Palatable Substances Research Articles

The parasubthalamic nucleus refeeding ensemble delays feeding initiation and hastens water drinking.

The parasubthalamic nucleus (PSTN) is activated by refeeding after food deprivation and several PSTN subpopulations have been shown to suppress feeding. However, no study to date directly addressed the role of PSTN neurons activated upon food access in the control of ensuing food consumption. Here we identify consumption latency as a sensitive behavioral indicator of PSTN activity, and show that, in hungry mice, the ensemble of refeeding-activated PSTN neurons drastically increases the latency to initiate refeeding with both familiar and a novel, familiar food, but does not control the amount of food consumed. In thirsty mice, this ensemble also delays sucrose consumption but accelerates water consumption, possibly reflecting anticipatory prandial thirst, with again no influence on the amount of fluid consumed. We next sought to identify which subpopulations of PSTN neurons might be driving these latency effects, using cell-type and pathway-specific chemogenetic manipulations. Our results suggest a prominent role of PSTN Tac1 neurons projecting to the central amygdala in the hindrance of feeding initiation. While PSTN Crh neurons also delay the latency of hungry mice to ingest familiar foods, they surprisingly promote the consumption of novel, palatable substances. Furthermore, PSTN Crh neurons projecting to the bed nucleus of the stria terminalis accelerate rehydration in thirsty mice. Our results demonstrate the key role of endogenous PSTN activity in the control of feeding and drinking initiation and delineate specific circuits mediating these effects, which may have relevance for eating disorders.

Conditioned overconsumption is dependent on reinforcer type in lean, but not obese, mice.

Associative learning can drive many different types of behaviors, including food consumption. Previous studies have shown that cues paired with food delivery while mice are hungry will lead to increased consumption in the presence of those cues at later times. We previously showed that overconsumption can be driven in male mice by contextual cues, using chow pellets. Here we extended our findings by examining other parameters that may influence the outcome of context-conditioned overconsumption training. We found that the task worked equally well in males and females, and that palatable substances such as high-fat diet and Ensure chocolate milkshake supported learning and induced overconsumption. Surprisingly, mice did not overconsume when sucrose was used as the reinforcer during training, suggesting that nutritional content is a critical factor. Interestingly, we also observed that diet-induced obese mice did not learn the task. Overall, we find that context-conditioned overconsumption can be studied in lean male and female mice, and with multiple reinforcer types.

Juvenile stress exerts sex-independent effects on anxiety, antidepressant-like behaviours and dopaminergic innervation of the prelimbic cortex in adulthood and does not alter hippocampal neurogenesis

Stress, particularly during childhood, is a major risk factor for the development of depression. Depression is twice as prevalent in women compared to men, which suggests that biological sex also contributes to depression susceptibility. However, the neurobiology underpinning sex differences in the long-term consequences of childhood stress remains unknown. Thus, the aim of this study was to determine whether stress applied during the prepubertal juvenile period (postnatal day 27–29) in rats induces sex-specific changes in anxiety-like behaviour, anhedonia, and antidepressant-like behaviour in adulthood in males and females. The impact of juvenile stress on two systems in the brain associated with these behaviours and that develop during the juvenile period, the mesocorticolimbic dopaminergic system and hippocampal neurogenesis, were also investigated. Juvenile stress altered escape-oriented behaviours in the forced swim test in both sexes, decreased latency to drink a palatable substance in a novel environment in the novelty-induced hypophagia test in both sexes, and decreased open field supported rearing behavior in females. These behavioural changes were accompanied by stress-induced increases in tyrosine hydroxylase immunoreactivity in the prefrontal cortex of both sexes, but not other regions of the mesocorticolimbic dopaminergic system. Juvenile stress did not impact anhedonia in adulthood as measured by the saccharin preference test and had no effect hippocampal neurogenesis across the longitudinal axis of the hippocampus. These results suggest that juvenile stress has long-lasting impacts on antidepressant-like and reward-seeking behaviour in adulthood and these changes may be due to alterations to catecholaminergic innervation of the medial prefrontal cortex.

