No abstract

The effects of the high-affinity dopamine reuptake inhibitor, GBR 12909, were studied on responding maintained under multiple fixed ratio schedules of food and cocaine delivery in rhesus monkeys (Macaca mulatta). GBR 12909 decreased rates of responding maintained by both events in a dose-related manner, however large decreases in cocaine-maintained responding could be obtained with doses of GBR 12909 that had little effect on food-maintained responding. This behaviorally selective effect of GBR 12909 on cocaine-maintained responding was inversely related to the unit dose of cocaine. When responding was maintained by low doses of cocaine, GBR 12909 (1 mg/kg) decreased cocaine-maintained responding almost completely. When responding was maintained by the highest dose, the same dose of GBR 12909 had little effect on responding. To the extent that higher doses of cocaine may be expected to be more reinforcing, the current results suggest that the effect of GBR 12909 on cocaine-maintained responding was determined by the reinforcing efficacy of the unit dose of cocaine.

Gamma-aminobutyric acid (GABA), dopamine, and opioids are implicated in impulse control, addiction and binge eating. Recent evidence suggests that sucrose alters the effects of GABAergic, dopaminergic, and opioid receptor ligands on consumption of a fatty food in a rat limited-access binge protocol. This study determined the independent effects of fat and sucrose on the efficacy of these ligands under limited-access conditions. Nonfood-deprived male Sprague-Dawley rats had 1 h access to fat (vegetable shortening) or sucrose (3.2, 10, or 32% w/v). Half had intermittent access (Monday, Wednesday, Friday) and half had daily access. Effects of baclofen (GABAB agonist), SCH 23390 (D1 antagonist), raclopride (D2 antagonist), and naltrexone (opioid antagonist) were assessed. Baclofen and naltrexone reduced fat intake regardless of the access schedule. Baclofen had no effect on sucrose intake; naltrexone reduced sucrose intake at higher doses than were required to reduce fat intake. Raclopride stimulated fat intake in intermittent-access rats and had no effect in daily-access rats; raclopride reduced sucrose intake in all groups. SCH 23390 reduced intake in a nonspecific manner. The results indicate the involvement of GABAB receptors in fat but not sucrose intake, and of D2 receptor dysfunction in rats with a history of bingeing on fat.

The GABA-B agonist baclofen reduces drug self-administration in rats and has shown promise clinically in the treatment of substance abuse. Baclofen generally does not reduce food intake in non-binge feeding protocols. In this study, baclofen was tested in a fat-binge protocol. Thirty male rats were divided into three groups (B: binge; FM: fat-matched; C: chow). B received a bowl of vegetable shortening for 2 h on Monday, Wednesday, and Friday (MWF) and continuous access to powdered chow (regular chow) in all phases. FM had continuous access to a regular chow+shortening mixture (FM chow) that provided the same proportion of shortening and regular chow that the B rats consumed in all phases. In addition, FM had the following: phase 1: no separate bowl of shortening; phase 2: 2-h MWF access to a separate bowl of shortening; phase 3, daily 2-h access to a separate bowl of shortening; C rats had continuous access to the regular chow in all phases. In addition, C had the following: phase 1: no separate bowl of shortening; phase 2: 2-h MWF access to a separate bowl of shortening; in phase 3, daily 2-h access to a separate bowl of shortening. Baclofen (1.0, 1.8 mg/kg, i.p.) reduced shortening intake regardless of access condition. Baclofen had no effect on, or stimulated, FM and regular chow intake. These results demonstrate that baclofen can reduce fat intake in rats under binge-type conditions. Furthermore, these results indicate that bingeing, as modeled in our protocol, is different from other forms of food intake and may share similarities with substance abuse.

A previous study (J.R. Glowa, F.H.E. showed that acute doses of GBR 12909 selectively decreased cocaine-maintained responding without affecting foodmaintained responding. This report extended these observations to some related drugs and to the effects of repeated administration. When responding was maintained under a multiple fixed ratio (FR) 30 food, FR 30 cocaine schedule, acute doses of GBR 12935, CFT, and d-amphetamine decreased cocaine-maintained responding more than food-maintained responding. However, in contrast to GBR 12909, none of these drugs completely decreased cocaine-maintained responding without affecting food-maintained responding. Repeated administration of GBR 12909 sustained, and of GBR 12935 improved, these selective decreases in cocaine-maintained responding. The selective effect of these dopamine reuptake inhibitors on cocaine-maintained responding is consistent with their known pharmacological selectivity for the dopamine reuptake site and can be well-maintained with repeated administration.Glowa, found that the high-affinity dopamine (DA) reuptake inhibitor, GBR 12909, could decrease responding maintained by cocaine at doses that did not have effects on comparable rates of food-maintained responding. Similar results have been reported for other drugs. For example, Mello, Mendelson, Bree, & Lucas (1989) reported that the opioid buprenorphine suppressed cocaine self-administration in rhesus monkeys at doses that had little effect on food-maintained responding. These types of effects are of interest because few studies have reported comparable differences in the effects of other drugs on food-and drugmaintained responding. To the extent that it would be desirable for a treatment drug to selectively decrease cocaineseeking behavior, this type of effect may be useful in identifying therapeutic agents comparable to those used for heroin (e.g., methadone) or nicotine (e.g., nicotine patches) abuse. In

