effect and developing means of overcoming it within a clinical practice would be useful goals.

Differential rearing conditions alter operant responding for ethanol in outbred rats.

BACKGROUND: Differential rearing environments affect a number of behaviors displayed by rats in adulthood. For example, rats reared in an impoverished condition (IC; reared alone in hanging metal cages), social condition (SC; reared in standard shoebox cages, 2 per cage), or enriched condition (EC; reared in a large metal cage with bedding, 14 novel objects, and 10 cohorts) display clear differences in the amount of drug they consume and/or self-administer through operant responding. Animals reared in an EC consume greater amounts of ethanol compared with rats reared in an IC when provided free access, but it is not known how differential rearing conditions affect operant responding for ethanol. METHODS: Twenty-eight male Long-Evans rats were reared in 1 of 3 environments (IC, SC, or EC) during postnatal days 21 to 111. At the conclusion of the rearing period, all rats underwent sucrose/ethanol fading and then were tested for lever press responding for 10% ethanol as well as ethanol preference. RESULTS: Rats reared in an IC responded for 10% ethanol at significantly higher rates than SC and EC rats. A greater percentage of IC rats were able to switch lever responding when the ethanol availability was changed to a second lever. Lastly, the IC group was the only one to display a clear preference for 10% ethanol when both this fluid and water were available. CONCLUSION: Rats reared in an IC show greater proclivity to respond operantly for 10% ethanol compared with rats raised in either SC or EC (which did not differ from each other). These findings agree with a number of studies that have shown isolate reared animals to consume greater amounts of ethanol compared with their socially reared counterparts yet contrast some studies showing EC animals consume greater amounts of ethanol than IC rats. The current findings illustrate that rearing environment also plays an important role in an animal's proclivity to respond for ethanol.

Delta receptor antagonism, ethanol taste reactivity, and ethanol consumption in outbred male rats.

Naltrexone, a nonspecific opioid antagonist, produces significant changes in ethanol responsivity in rats by rendering the taste of ethanol aversive as well as producing a decrease in voluntary ethanol consumption. The present study investigated the effect of naltrindole, a specific antagonist of delta opioid receptors, on ethanol taste reactivity and ethanol consumption in outbred rats. In the first experiment, rats received acute treatment of naltrexone, naltrindole, or saline followed by the measurement of ethanol consumption in a short-term access period. The second experiment involved the same treatments and investigated ethanol palatability (using the taste-reactivity test) as well as ethanol consumption. Results indicated that treatment with 3 mg/kg naltrexone significantly affected palatability (rendered ethanol more aversive, Experiment 2) and decreased voluntary ethanol consumption (Experiments 1 and 2). The effects of naltrindole were inconsistent. In Experiment 1, 8 mg/kg naltrindole significantly decreased voluntary ethanol consumption but this was not replicated in Experiment 2. The 8 mg/kg dose produced a significant increase in aversive responding (Experiment 2) but did not affect ingestive responding. Lower doses of naltrindole (2 and 4 mg/kg) were ineffective in altering rats' taste-reactivity response to and consumption of ethanol. While these data suggest that delta receptors are involved in rats' taste-reactivity response to ethanol and rats' ethanol consumption, it is likely that multiple opioid receptors mediate both behavioral responses.

Ethanol familiarity and naltrexone treatment affect ethanol responses in rats.

In the present study, the effects of ethanol familiarity on the ability of naltrexone to alter ethanol palatability and consumption were examined. One group of rats was allowed continuous access to 10% vol/vol ethanol and water for 3 weeks. A second group received only water. At the end of this time, the groups were further subdivided and injected with either 3mg/kg naltrexone or saline (total of four groups; n=11-13 per group) before ethanol taste reactivity tests with 10% vol/vol ethanol and ethanol consumption tests. Results showed that naltrexone effectively decreased ingestive responding and increased aversive responding. Further, rats familiar with alcohol made more ingestive responses to 10% vol/vol ethanol. A significant interaction of drug treatment and familiarity was found in the data for aversive responses: naltrexone treatment produced more aversive responses in ethanol-familiar rats, whereas saline treatment resulted in fewer aversive responses in rats familiar with ethanol. Naltrexone treatment clearly reduced consumption of 10% vol/vol ethanol, although its effects were attenuated somewhat by ethanol familiarity. The present data indicate that both alcohol familiarity and naltrexone treatment affect ethanol reactivity and ethanol consumption in outbred rats. The interaction of naltrexone treatment and ethanol familiarity only for aversive reactivity and the lack of such an interaction for the consumption measures suggests that the mechanisms underlying ethanol reactivity and ethanol consumption may be dissociable at the neural level.

Ethanol palatability and consumption by high ethanol-drinking rats: manipulation of the opioid system with naltrexone.

Three experiments examined the effect of acute naltrexone treatment on both taste reactivity and consumption of ethanol in high ethanol-preferring rat lines: Alko Alcohol-Accepting (AA) rats (Experiments 1 and 2) and Alcohol-Preferring (P) rats (Experiment 3). A 3.0 mg/kg naltrexone dose was ineffective at altering ethanol palatability for either line, whereas 7.5 mg/kg was effective at reducing palatability of 10% ethanol for AA, but not P, rats, as reflected by both a decrease in ingestive responding and an increase in aversive responding. The effects of naltrexone on ethanol consumption were quite consistent: At both dosages, acute naltrexone treatment significantly decreased consumption of 10% ethanol. Termination of naltrexone resulted in an immediate increase in ethanol consumption to control levels. Results show that ethanol palatability and consumption can be dissociated in the rat and that the organization of opioidergic mechanisms that mediate ethanol responses may vary between rat lines.

Behavioral analysis of male rat sexual motivation and performance following acute ethanol treatment.

