Opioid modulation of social play reward in juvenile rats.

Social play behaviour is a vigorous form of social interaction abundant during the juvenile and adolescent phases of life in many mammalian species, including rats and humans. Social play is thought to be important for social, emotional and cognitive development. Being a rewarding activity, the expression of social play depends on its pleasurable and motivational properties. Since opioids have been widely implicated in reward processes, in the present study we investigated the role of opioids in the pleasurable and motivational properties of social play behaviour in rats. To assess social play motivation, an operant conditioning setup was used in which rats responded for social play under a progressive ratio schedule of reinforcement. Treatment with the opioid receptor agonist morphine reduced responding for social play at the highest dose tested, likely due to its rate-limiting effects. Morphine treatment increased the expression of social play behaviour during reinforced periods. The acquisition of social play-induced conditioned place preference (CPP) in a subeffective conditioning protocol was enhanced by treatment with morphine. Morphine treatment alone also induced CPP. In contrast, antagonizing opioid receptors with naloxone reduced responding for social play, the expression of social play and blocked the development of social play-induced CPP. These data implicate opioid neurotransmission in both the pleasurable and the motivational aspects of social play behaviour in rats. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Inactivation of the prelimbic or infralimbic cortex impairs decision-making in the rat gambling task.

RATIONALE: Studies employing the Iowa Gambling Task (IGT) demonstrated that areas of the frontal cortex, including the ventromedial prefrontal cortex, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex, and anterior cingulate cortex (ACC), are involved in the decision-making process. However, the precise role of these regions in maintaining optimal choice is not clear. OBJECTIVES: We used the rat gambling task (rGT), a rodent analogue of the IGT, to determine whether inactivation of or altered dopamine signalling within discrete cortical sub-regions disrupts decision-making. METHODS: Following training on the rGT, animals were implanted with guide cannulae aimed at the prelimbic (PrL) or infralimbic (IL) cortices, the OFC, or the ACC. Prior to testing, rats received an infusion of saline or a combination of baclofen and muscimol (0.125 µg of each/side) to inactivate the region and an infusion of a dopamine D2 receptor antagonist (0, 0.1, 0.3, and 1.0 µg/side). RESULTS: Rats tended to increase their choice of a disadvantageous option and decrease their choice of the optimal option following inactivation of either the IL or PrL cortex. In contrast, OFC or ACC inactivation did not affect decision-making. Infusion of a dopamine D2 receptor antagonist into any sub-region did not alter choice preference. CONCLUSIONS: Online activity of the IL or PrL cortex is important for maintaining an optimal decision-making strategy, but optimal performance on the rGT does not require frontal cortex dopamine D2 receptor activation. Additionally, these results demonstrate that the roles of different cortical regions in cost-benefit decision-making may be dissociated using the rGT.

THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine addiction.

Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using Δ(9)-tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction.

Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity.

Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.

Within-litter variation in maternal care received by individual pups correlates with adolescent social play behavior in male rats.

Maternal care represents an essential environmental factor during the first post-natal week(s) of rodents and is known to have lasting consequences for neuronal structure, brain function as well as behavioral outcome later in life, including social functions and reward-related processes. Previous experiments have shown that the amount of maternal care received by individual pups varies substantially, even within one litter. During adolescence, mammals display high levels of social play behavior, a rewarding form of social interaction that is of great importance for social and cognitive development. In order to investigate how maternal care influences adaptive social behavior later in life, we here examined whether individual differences in maternal licking and grooming (%LG) received during the first postnatal week affect social play behavior during adolescence. We observed that %LG received by male rats early in life correlates positively with the frequency and duration of pouncing and pinning, the two most characteristic behavioral expressions of social play behavior in rats. The latency to engage in social exploration also correlated with %LG. In female rats we observed no correlation between %LG and any social parameter. The data indicate that subtle variations in maternal care received early in life influence social interactions in male adolescent rats. These changes in social play likely have repercussions for the social development of male rats, suggesting that maternal care can have both direct and indirect effects on the behavioral development of the offspring.

Seeking-taking chain schedules of cocaine and sucrose self-administration: effects of reward size, reward omission, and α-flupenthixol.

