The Uncompetitive N-methyl-D-Aspartate Antagonist Memantine Reduces Binge-Like Eating,Food-Seeking Behavior,and Compulsive Eating: Role of the Nucleus Accumbens Shell

Binge-eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. The role of the glutamatergic N-methyl-D-aspartate (NMDA) receptor system in hedonic feeding is poorly understood. The aim of this study was to characterize the effects of the uncompetitive NMDA receptor antagonist memantine on palatable food-induced behavioral adaptations using a rat model, which mimics the characteristic symptomatology observed in binge-eating disorder. For this purpose, we allowed male Wistar rats to respond to obtain a highly palatable, sugary diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day, under a fixed-ratio 1 (FR1) schedule of reinforcement. Upon stabilization of food responding, we tested the effects of memantine on the Chow and Palatable food groups'' intake. Then, we tested the effects of memantine on food-seeking behavior, under a second-order schedule of reinforcement. Furthermore, we investigated the effects of memantine on the intake of food when it was offered in an aversive, bright compartment of a light/dark conflict test. Finally, we evaluated the effects of memantine on FR1 responding for food, when microinfused into the nucleus accumbens (NAcc) shell or core. Memantine dose-dependently decreased binge-like eating and fully blocked food-seeking behavior and compulsive eating, selectively in the Palatable food group. The drug treatment did not affect performance of the control Chow food group. Finally, intra-NAcc shell, but not core, microinfusion of memantine decreased binge-like eating. Together, these findings substantiate a role of memantine as a potential pharmacological treatment for binge-eating disorder.     

Impulsivity on a Go/No-go task for intravenous cocaine or food in male and female rats selectively bred for high and low saccharin intake

The purpose of this study was to examine a form of impulsive behavior (impaired inhibition) using cocaine or food reward in addiction-prone and addiction-resistant rats that were bred for high saccharin (HiS) or low saccharin (LoS) intake, respectively. A Go/No-go procedure was used to examine cocaine and food reinforcement (Go component) and the inhibition of responding during a subsequent period of nonreward (No-go component). Rats were initially trained to self-administer intravenous cocaine (0.4 mg/kg) under an FR 1 schedule during daily Go/No-go sessions consisting of three components of cocaine reinforcement (Go) alternating with two nonreward components (No-go), each signaled by different stimuli. Responding and drug intake were compared under three FR values (FR 1, FR 3, and FR 5) and three cocaine doses (0.2, 0.4, and 0.8 mg/kg). A similar Go/No-go procedure was used with food reinforcement and the same three FR conditions. During the Go components for intravenous cocaine, female rats self-administered more infusions at the 0.2 and 0.4 mg/kg doses than males, indicating a sex difference in cocaine intake. During the No-go periods under the cocaine condition, HiS rats and females responded significantly more than LoS rats and males, indicating phenotype and sex differences in impaired inhibition. During the Go components with food reward, males responded more and earned more pellets than females, but there were no phenotype or sex differences in No-go responding (impulsivity). The results indicate that HiS rats and females are more prone than LoS rats and males to impulsive drug-seeking behavior.     

Suppression by the cannabinoid CB1 receptor antagonist, rimonabant, of the reinforcing and motivational properties of a chocolate-flavoured beverage in rats

Pharmacological blockade of the cannabinoid CB1 receptor has been repeatedly reported to suppress intake of food, including highly palatable foods, in laboratory animals. This study was designed to investigate whether treatment with the cannabinoid CB1 receptor antagonist, rimonabant, would reduce the reinforcing and motivational properties of a chocolate-flavoured beverage [containing 5% (w/v) chocolate powder] in nonfood-deprived and nonwater-deprived Wistar rats trained to self-administer this beverage under an operant conditioning procedure. This study was also aimed at assessing to what degree self-administration behaviour could be manipulated environmentally. After a period of training and maintenance of the self-administration behaviour, separate groups of rats were exposed to different experimental conditions [session length varying from 20 to 120 min; fixed ratio (FR) schedule of reinforcement varying from FR10 to FR40; reinforcer presentation varying from 2.5 to 10 s; concentration of the chocolate powder varying from 5% (w/v) to 0%]; other rat groups were used to test the effect of acute and repeated treatment with rimonabant (1-5.6 mg/kg, intraperitoneally) on two schedules of reinforcement (FR10 and progressive ratio) and extinction responding. All rats rapidly acquired and steadily maintained high levels of self-administration of the chocolate-flavoured beverage. Changes in experimental conditions modified the rats' self-administration behaviour; these changes seemed to be the result of the rats' attempt to adjust their behaviour so as to consume as much of the chocolate-flavoured beverage as possible when it was presented at its most palatable 5% concentration. Treatment with rimonabant dose-dependently suppressed self-administration of the chocolate-flavoured beverage. When rimonabant was administered repeatedly, only a modest degree of tolerance developed to its reducing effect. Finally, treatment with rimonabant resulted in a dose-dependent reduction of the motivational properties of the chocolate-flavoured beverage, measured by the progressive ratio schedule of reinforcement and extinction-responding procedure. These results suggest that self-administration of a chocolate-flavoured beverage can be rapidly and reliably established in rats and that this behaviour is environmentally manipulable. These results also suggest that the cannabinoid CB1 receptor is a crucial component of the neural substrate mediating the reinforcing and motivational properties of a highly palatable food such as a chocolate-flavoured beverage.     