The GluA1 AMPAR subunit is necessary for hedonic responding but not hedonic value in female mice

The GluA1 subunit of the AMPA receptor has been implicated in anhedonia. Mice that lack GluA1 (Gria1 knockout mice) show reduced lick cluster size, a measure of palatability in feeding behaviour. This deficit may reflect a role for GluA1 in encoding the hedonic value of palatable substances or instead a role for GluA1 in the behavioural expression of hedonic value. We tested the role of GluA1 in hedonic value by assessing sensitivity to changes in the rewarding property of sucrose as a consequence of negative/positive contrast effects in female mice. During training, on half of the days consumption of a flavour (CS+) mixed with 4% sucrose was preceded by consumption of 1% sucrose (positive contrast). On the other half of days consumption of a different flavour (CS–) mixed with 4% sucrose was preceded by consumption of 16% sucrose (negative contrast). In the test session both wild-type, controls and Gria1 knockout mice consumed more of the CS+ flavour than the CS– flavour. While Gria1 knockout mice showed reduced lick cluster sizes, both genotypes made larger lick clusters for the CS+ flavour than the CS– flavour suggesting that the CS+ was more palatable than the CS–. A follow up experiment in normal mice demonstrated that the negative contrast procedure resulted in a conditioned reduction of palatability of the CS– in comparison to an associatively neutral, novel flavour. The results failed to demonstrate a role for GluA1 in hedonic value suggesting that, instead, GluA1 is necessary for hedonic responding.

Innate and Acquired Quinine-Resistant Alcohol, but not Saccharin, Drinking in Crossed High-Alcohol-Preferring Mice.

Alcohol consumption despite aversive consequences is often a key component of an alcoholism diagnosis. Free-choice alcohol consumption despite bitter quinine adulteration in rodents has been seen following several months of free-choice drinking, but there has been little study of whether prolonged access to other palatable substances such as saccharin yields quinine resistance. Selectively bred crossed high-alcohol-preferring (cHAP) mice average blood alcohol levels of over 250mg/dl during free-choice access, considerably higher than other models. We hypothesized that higher intakes would yield more rapid development of quinine-resistant alcohol (QRA) drinking and quinine-resistant saccharin (QRS) drinking. All experiments used male and female cHAP mice. Experiment 1 compared mice with either 0 or 5weeks of alcohol drinking history, testing varying (0.032, 0.10, 0.32g/l) quinine concentrations in ethanol. Experiment 2 examined whether innate QR may exist, comparing animals with a 1 or zero day of drinking history. Experiment 3 examined the effect of varying histories (0, 2, or 5weeks) of free-choice 10% alcohol drinking on QR alcohol consumption at high quinine concentrations. Finally, Experiment 4 investigated the development of QRS drinking. We found that we could not detect a history effect in commonly used quinine concentrations, indicating that cHAP mice are innately quinine resistant to 0.10g/l quinine. However, we were able to determine that a 2-week drinking history was sufficient to induce QRA drinking in cHAP mice at extremely high quinine concentrations (0.74 and 0.32g/l). However, the history effect was specific to QRA, a saccharin drinking history, did not yield QRS drinking. These data suggest that an alcohol drinking history induces maladaptive behaviors, such as drinking in spite of negative consequences, a pattern not seen with saccharin. Furthermore, a strong genetic predisposition to drink may promote an innate aversion resistance compared with commonly used inbred strains.

Effect of chronic variable stress on sensitization to amphetamine in high and low sucrose-consuming rats.