Previous work in rats has demonstrated that an Intermittent (Monday, Wednesday, Friday) schedule of access promotes binge-type consumption of 100% vegetable shortening during a 1-hour period of availability. The present study used novel shortening-derived stable solid emulsions of various fat concentrations. These emulsions were the consistency of pudding and did not demonstrate oil and water phase separation previously reported with oil-based liquid emulsions. Male Sprague-Dawley rats were grouped according to schedule of access (Daily or Intermittent) to one of three concentrations (18%, 32%, 56%) of solid fat emulsion. There were no significant Intermittent vs. Daily differences in amount consumed, due to high intakes in all groups. This indicated the acceptability of the emulsions. Baclofen (GABA-B agonist) and raclopride (D2-like antagonist) both significantly reduced emulsion intake in all Daily groups, but only in the 56% fat Intermittent group. Naltrexone (opioid antagonist), in contrast, significantly reduced 32% and 56% fat emulsion intake in the Intermittent, as well as the Daily groups. These results indicate that the fat intake reducing effects of GABA B activation and D2 blockade depend upon fat concentration and schedule of fat access, while the fat intake reducing effects of opioid blockade depend upon fat concentration but not schedule of access.

Binge eating and substance dependence are disorders characterized by a loss of control over consummatory behaviors. Given the common characteristics of these two types of disorders, it is not surprising that the comorbidity between eating disorders and substance abuse disorders is high (20–40%; Conason et al., 2006). It is unknown, however, whether loss of control in one disorder predisposes an individual to loss of control in the other. The present study, therefore, used a rodent model to test whether a history of binge eating would augment subsequent responding for cocaine. Using the limited access protocol described by Corwin et al. (1998), 45 adult male Sprague-Dawley rats were maintained on one of four dietary protocols for a period of six weeks: chow only (Chow; n=9), continuous access to an optional source of dietary fat (Ad Lib; n=12), 1-h access to an optional source of dietary fat daily (Daily; n=12), or 1-h access to an optional source of dietary fat on Monday, Wednesday, and Friday (MWF; n=12). All four groups also had unrestricted access to a nutritionally complete diet of chow and water. Fat-bingeing behaviors developed in the MWF rats, the group with the most restricted access to the optional fat. Thereafter, cocaine-seeking and –taking behaviors were assessed in all rats using a self-administration protocol modified from that described by Deroche-Gamonet et al. (2004), which focus on the motivation for and preoccupation with obtaining and consuming drug (assessed using a progressive ratio (PR) schedule of reinforcement) and persistence in responding for drug during periods of signaled drug non-availability (SNA). Rats with the MWF history tended to take more cocaine late in fixed ratio (FR) training, they persisted in their efforts to obtain cocaine in the face of signaled non-availability, worked harder for cocaine on a PR schedule of reinforcement, and exhibited more goal-directed behavior towards the cocaine-associated operandum. These results demonstrate a link between binge-type intake of fat and the development of drug-seeking and -taking behaviors, suggesting that a history of fat bingeing may predispose individuals to exhibit more robust “addiction-like” behaviors toward a substance of abuse. Thus, it appears that conditions promoting excessive behavior toward one substance (e.g., a palatable fatty food) beget excessive behavior toward another (e.g., cocaine).

Operant performance of non-food deprived rats (n=8) was assessed under progressive ratio (PR) and concurrent PR-fixed ratio schedules of food pellet and/or vegetable shortening reinforcement. Post operant baselines, rats were matched and divided into 2 groups based upon the schedule of shortening availability: High restriction binge group (H, 1-hr home cage shortening access each week on Monday, Wednesday, and Friday) and Low restriction (L, 1-hr shortening access daily). Chow and water were continuously available; only access to the shortening was restricted. After 8 weeks, operant performance was reassessed. Lever pressing for shortening increased in the H rats for all schedules, but was either unaffected or decreased in the L rats. Pellet responding under the concurrent schedules increased for both groups. The effects of four dosages of (R)-baclofen (0.3-1.8 mg/kg, i.p.) on operant performance were also assessed. For both groups, 1.0 mg/kg baclofen significantly reduced shortening responding relative to saline for all schedules except one, but had no or minimal effect on pellet responding. This suggests a specific effect of baclofen on responding maintained by fat. These results indicate that intermittent episodes of bingeing on fat can increase the reinforcing efficacy of fat and that GABAB receptor activation can attenuate this effect.