BDNF Overexpression in the Ventral Tegmental Area Prolongs Social Defeat Stress-induced Cross-Sensitization to Amphetamine and Increases ΔFosB Expression in Mesocorticolimbic Regions of Rats

Social defeat stress induces persistent cross-sensitization to psychostimulants, but the molecular mechanisms underlying the development of cross-sensitization remain unclear. One candidate is brain-derived neurotrophic factor (BDNF). The present research examined whether ventral tegmental area (VTA) BDNF overexpression would prolong the time course of cross-sensitization after a single social defeat stress, which normally produces transient cross-sensitization lasting <1 week. ΔFosB, a classic molecular marker of addiction, was also measured in mesocorticolimbic terminal regions. Separate groups of intact male Sprague-Dawley rats underwent a single episode of social defeat stress or control handling, followed by amphetamine (AMPH) challenge 3 or 14 days later. AMPH cross-sensitization was apparent 3, but not 14, days after stress. Intra-VTA infusion of adeno-associated viral (AAV-BDNF) vector resulted in a twofold increase of BDNF level in comparison to the group receiving the control virus (AAV-GFP), which lasted at least 45 days. Additionally, overexpression of BDNF in the VTA alone increased ΔFosB in the nucleus accumbens (NAc) and prefrontal cortex. Fourteen days after viral infusions, a separate group of rats underwent a single social defeat stress or control handling and were challenged with AMPH 14 and 24 days after stress. AAV-BDNF rats exposed to stress showed prolonged cross-sensitization and facilitated sensitization to the second drug challenge. Immunohistochemistry showed that the combination of virally enhanced VTA BDNF, stress, and AMPH resulted in increased ΔFosB in the NAc shell compared with the other groups. Thus, elevation of VTA BDNF prolongs cross-sensitization, facilitates sensitization, and increases ΔFosB in mesocorticolimbic terminal regions. As such, elevated VTA BDNF may be a risk factor for drug sensitivity.     

Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.     

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

ΔFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased ΔFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether ΔFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased ΔFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of ΔFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that ΔFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.     

The CB1 Receptor as an Important Mediator of Hedonic Reward Processing

The endocannabinoid (ECB) system has emerged recently as a key mediator for reward processing. It is well known that cannabinoids affect appetitive learning processes and can induce reinforcing and rewarding effects. However, the involvement of the ECB system in hedonic aspects of reward-related behavior is not completely understood. With the present study, we investigated the modulatory role of the ECB system on hedonic perception, measured by the pleasure attenuated startle (PAS) paradigm for a palatable food reward. Here, a conditioned odor is thought to induce a pleasant affective state that attenuates an aversive reflex—the acoustic startle response. Modulatory effects of the CB1 receptor antagonist/inverse agonist SR1411716 and the cannabinoid agonist WIN 55 212-2 on PAS were examined in rats. PAS was also measured in CB1 receptor knockout (KO) and wild-type (WT) mice. Pharmacological inhibition as well as the absence of CB1 receptors was found to reduce PAS, whereas WIN 55 212-2 administration increased PAS. Finally, presentation of a conditioned reward cue was found to induce striatal FosB/ΔFosB expression in WT mice, but not in KO mice, indicating a reduced stimulation of reward-related brain regions in conditioned KO mice by odor presentation. We here show that in addition to our previous studies in rats, PAS may also serve as a valuable and suitable measure to assess hedonic processing in mice. Our data further indicate that the ECB system, and in particular CB1 receptor signaling, appears to be highly important for the mediation of hedonic aspects of reward processing.     