RATIONALE: In heterogeneous seeking-taking (ST) chain schedules of self-administration, seeking rewards and taking rewards are distinct actions, giving animals explicit control over their intake of the reward. However, the neurobehavioral characteristics of ST chain schedules are relatively unexplored. OBJECTIVES: This study was made to evaluate two variants of ST chain schedules of self-administration to measure seeking and taking of sucrose and cocaine in rats. METHODS: Rats had to respond on one lever (seeking lever) under a random interval (RI) or under a progressive ratio (PR) schedule, to gain access to a second lever (taking lever), responding on which under a fixed-ratio 1 (FR-1) schedule of reinforcement delivered the reward. We assessed the effects of reward size, reward omission, and administration of the dopamine receptor antagonist α-flupenthixol. The effects of α-flupenthixol on responding for cocaine or sucrose under an FR-1 schedule of reinforcement were also assessed. RESULTS: Cocaine seeking under both schedules was reduced by decreasing reward size, reward omission, and α-flupenthixol treatment. Cocaine taking was decreased by α-flupenthixol treatment and reward omission, but not by altering reward size. Sucrose seeking was not affected by reward size, but was reduced by α-flupenthixol and reward omission. Sucrose taking was diminished by reward omission only. α-Flupenthixol increased cocaine but not sucrose intake under an FR-1 schedule of reinforcement. CONCLUSIONS: Both ST(PR) and ST(RI) schedules can be used to assess seeking and taking of sucrose and cocaine. Dopaminergic neurotransmission mediates the positive subjective properties of cocaine but not sucrose and the motivational properties of both sucrose and cocaine.

Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine.

RATIONALE: Drugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role in sensitization is unclear. Stimulation of dopamine receptors plays an important role in drug reward, but not in the sensitizing properties of cocaine and morphine. OBJECTIVE: This study aims to evaluate the role of mGlu5 and dopamine receptors in the development of cocaine- and morphine-induced conditioned place preference (CPP) and psychomotor sensitization. MATERIALS AND METHODS: Rats were treated with the mGlu5 receptor antagonist MTEP (0, 1, 3, and 10 mg/kg, i.p.) or the dopamine receptor antagonist α-flupenthixol (0, 0.125, 0.25, and 0.5 mg/kg, i.p.) during place conditioning with either morphine (3 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). Furthermore, MTEP (1 mg/kg, i.p.) or α-flupenthixol (0.5 mg/kg, i.p.) was co-administered during cocaine (30 mg/kg, i.p.) or morphine (3.0 mg/kg, s.c.) pretreatment and psychomotor sensitization was tested 3 weeks post-treatment. RESULTS: MTEP attenuated the development of morphine- but not cocaine-induced CPP. In contrast, MTEP suppressed the development of cocaine- but not morphine-induced psychomotor sensitization. α-Flupenthixol blocked the development of both cocaine- and morphine-induced CPP but did not affect the development of sensitization to either drug. CONCLUSION: Dopamine receptor stimulation mediates cocaine and morphine reward but not sensitization. In contrast, the role of mGlu5 receptors in reward and sensitization is drug-specific.

Expression of amphetamine sensitization is associated with recruitment of a reactive neuronal population in the nucleus accumbens core.

RATIONALE: Repeated exposure to psychostimulant drugs causes a long-lasting increase in the psychomotor and reinforcing effects of these drugs and an array of neuroadaptations. One such alteration is a hypersensitivity of striatal activity such that a low dose of amphetamine in sensitized animals produces dorsal striatal activation patterns similar to acute treatment with a high dose of amphetamine. OBJECTIVES: To extend previous findings of striatal hypersensitivity with behavioral observations and with cellular activity in the nucleus accumbens and prefrontal cortex in sensitized animals. MATERIALS AND METHODS: Rats treated acutely with 0, 1, 2.5, or 5 mg/kg i.p. amphetamine and sensitized rats challenged with 1 mg/kg i.p. amphetamine were scored for stereotypy, rearing, and grooming, and locomotor activity recorded. c-fos positive nuclei were quantified in the nucleus accumbens and prefrontal cortex after expression of sensitization with 1 mg/kg i.p. amphetamine. RESULTS: Intense stereotypy was seen in animals treated acutely with 5 mg/kg amphetamine, but not in the sensitized group treated with 1 mg/kg amphetamine. The c-fos response to amphetamine in the accumbens core was augmented in amphetamine-pretreated animals with a shift in the distribution of optical density, while no effect of sensitization was seen in the nucleus accumbens shell or prefrontal cortex. CONCLUSIONS: A lack of stereotypy in the sensitized group indicates a dissociation of behavioral responses to amphetamine and striatal immediate-early gene activation patterns. The increase in c-fos positive nuclei and shift in the distribution of optical density observed in the nucleus accumbens core suggests recruitment of a new population of neurons during expression of sensitization.