To characterize the effects of acute ethanol treatment on sexual motivation and performance, 30 male Long-Evans rats were assigned to one of three treatment conditions: saline (n=9), 0.25 g/kg ethanol (n=10), or 1.0 g/kg ethanol (n=11). Males were injected intraperitoneally 30 min before behavioral testing. Male rats were placed in a multilevel testing chamber 5 min prior to the introduction of a receptive female rat and level changes were recorded as an index of sexual motivation. After the female rat was placed in the chamber, standard measures of sexual performance were recorded over three weekly tests. Results indicated that the highest dose of ethanol (1.0 g/kg) increased male rat level-changing behavior compared to the saline group. Although ethanol treatment failed to affect most measures of sexual performance, males administered 1.0 g/kg ethanol had fewer anogenital investigations and had longer postejaculatory intervals (PEIs) compared to control animals. The data from this experiment suggest that ethanol increases rodent sexual motivation but impairs specific parameters of sexual performance.

Chemosensory factors influencing alcohol perception, preferences, and consumption.

This article presents the proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, California, co-organized by Julie A. Mennella and Alexander A. Bachmanov of the Monell Chemical Senses Center. The goal of this symposium was to review the role that chemosensory factors (taste, smell, and chemical irritation) play in the perception, preference, and consumption of alcohol. The presented research focused on both humans and laboratory animals and used a variety of approaches including genetic, developmental, pharmacological, behavioral, and psychophysical studies. The presentations were as follows: (1) Introduction and overview of the chemical senses (Julie A. Mennella and Alexander A. Bachmanov); (2) Taste reactivity as a measure of alcohol palatability and its relation to alcohol consumption in rats (Stephen W. Kiefer); (3) Early learning about the sensory properties of alcohol in laboratory animals (Juan Carlos Molina); (4) Early learning about the sensory properties of alcohol in humans (Julie A. Mennella); (5) Genetic dissection of the ethanol-sweet taste relationship in mice (Alexander A. Bachmanov and Michael Tordoff); and (6) Human genetic variation in taste: connections with alcohol sensation and intake (Valerie B. Duffy and Linda M. Bartoshuk). The symposium concluded with a general discussion.

Naltrexone modifies the palatability of basic tastes and alcohol in outbred male rats.

Naltrexone, an opioid antagonist, has been shown to reduce the palatability of 10% alcohol solutions in rats, as measured by taste reactivity. In the present study, the effect of acute naltrexone treatment on taste reactivity to a variety of taste solutions and concentrations was tested to determine whether naltrexone has generalized effects on taste responsiveness. Thirty minutes before a taste reactivity test, rats were injected with either naltrexone (3 mg/kg; n = 15) or saline (n = 15). On separate days, rats were tested with distilled water and three concentrations each of sucrose (0.1, 0.5, and 1.0 M), sodium chloride (0.06, 0.10, and 0.30 M), quinine hydrochloride (0.0005, 0.001, and 0.005 M), and alcohol [10%, 20%, and 40% (vol./vol.)]. In Experiment 1, naltrexone consistently reduced the palatability of alcohol and sodium chloride solutions (across concentrations), as reflected by a decrease in ingestive responding and an increase in aversive responding. Naltrexone increased aversive responding for sucrose but did not affect ingestive responding for these solutions. Finally, there was no significant effect of naltrexone on responding to quinine hydrochloride. A second experiment with naive rats and five concentrations of sucrose (0.01, 0.05, 0.1, 0.5, and 1.0 M) replicated the initial data: Across concentrations, naltrexone produced a significant increase in aversive responding but did not alter ingestive responding. In Experiment 3, naive rats were tested with five concentrations of quinine hydrochloride (0.00001, 0.00005, 0.0001, 0.0005, and 0.005 M). Results indicated that naltrexone significantly altered taste reactivity to the bitter solutions (less ingestive responding and more aversive responding), particularly at the lower concentrations. The results indicate that naltrexone treatment has significant effects on taste reactivity to some aqueous solutions (alcohol, sodium chloride), regardless of solution concentration. The effects of naltrexone on sucrose and quinine reactivity are more difficult to describe because the drug effects seemed to be dependent on the specific measure examined (ingestive vs. aversive responses) and the concentration of the solution. These results support the suggestion that naltrexone has a fairly generalized effect on taste reactivity to taste solutions; specifically, naltrexone seems to make solutions more aversive, as revealed by a decrease in ingestive responding and an increase in aversive responding.

Low doses of naltrexone reduce palatability and consumption of ethanol in outbred rats.

The opioid antagonist naltrexone, at doses of 1 and 3 mg/kg, has been shown to decrease the palatability and consumption of 10% ethanol in rats. However, a dose of 0.5 mg/kg of naltrexone has produced equivocal results. The purpose of the present study was to clarify the effects of low doses of naltrexone (0.0 [control], 0.25, 0.50, 0.75, and 1.0 mg/kg) on palatability and consumption of 10% ethanol. Sixty-four, male, Long-Evans hooded rats were divided into five groups matched for ethanol consumption. Each rat was injected over four consecutive days with one of five doses of naltrexone exactly 30 min before taste reactivity testing with 10% ethanol. When reactivity testing was completed, rats were acclimated to drink during a period of restricted access to fluid under conditions of mild fluid deprivation. Then, on four consecutive test days, rats were injected with naltrexone 10 min before 10% ethanol was made available for 30 min. Although each dose of naltrexone decreased ingestive responding to 10% ethanol over four days, this effect was not statistically reliable. However, all doses of naltrexone produced significant increases in aversive responding to the ethanol solution. Naltrexone, at the three highest doses, produced significant decreases in consumption of 10% ethanol. These results were consistent with the interpretation that naltrexone, even at low doses, reliably reduces palatability and consumption of 10% ethanol.