Antagonism of Sigma-1 Receptors Blocks Compulsive-Like Eating

Binge eating disorder is an addiction-like disorder characterized by episodes of rapid and excessive food consumption within discrete periods of time which occur compulsively despite negative consequences. This study was aimed at determining whether antagonism of Sigma-1 receptors (Sig-1Rs) blocked compulsive-like binge eating. We trained male wistar rats to obtain a sugary, highly palatable diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day under fixed ratio 1 operant conditioning. Following intake stabilization, we evaluated the effects of the selective Sig-1R antagonist BD-1063 on food responding. Using a light/dark conflict test, we also tested whether BD-1063 could block the time spent and the food eaten in an aversive, open compartment, where the palatable diet was offered. Furthermore, we measured Sig-1R mRNA and protein expression in several brain areas of the two groups, 24 h after the last binge session. Palatable rats rapidly developed binge-like eating, escalating the 1 h intake by four times, and doubling the eating rate and the regularity of food responding, compared to Chow rats. BD-1063 dose-dependently reduced binge-like eating and the regularity of food responding, and blocked the increased eating rate in Palatable rats. In the light/dark conflict test, BD-1063 antagonized the increased time spent in the aversive compartment and the increased intake of the palatable diet, without affecting motor activity. Finally, Palatable rats showed reduced Sig-1R mRNA expression in prefrontal and anterior cingulate cortices, and a two-fold increase in Sig-1R protein expression in anterior cingulate cortex compared to control Chow rats. These findings suggest that the Sig-1R system may contribute to the neurobiological adaptations driving compulsive-like eating, opening new avenues of investigation towards pharmacologically treating binge eating disorder.     

The selective dopamine D1 receptor agonist SK&F 38393: its effects on palatability- and deprivation-induced feeding, and operant responding for food

A series of experiments investigated the involvement of the dopamine D1 receptor subtype in relation to feeding responses. The selective D1 agonists, SK&F 38393 (1.0-20 mg/kg) and SK&F 75760 (5 mg/kg), significantly reduced palatable food consumption in nondeprived rats. The anorectic effect of SK&F 38393 (10 mg/kg) was additive with that of the selective D2 receptor agonist, N-0437 (0.3 mg/kg). In nondeprived mice, SK&F 38393 had a stereoselective effect to reduce palatable food intake. At a peripherally-selective dose (3.0 mg/kg), the peripheral dopamine D1 receptor agonist, fenoldopam, had no effect on food intake. At 10 mg/kg, however, it exhibited anorectic properties, although this may have been due to some penetration of the blood-brain barrier. In rats adapted to a food-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) produced significant dose-dependent reductions in consumption of powdered chow and in lever-pressing for food pellets on a FR8 schedule of reinforcement. In rats adapted to a water-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) was substantially less effective in reducing water intake. The results are discussed in terms of a possible selective effect of D1 agonist activity on feeding behaviour.     

The Neurometabolic Fingerprint of Excessive Alcohol Drinking

‘Omics'' techniques are widely used to identify novel mechanisms underlying brain function and pathology. Here we applied a novel metabolomics approach to further ascertain the role of frontostriatal brain regions for the expression of addiction-like behaviors in rat models of alcoholism. Rats were made alcohol dependent via chronic intermittent alcohol vapor exposure. Following a 3-week abstinence period, rats had continuous access to alcohol in a two-bottle, free-choice paradigm for 7 weeks. Nontargeted flow injection time-of-flight mass spectrometry was used to assess global metabolic profiles of two cortical (prelimbic and infralimbic) and two striatal (accumbens core and shell) brain regions. Alcohol consumption produces pronounced global effects on neurometabolomic profiles leading to a clear separation of metabolic phenotypes between treatment groups, particularly. Further comparisons of regional tissue levels of various metabolites, most notably dopamine and Met-enkephalin, allow the extrapolation of alcohol consumption history. Finally, a high-drinking metabolic fingerprint was identified indicating a distinct alteration of central energy metabolism in the accumbens shell of excessively drinking rats that could indicate a so far unrecognized pathophysiological mechanism in alcohol addiction. In conclusion, global metabolic profiling from distinct brain regions by mass spectrometry identifies profiles reflective of an animal''s drinking history and provides a versatile tool to further investigate pathophysiological mechanisms in alcohol dependence.     