Individual vulnerability to stress manifests in the interaction of innate properties and environment. There is a growing interest in the individual variability in vulnerability to stress and how it contributes to the development of psychiatric disorders. Intake of palatable substances is often measured in animal models. We have previously demonstrated that the consumption of sucrose solution is a stable trait in rats. The present study aimed to compare the sensitivity of rats with high vs low liquid sucrose consumption to chronic variable stress and the stress effect on behavioural sensitization to amphetamine. Male Wistar rats were subjected to a chronic stress regimen and subsequent repeated treatment with amphetamine (1 mg/kg, intraperitoneally). Fifty-kHz ultrasonic vocalizations, locomotor activity and stereotypies were measured. In no-stress baseline conditions, the behavioural response to acute amphetamine was similar in rats with high vs low sucrose consumption. Prior chronic stress potentiated the effect of amphetamine only in rats with high sucrose consumption. Behavioural sensitization to repeated administration of amphetamine was observed in non-stressed rats with lower sucrose preference, but not in the respective stressed group that had increased monoamine turnover in the nucleus accumbens. In contrast, in rats with high sucrose preference the amphetamine sensitization effect was prevalent in stressed rats, but not in non-stressed animals. Chronic stress can change the psychostimulant effect but this depends on the inherent reward sensitivity of the animal. Trait-wise, sucrose intake reflects vulnerability to chronic stress and may interact with the development of addiction.

Environmental Enrichment Modulates Drug Addiction and Binge-Like Consumption of Highly Rewarding Substances: A Role for Anxiety and Compulsivity Brain Systems?

Drug addiction is a chronic disorder comprising components of both impulsivity and compulsivity in the so called “addiction cycle” which develops over time from early non-dependent, repetitive, binge-consumption to later post-dependent compulsive consumption. Thus, frequent binge-like intake is a typical pattern of excessive drug intake characteristic of the pre-dependent phase of the addiction cycle, which represent an important risk factor to develop addiction in vulnerable individuals. In this framework, it is of paramount interest to further understand the earliest stage of the addiction cycle so novel approaches would emerge aimed to control repetitive episodes of binge-consumption in non-dependent subjects, protecting vulnerable individuals from transition to dependence. Environmental enrichment (EE) is a preclinical animal model in which animals are housed under novel, social enriched conditions, which allows exercising and provides sensory and cognitive stimulation. EE promotes important improvements for a variety of cognitive processes and clear therapeutic and protective effects preventing ethanol (EtOH) and drug addiction as well. Interestingly, recent observations suggest that EE might additionally modulate binge-like intake of highly palatable caloric substances, including EtOH, which suggests the ability of EE to regulate consumption during the initial stage of the addiction cycle. We have proposed that EE protective and therapeutic effects on binge-consumption of palatable substances might primarily be mediated by the modulatory control that EE exerts on anxiety and impulsivity/compulsivity traits, which are all risk factors favoring transition to drug addiction.

The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders.

The hypocretin/orexin (ORX) system has been repeatedly demonstrated to regulate motivation for drugs of abuse, including alcohol. In particular, ORX seems to be critically involved in highly motivated behaviors, as is observed in high-seeking individuals in a population, in the seeking of highly palatable substances, and in models of dependence. It seems logical that this system could be considered as a potential target for treatment for addiction, particularly alcohol addiction, as ORX pharmacological manipulations significantly reduce drinking. However, the ORX system also plays a role in a wide range of other behaviors, emotions, and physiological functions and is disrupted in a number of non-dependence-associated disorders. It is therefore important to consider how the ORX system might be optimally targeted for potential treatment for alcohol use disorders either in combination with or separate from its role in other functions or diseases. This review will focus on the role of ORX in alcohol-associated behaviors and whether and how this system could be targeted to treat alcohol use disorders while avoiding impacts on other ORX-relevant functions. A brief overview of the ORX system will be followed by a discussion of some of the factors that makes it particularly intriguing as a target for alcohol addiction treatment, a consideration of some potential challenges associated with targeting this system and, finally, some future directions to optimize new treatments.