A reciprocal interaction between food-motivated behavior and diet-induced obesity.

OBJECTIVES: One of the main causes of obesity is overconsumption of diets high in fat and sugar. We studied the metabolic changes and food-motivated behavior when rats were subjected to a choice diet with chow, lard and a 30% sucrose solution (high fat high sugar (HFHS)-choice diet). Because rats showed considerable variations in the feeding response to HFHS-choice diet and in food-motivated behavior, we investigated whether the motivation to obtain a sucrose reward correlated with the development of obesity when rats were subsequently subjected to HFHS-choice diet. METHOD: We first studied feeding, locomotor activity and body temperature, fat weights and hormonal concentrations when male Wistar rats were subjected to HFHS-choice diet for 1 week. Second, we studied sucrose-motivated behavior, using a progressive ratio (PR) schedule of reinforcement in rats that were subjected to the HFHS-choice diet for at least 2 weeks, compared to control rats on a chow diet. Third, we measured motivation for sucrose under a PR schedule of reinforcement in rats that were subsequently subjected to HFHS-choice diet or a chow diet for 4 weeks. Fat weights were measured and correlated with the motivation to obtain sucrose pellets. RESULTS: One week on the HFHS-choice diet increased plasma concentrations of glucose and leptin, increased fat stores, but did not alter body temperature or locomotor activity. Moreover, consuming the HFHS-choice diet for several weeks increased the motivation to work for sucrose pellets. Furthermore, the motivation to obtain sucrose pellets correlated positively with abdominal fat stores in rats subsequently subjected to the HFHS-choice diet, whereas this correlation was not found in rats fed on a chow diet. CONCLUSION: Our data suggest that the motivation to respond for palatable food correlates with obesity due to an obesogenic environment. Conversely, the HFHS-choice diet, which results in obesity, also increased the motivation to work for sucrose. Thus, being motivated to work for sucrose results in obesity, which, in turn, increases food-motivated behavior, resulting in a vicious circle of food motivation and obesity.

Augmented reinforcer value and accelerated habit formation after repeated amphetamine treatment.

Various processes might explain the progression from casual to compulsive drug use underlying the development of drug addiction. Two of these, accelerated stimulus-response (S-R) habit learning and augmented assignment of motivational value to reinforcers, could be mediated via neuroadaptations associated with long-lasting sensitization to psychostimulant drugs, i.e. augmented dopaminergic neurotransmission in the striatum. Here, we tested the hypothesis that both processes, which are often regarded as mutually exclusive alternatives, are present in amphetamine-sensitized rats. Amphetamine-sensitized rats showed increased responding for food under a random ratio schedule of reinforcement, indicating increased incentive motivational value of food. In addition, satiety-specific devaluation experiments under a random interval schedule of reinforcement showed that amphetamine-sensitized animals exhibit accelerated development of S-R habits. These data show that both habit formation and motivational value of reinforcers are augmented in amphetamine-sensitized rats, and suggest that the task demands determine which behavioral alteration is most prominently expressed.

Reduced psychostimulant effects on dopamine dynamics in the nucleus accumbens of mu-opioid receptor knockout mice.

Dopamine neurotransmission in the nucleus accumbens plays a pivotal role in the reinforcing properties of drugs of abuse. Two interacting processes regulate nucleus accumbens dopamine overflow: release of dopamine from presynaptic terminals and the subsequent reuptake by dopamine transporters. Opioid neurotransmission, primarily through mu-opioid receptors has also been strongly implicated in drug reward. We have previously shown that mice lacking the mu-opioid receptor display decreased cocaine self-administration. In addition, we found decreased impulse activity of midbrain dopaminergic neurons and an increased GABAergic input to these neurons in mu-opioid receptor knockout mice. In the present study we investigated whether these changes in dopaminergic cell bodies are accompanied by altered dopamine dynamics at the terminal level. To that aim, we measured nucleus accumbens dopamine overflow using fast scan cyclic voltammetry. Our data demonstrate that in mu-opioid receptor knockout mice 1) the reuptake of dopamine in the nucleus accumbens is slower, and 2) the relative effect of cocaine and amphetamine on the reuptake of dopamine is smaller compared with wild type mice. These data provide a mechanism for the decreased reinforcing properties of cocaine observed in mu-opioid receptor knockout mice.