Impulsivity predicts the escalation of cocaine self-administration in rats

Impulsivity, as measured by the delay-discounting task, predicts the acquisition of cocaine self-administration and reinstatement of cocaine seeking in rats. The purpose of this study was to extend these results to the escalation phase of drug self-administration. Female rats were initially screened for high (HiI) or low (LoI) impulsivity for food reinforcement using a delay-discounting procedure. They were then implanted with i.v. catheters and trained to lever press for cocaine infusions (0.8 mg/kg). Once cocaine intake stabilized, rats were allowed to self-administer cocaine (0.4 mg/kg) under a fixed-ratio 1 (FR 1) schedule during three, 2 h short-access sessions. Subsequently, performance was briefly assessed under a progressive ratio (PR) schedule for 3 doses of cocaine (0.2, 0.8, and 3.2 mg/kg). Following PR testing, the cocaine dose was then changed to 0.4 mg/kg. Session length was then extended to 6 h for 21 days (extended access), and 0.4 mg/kg cocaine was available under a FR 1 schedule. After the 21-day extended access phase, responses and infusions under the short access FR and PR dose-response conditions were reassessed. The results indicated that HiI rats escalated cocaine-reinforced responding during the extended access condition, but LoI rats did not. HiI rats also earned significantly more infusions than LoI rats under the post-escalation short access FR condition. However, HiI and LoI rats did not differ under the pre- and post-extended access PR conditions. This study suggests that individual differences in impulsivity predict escalation of cocaine self-administration in female rats, which may have implications in the prediction of binge-like patterns of cocaine intake in women.     

Parametric studies of selective D1 or D2 antagonists: effects on appetitive and feeding behaviour

Dopamine receptor antagonists have long been known to suppress food intake. The main purpose of the present series of experiments was to investigate feeding in rats across several paradigms evaluating the effects of selective dopamine D1 and D2 antagonists. The selective D1 antagonist, SCH 23390, reduced FR8 operant responding for food (0.03mg/kg, s.c.) at a dose lower than that required to reduce food intake in two free-feeding situations (0.1mg/kg, s.c.). The selective D2 antagonist, YM 09151-2, had a biphasic effect on food intake in food-deprived rats, increasing food intake at a low dose (0.01mg/kg, i.p.), but decreasing intake at higher doses in deprived rats (0.1mg/kg, i.p.). A combination of subthreshold doses of SCH 23390 and YM 09151-2 resulted in a significant reduction in food intake. In nondeprived rats eating palatable food and in animals trained on an FR8 schedule of reinforcement, YM09151-2 exerted significant suppressant effects. The results suggest that the operant response is more sensitive to the effects of selective D1 and D2 antagonism than is the consummatory response. The findings also suggest a specific inhibitory role for dopamine D2 (and not D1) receptors on food intake, since selective D1 antagonism did not produce increases in food intake at any of the doses tested. This provides evidence that under some circumstances the effects of D1 and D2 receptor blockade are dissociable.     

Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats

Rationale Previous research in humans suggests a relationship between drug abuse and impulsivity as shown by selection of a smaller immediate reward over a larger delayed reward. However, it is not clear whether impulsivity precedes drug abuse or drug abuse influences impulsivity.Objective The hypothesis of the present experiment was that rats selected for choosing smaller, immediate over larger, delayed food would acquire IV cocaine self-administration faster than those choosing larger, delayed food rewards.Methods Female rats were screened for locomotor activity and trained on a delay discounting procedure that allowed them access to two response levers and a food pellet dispenser. Under a fixed-ratio (FR) 1 schedule, responding on one lever resulted in immediate delivery of one 45 mg pellet, while responding on the other lever resulted in delivery of three 45 mg pellets after a variable delay that increased after responses on the delay lever and decreased after responses on the immediate lever. For each rat, a mean adjusted delay (MAD) was calculated for each daily session, and stability was defined as MADs varying less than 5 s across 5 days. Based on their average MADs, rats were separated into low impulsive (LoI) and high impulsive (HiI) groups, implanted with an indwelling IV catheter, and trained to lever press for cocaine (0.2 mg/kg) under an FR1 schedule.Results There were no differences in locomotor activity between the LoI and HiI groups; however, a greater percentage of the HiI group acquired cocaine self-administration, and they did so at a significantly faster rate than the LoI rats.Conclusions Performance on the delay discounting model of impulsivity predicted vulnerability to subsequent acquisition of cocaine self-administration.     