The Limits of Romancing Food in the Neoliberal Era: Ruth L. Ozeki’s My Year of Meats

Ruth L. Ozeki`s My Year of Meats houses a tension between two ways of engaging with food: one is taking a “romantic” approach by depicting food as a source of inspiration and pleasure that enables cross-cultural rapport, and the other is taking an expository approach that involves investigating the process of food production, circulation, and consump tion as framed by the global neoliberal economy. The interplay of these two perspectives is productive in that it highlights how food operates on a number of different levels: as a livelihood, a cultural signifier, and eco nomic currency. It is, however, the investigative approach that subsumes the romantic approach in the end, for its impulsive, idiosyncratic, and aes thetic ways of engaging with food is found to downplay, and even neu tralize, the gruesome reality of modern-day food production. This conclu sion is especially pertinent to the current times, in which writings about food increasingly stress the necessity of knowing the ontology of food, or experiencing food viscerally, as a highly affective, spontaneous, and vital substance. The journey the novel takes into the underbelly of meat indus try is a reminder that food is an asset circulating according to the dictates of efficiency and profit, not an object of romance that captivates the con sumer with its palatable and transformative substance.

Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning

Diet can impact sensitivity of rats to some of the behavioral effects of drugs acting on dopamine systems. The current study tested whether continuous access to sucrose is necessary to increase yawning induced by the dopamine receptor agonist quinpirole, or if intermittent access is sufficient. These studies also tested whether sensitivity to quinpirole-induced yawning increases in rats drinking the non-caloric sweetener saccharin. Dose–response curves (0.0032–0.32mg/kg) for quinpirole-induced yawning were determined once weekly in rats with free access to standard chow and either continuous access to water, 10% sucrose solution, or 0.1% saccharin solution, or intermittent access to sucrose or saccharin (i.e., 2 days per week with access to water on other days). Cumulative doses of quinpirole increased then decreased yawning, resulting in an inverted U-shaped dose–response curve. Continuous or intermittent access to sucrose enhanced sensitivity to quinpirole-induced yawning. Continuous, but not intermittent, access to saccharin also enhanced sensitivity to quinpirole-induced yawning. In all groups, pretreatment with the selective D3 receptor antagonist PG01037 shifted the ascending limb of the quinpirole dose–response curve to the right, while pretreatment with the selective D2 receptor antagonist L-741,626 shifted the descending limb to the right. These results suggest that even intermittent consumption of diets containing highly palatable substances (e.g. sucrose) alters sensitivity to drugs acting on dopamine systems in a manner that could be important in vulnerability to abuse drugs.

Binge-like consumption of caloric and non-caloric palatable substances in ad libitum-fed C57BL/6J mice: Pharmacological and molecular evidence of orexin involvement

The orexin (OX) system has been implicated in food-reinforced behavior, food-seeking and food overconsumption. Recent evidence suggests that OX signaling might influence consumption of palatable foods with high reinforcing value depending upon the caloric status of the animal. The present study evaluates from a pharmacological and a molecular approach the contribution of OX to excessive binge-like consumption of highly preferred palatable substances (sucrose and saccharin) in ad libitum-fed C57BL/6J mice. The main findings of this study are: (1) intraperitoneal (ip) injection of SB-334867 (10, 20 or 30mg/kg), a selective OXR1 antagonist, significantly decreased binge-like consumption of sucrose (10%, w/v) and saccharin (0.15%, w/v) during the test day in a Drinking in the Dark procedure in ad libitum-fed animals, without evidence of any significant alteration of locomotor activity. (2) Four repetitive, 2-h daily episodes of sucrose and saccharin (but not water) binge-like drinking significantly dampened OX mRNA expression in the LH. Present findings show for the first time a role for OXR1 signaling in binge-like consumption of palatable substances in animals under no caloric needs. Targeting OXR1 could represent a novel pharmacological approach to treat binge-eating episodes.

