Stephen W. Kiefer

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.

Ethanol consumption in rats selectively bred for differential saccharin intake.

Rat lines selectively bred for high ethanol consumption consume more saccharin solution than do their low-ethanol-consuming counterparts. The present study utilized the technique of reciprocal selection to examine the reliability of the saccharin/ethanol relationship; specifically, consumption of 1-10% ethanol solution was measured in rats selectively bred for high vs. low saccharin consumption (Occidental HiS and LoS lines). HiS rats consumed more ethanol than did LoS rats. These results support the idea that individual differences in ethanol and saccharin consumption share some common mechanism(s).

Taste avoidance, but not aversion, learning in rats lacking gustatory cortex

Control rats rapidly learned to avoid drinking either a sucrose solution (Experiment 1) or a NaCl solution (Experiment 2) when the taste was paired with illness. These rats also produced aversive reactivity to each of these solutions in a taste reactivity test. Rats that lacked gustatory cortex (GC) learned to avoid drinking sucrose and NaCl, albeit at a slower rate than control rats. GC rats failed to display aversive reactivity to these tastes. The GC rats did show normal aversive reactivity to a strong quinine HCl solution during additional tests. It is suggested that the avoidance developed by GC rats did not entail a palatability shift of the conditional stimulus as it did in control rats. This altered learning strategy may account for the consistent learning deficits found in GC rats trained to avoid tastes.

Neural Mediation of Conditioned Food Aversions

The above discussion is only a brief review of what is known about the neural mediation of conditioned food aversions. Although several other approaches were not mentioned (e.g. biochemical studies), one can still appreciate the value of the aversion paradigm for providing important information about neural mechanisms in learning and memory. A theoretical approach that may be valuable in understanding brain function in conditioned food aversion data is Hughlings Jacksons hierarchical notions of nervous organization. Hedonic responses to food stimuli appear to be brainstem reflexes. On top of these are rostral brain structures that add greater complexity to the consummatory behavior of the organism. An important aspect of this complexity is reflected in an animals ability to form conditioned food aversions, a process undoubtedly tied intimately to particular neural mechanisms.

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

Our previous studies have shown that the selective dopamine D3 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 D3 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 D3 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 D3 antagonists in the treatment of methamphetamine addiction.

Dopamine D3 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.

Microinjections of Dopaminergic Agents in the Nucleus Accumbens Affect Ethanol Consumption But Not Palatability

It was determined whether ethanol palatability in rats could be changed by manipulating the reinforcement experienced during limited access consumption. During the first 3 days of the experiment, initial taste reactivity (TR) testing to distilled water (1 day) and 10% alcohol (2 days) was performed. Following the establishment of baseline TR, separate groups of animals received bilateral microinjections (0.5 microl/side) into the nucleus accumbens of either the nonspecific dopamine agonist d-amphetamine sulfate (20 microg, n = 10), the D(2) antagonist raclopride (1.0 microg, n = 8), or physiological saline (n = 5). The injections occurred at the same time each day for 5 consecutive days. Five minutes after the microinjection, the fluid-deprived rats were given 30-min access to 10% ethanol. Over the 3 days following drug administration, TR to distilled water and 10% alcohol was repeated. After this, the rats were once again given 30 min of access to 10% ethanol for 5 consecutive days, but without drug microinjection prior to alcohol access. A final TR exposure (the same as the others) was performed over the final 3 days of the study. Both raclopride and d-amphetamine administration produced reductions in ethanol consumption (in comparison to saline treatment). However, treatment with d-amphetamine and raclopride during ethanol consumption did not cause significant, conditioned changes in palatability as measured by the taste reactivity procedure. These results suggest that dopamine plays a role in the motivation to consume ethanol but this neurotransmitter is not involved in evaluating its incentive value.

Similarity of taste reactivity responses to alcohol and sucrose mixtures in rats

The orofacial responses of rats following infusion of taste solutions were examined in two experiments. In the first experiment, naive rats were presented with a 6% alcohol solution and three sucrose mixtures (sucrose combined with quinine hydrochloride, hydrochloric acid, and sodium chloride, respectively) on separate trials and the resulting taste reactivity was examined. The only difference among the solutions was that alcohol elicited a significantly larger number of aversive responses (e.g., gapes, passive drips) than the sucrose mixtures. In the second experiment, naive rats were trained to avoid 6% alcohol using standard conditioned aversion procedures; rats were then tested for reactivity to the three sucrose mixtures and the alcohol solution. With the alcohol solution, trained rats displayed significantly fewer ingestive responses and significantly more aversive responses than control rats. The response of trained rats to the sucrose + quinine solution was similar to that of alcohol: fewer ingestive responses and more aversive responses than control rats. The number of aversive responses to the alcohol and the sucrose + quinine mixture by the trained rats did not differ significantly. Reactivity to the sucrose + hydrochloric acid and sucrose + sodium chloride solutions did not differ between trained rats and control rats. The results suggest that a sucrose + quinine solution has a perceived taste (as revealed by elicited orofacial reflexes) similar to alcohol and that the sucrose mixture is avoided by rats with alcohol aversions because it is unpalatable.

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.

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.