Reward-potentiating effects of D-1 dopamine receptor agonist and AMPAR GluR1 antagonist in nucleus accumbens shell and their modulation by food restriction

RATIONALE: Previous studies have suggested that chronic food restriction (FR) increases sensitivity of a neural substrate for drug reward. The neuroanatomical site(s) of key neuroadaptations may include nucleus accumbens (NAc) where changes in D-1 dopamine (DA) receptor-mediated cell signaling and gene expression have been documented. OBJECTIVES: The purpose of the present study was to begin bridging the behavioral and tissue studies by microinjecting drugs directly into NAc medial shell and assessing behavioral effects in free-feeding and FR subjects. MATERIALS AND METHODS: Rats were implanted with microinjection cannulae in NAc medial shell and a subset were implanted with a stimulating electrode in lateral hypothalamus. Reward-potentiating effects of the D-1 DA receptor agonist, SKF-82958, AMPAR antagonist, DNXQ, and polyamine GluR1 antagonist, 1-na spermine, were assessed using the curve-shift method of self-stimulation testing. Motor-activating effects of SKF-82958 were also assessed. RESULTS: SKF-82958 (2.0 and 5.0 mug) produced greater reward-potentiating and motor-activating effects in FR than ad libitum fed (AL) rats. DNQX (1.0 mug) and 1-na spermine (1.0 and 2.5 mug) selectively decreased the x-axis intercept of rate-frequency curves in FR subjects, reflecting increased responding for previously subthreshold stimulation. CONCLUSIONS: Results suggest that FR may facilitate reward-directed behavior via multiple neuroadaptations in NAc medial shell including upregulation of D-1 DA receptor function involved in the selection and expression of goal-directed behavior, and increased GluR1-mediated activation of cells that inhibit nonreinforced responses.     

Behavioral effects of arecoline in rats

Summary Effects of arecoline (0.25–4 mg/kg) were studied on several behavioral schedules in rats. It usually decreased the responses, especially at high doses, in schedules including spontaneous motor activity, FR (water and food) and FI (food) reinforcement, DRL and shock avoidance. Slight enhancement of responses was observed at low doses in spontaneous activity, FR (food) reinforcement, FI reinforcement and shock avoidance. Arecoline methiodide had negligible and insignificant effects.The depressant effect of arecoline (2 mg/kg) in the spontaneous activity schedule could be antagonized by scopolamine (0.25 and 0.1 mg/kg), but not by methylscopolamine (0.5 mg/kg) and mecamylamine (2 mg/kg). On the other hand, arecoline induced behavioral depression under FR water and food reinforcement could neither be antagonized by scopolamine (0.025–0.1 mg/kg) that itself caused depression, nor by mecamylamine (2 mg/kg).Supported by a Grant No. U100472 from the U. S. Public Health Service.     

Sex-dependent effects of periadolescent exposure to the cannabinoid agonist CP-55,940 on morphine self-administration behaviour and the endogenous opioid system

Early cannabinoid consumption may predispose individuals to the misuse of addictive drugs later in life. However, there is a lack of experimental evidence as to whether cannabinoid exposure during adolescence might differently affect opiate reinforcing efficacy and the opioid system in adults of both sexes. Our aim was to examine whether periadolescent chronic exposure to the cannabinoid agonist CP-55,940 could exert sex-dependent effects on morphine reinforcing and the opioid system in adulthood. Morphine reinforcing was studied under a progressive ratio (PR) reinforcement schedule in adult male and female rats that previously acquired morphine self-administration under a fixed ratio 1 (FR1) schedule. Binding levels and functionality of mu-opioid receptors were also evaluated. Periadolescent cannabinoid exposure altered morphine self-administration and the opioid system in adult rats in a sex-dependent manner. CP-55,940-exposed males exhibited higher self-administration rates under a FR1, but not under a PR schedule. In females, CP-55,940 did not modify morphine self-administration under either schedule. Moreover, CP-55,940 also increased mu-opioid receptor levels in the subcallosal streak of pre-treated animals and decreased mu-opioid receptor functionality in the nucleus accumbens shell but again, only in males. Our data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.