Effects of chronic mild stress on rats selectively bred for behavior related to bipolar disorder and depression

To test the possibility that chronic mild stress (CMS) might be unreliable in producing its often-intended outcome (i.e., decreased preference for sucrose, hypothesized to represent depression-relevant anhedonia) because it is typically applied to “normal” rats, a CMS procedure was applied to rats that may possess genetic susceptibility to affective disorders, having had been selectively-bred to show behavior indicative of such disorders. These rat lines were: Hyperactive (HYPER) rats, which show characteristics of bipolar disorder, Swim-test Susceptible (SUS) and Swim-test Resistant (RES) rats, being susceptible or resistant to effects of stress in the swim test, Swim High-active (SwHi) and Swim Low-active (SwLo) rats, which innately show high or low activity in the swim test. These selectively-bred lines were compared to normal, non-selectively bred (NS) rats. During CMS, HYPER rats, both females and males, as well as RES and SwHi rats, showed reduced consumption of a palatable 2% sucrose solution, and reduced preference for sucrose (vs. water) in comparison to non-stressed rats (no CMS) of the same lines. In contrast, CMS produced no decrease in sucrose consumption or in preference for sucrose in normal NS rats, and actually a caused a slight increase in sucrose consumption and preference in male NS rats. Other measures that indicate depression – food intake and motor activity in the home cage – were also assessed. SwLo and SwHi showed greater sensitivity to having their home-cage ambulatory activity reduced by CMS than did NS rats, but no other such differences relative to NS rats were seen for these other measures; thus, changes in sucrose intake or preference could not be explained by a change in caloric intake. These results suggest that the genetic attributes of animals can influence the outcome of CMS, and that the application of CMS to normal, non-selected rats may account, at least in part, for the unreliability of CMS in decreasing consumption of palatable substances and decreasing preference for such substances.

Differential orexin/hypocretin expression in addiction-prone and -resistant rats selectively bred for high (HiS) and low (LoS) saccharin intake

Rats that have been selectively bred for high (HiS) saccharin intake demonstrate elevated drug-seeking behavior in several phases of addiction compared to those bred for low (LoS) saccharin intake. HiS rats also consume greater amounts of highly palatable substances compared to LoS rats; however, little is known about the neurobiological substrates moderating the divergent behaviors found between the HiS and LoS lines. Orexins are neuropeptides that have been implicated in the conditioned cue aspects of drug abuse and overconsumption of palatable substances, and differential orexin activity in the HiS and LoS phenotypes may enhance our understanding of the close relationship between food and drug reward, and ultimately food and drug addiction. The lateral hypothalamus (LH) and perifornical area (PFA) are brain regions that have been implicated in regulating feeding behavior and addiction processes, and they contain orexinergic neurons that project broadly throughout the brain. Thus, we investigated orexin and c-Fos expression in the LH and PFA using immunohistochemistry in HiS and LoS rats following either control or cocaine (15mg/kg) injections. Results indicated that HiS rats have higher orexin-positive cell counts compared to LoS rats in both the LH and PFA, regardless of cocaine (vs. saline) treatment. In contrast, neuronal activity indicated by c-Fos expression did not differ in either of these brain areas in HiS vs. LoS rats. These results suggest that the orexin system may be involved in aspects of genetically-mediated differences in vulnerability to compulsive, reward-driven behaviors.

Motor neurons controlling fluid ingestion in Drosophila

Rhythmic motor behaviors such as feeding are driven by neural networks that can be modulated by external stimuli and internal states. In Drosophila, ingestion is accomplished by a pump that draws fluid into the esophagus. Here we examine how pumping is regulated and characterize motor neurons innervating the pump. Frequency of pumping is not affected by sucrose concentration or hunger but is altered by fluid viscosity. Inactivating motor neurons disrupts pumping and ingestion, whereas activating them elicits arrhythmic pumping. These motor neurons respond to taste stimuli and show prolonged activity to palatable substances. This work describes an important component of the neural circuit for feeding in Drosophila and is a step toward understanding the rhythmic activity producing ingestion.

Cocaine abstinence alters nucleus accumbens firing dynamics during goal‐directed behaviors for cocaine and sucrose

Distinct subsets of nucleus accumbens (NAc) neurons differentially encode goal-directed behaviors for natural vs. drug rewards [R. M. Carelli et al. (2000)The Journal of Neuroscience, 20, 4255-4266], and the encoding of cocaine-seeking is altered following cocaine abstinence [J. A. Hollander & R. M. Carelli (2007) The Journal of Neuroscience, 27, 3535-3539]. Here, electrophysiological recording procedures were used to determine if the selective encoding of natural vs. cocaine reward by NAc neurons is: (i) maintained when the natural reinforcer is a highly palatable sweet tastant and (ii) altered by cocaine abstinence. Rats (n = 14) were trained on a multiple schedule of sucrose reinforcement and cocaine self-administration (2-3 weeks) and NAc activity was recorded during the task before and after 30 days of cocaine abstinence. Of 130 cells recorded before abstinence, 82 (63%) displayed patterned discharges (increases or decreases in firing rate, termed phasic activity) relative to operant responding for sucrose or cocaine. As in previous reports, the majority of those cells displayed nonoverlapping patterns of activity during responding for sucrose vs. cocaine. Specifically, only 17 (21%) showed similar patterns of activity (i.e. overlapping activity) across the two reinforcer conditions. After abstinence, this pattern was largely maintained, 23 of 70 phasic cells (33%) were overlapping. However, cocaine abstinence altered the overall percentage of selectively active neurons across reinforcer conditions. Specifically, significantly more neurons became selectively activated during cocaine-directed behaviors than during sucrose-directed behaviors. The results indicate that, although the selective encoding of cocaine and natural rewards is maintained even with a highly palatable substance, 30 days of cocaine abstinence dynamically alters the overall population encoding of natural and drug rewards by NAc neurons.

Hyponeophagia: A Measure of Anxiety in the Mouse

Before the present day, when fast-acting and potent rodenticides such as alpha-chloralose were not yet in use, the work of pest controllers was often hampered by a phenomenon known as "bait shyness". Mice and rats cannot vomit, due to the tightness of the cardiac sphincter of the stomach, so to overcome the problem of potential food toxicity they have evolved a strategy of first ingesting only very small amounts of novel substances. The amounts ingested then gradually increase until the animal has determined whether the substance is safe and nutritious. So the old rat-catchers would first put a palatable substance such as oatmeal, which was to be the vehicle for the toxin, in the infested area. Only when large amounts were being readily consumed would they then add the poison, in amounts calculated not to affect the taste of the vehicle. The poisoned bait, which the animals were now readily eating in large amounts, would then swiftly perform its function.Bait shyness is now used in the behavioural laboratory as a way of measuring anxiety. A highly palatable but novel substance, such as sweet corn, nuts or sweetened condensed milk, is offered to the mice (or rats) in a novel situation, such as a new cage. The latency to consume a defined amount of the new food is then measured.Robert M.J. Deacon can be reach at robert.deacon@psy.ox.ac.uk

Hyponeophagia: A Measure of Anxiety in the Mouse

Before the present day, when fast-acting and potent rodenticides such as alpha-chloralose were not yet in use, the work of pest controllers was often hampered by a phenomenon known as "bait shyness". Mice and rats cannot vomit, due to the tightness of the cardiac sphincter of the stomach, so to overcome the problem of potential food toxicity they have evolved a strategy of first ingesting only very small amounts of novel substances. The amounts ingested then gradually increase until the animal has determined whether the substance is safe and nutritious. So the old rat-catchers would first put a palatable substance such as oatmeal, which was to be the vehicle for the toxin, in the infested area. Only when large amounts were being readily consumed would they then add the poison, in amounts calculated not to affect the taste of the vehicle. The poisoned bait, which the animals were now readily eating in large amounts, would then swiftly perform its function. Bait shyness is now used in the behavioural laboratory as a way of measuring anxiety. A highly palatable but novel substance, such as sweet corn, nuts or sweetened condensed milk, is offered to the mice (or rats) in a novel situation, such as a new cage. The latency to consume a defined amount of the new food is then measured. Robert M.J. Deacon can be reach at robert.deacon@psy.ox.ac.uk

Drosophila Evaluates and Learns the Nutritional Value of Sugars

Living organisms need to search for and ingest nutritional chemicals, and gustation plays a major role in detecting and discriminating between chemicals present in the environment. Using Drosophila as a model organism, we asked whether animals have the ability to evaluate the nutritional value of sugars. In flies, chemosensilla on the tarsi and labellum are the gustatory organs used to discriminate between edible and nonedible compounds [1, 2]. We noticed that Drosophila do not assign nutritional values to all sweet chemicals. D-arabinose is sweet to flies, but it provides them with no nutrition. By contrast, the sugar alcohol D-sorbitol is not sensed as sweet, but flies can live on it. We performed behavioral and electrophysiological measurements to confirm these gustatory and feeding responses. We found that Drosophila can learn the nutritional value of nonsweet D-sorbitol when it is associated with an odor cue. The learning process involved the synapsin molecule, suggesting that a neuronal mechanism is involved. We propose that Drosophila uses neural machinery to detect, evaluate, and learn the nutritional value of foods after ingestion.

Motor Control in a Drosophila Taste Circuit

Tastes elicit innate behaviors critical for directing animals to ingest nutritious substances and reject toxic compounds, but the neural basis of these behaviors is not understood. Here, we use a neural silencing screen to identify neurons required for a simple Drosophila taste behavior and characterize a neural population that controls a specific subprogram of this behavior. By silencing and activating subsets of the defined cell population, we identify the neurons involved in the taste behavior as a pair of motor neurons located in the subesophageal ganglion (SOG). The motor neurons are activated by sugar stimulation of gustatory neurons and inhibited by bitter compounds; however, experiments utilizing split-GFP detect no direct connections between the motor neurons and primary sensory neurons, indicating that further study will be necessary to elucidate the circuitry bridging these populations. Combined, these results provide a general strategy and a valuable starting point for future taste circuit analysis.

18-Methoxycoronaridine: a potential new treatment for obesity in rats?

Excessive eating often leads to obesity. Although a variety of neurotransmitters and brain regions are involved in modulating food intake, a role of accumbal dopamine is thought to be critical for several aspects of this behavior. Since 18-methoxycoronaridine (18-MC), a selective antagonist of alpha3beta4 nicotinic receptors, was previously shown to alter dopamine release in the nucleus accumbens in response to chronic injections of cocaine and morphine, this drug could be a promising therapy for abnormal eating behavior. Assess the effect of 18-MC on the consumption of sucrose (15%) vs. water in a self-administration paradigm and on the intake of freely available palatable fluids (i.e., 5% sucrose, 0.1% saccharin, and 0.6% saline solutions) as well as on water intake. Determine whether repeated administration of 18-MC (20 mg/kg i.p.) affects weight gain, food intake, and fat deposition in rats drinking 30% sucrose solution. Acute administration of 18-MC (10-40 mg/kg i.p.) reduced operant responding for sucrose and decreased ad libitum ingestion of sucrose, saccharin, and saline. The highest dose of 18-MC also reduced consumption of water when palatable fluids were not available. In rats having unlimited access to sucrose (30%), chronic treatment with 18-MC (20 mg/kg i.p.) prevented sucrose-induced increases in body weight, decreased fat deposition, and reduced consumption of sucrose while not altering food intake. These data suggest that antagonism of alpha3beta4 nicotinic receptors may be involved in the regulation of intake of palatable substances regardless of its caloric value and may participate in maintaining obesity.