Naloxone-precipitated withdrawal causes an increase in impulsivity in morphine-dependent rats.

Opiate dependence is associated with increased impulsivity in both humans and animals. Although the state of withdrawal appears to contribute to this effect, a causal relationship has not been shown. Here, we test whether precipitating withdrawal in morphine-dependent rats through naloxone can cause increased impulsivity. Rats were trained on a delay discounting task and then randomly assigned to either a dependent group that received a nightly 30 mg/kg subcutaneous dose of morphine or a naive group that received nightly saline. Once dependence was established, 2-day test delay discounting curves were determined 1 h after three doses of naloxone (0, 0.25, 0.5 mg/kg). In dependent rats both doses of naloxone caused increased preference for the small reward at short delays. Naloxone had no effect on delay discounting in naive rats. We conclude that precipitating withdrawal in dependent rats can cause increased impulsivity.

Pharmacological Modulation of 5-HT2C Receptor Activity Produces Bidirectional Changes in Locomotor Activity, Responding for a Conditioned Reinforcer, and Mesolimbic DA Release in C57BL/6 Mice.

Converging lines of behavioral, electrophysiological, and biochemical evidence suggest that 5-HT2C receptor signaling may bidirectionally influence reward-related behavior through an interaction with the mesolimbic dopamine (DA) system. Here we directly test this hypothesis by examining how modulating 5-HT2C receptor activity affects DA-dependent behaviors and relate these effects to changes in nucleus accumbens (NAc) DA release. In C57BL/6 mice, locomotor activity and responding for a conditioned reinforcer (CRf), a measure of incentive motivation, were examined following treatment with three 5-HT2C receptor ligands: the agonist CP809101 (0.25-3 mg/kg), the antagonist SB242084 (0.25-1 mg/kg), or the antagonist/inverse agonist SB206553 (1-5 mg/kg). We further tested whether doses of these compounds that changed locomotor activity and responding for a CRf (1 mg/kg CP809101, 0.5 mg/kg SB242084, or 2.5 mg/kg SB206553) also altered NAc DA release using in vivo microdialysis in anesthetized mice. CP809101 reduced locomotor activity, responding for a CRf, and NAc DA release. In contrast, both SB242084 and SB206553 enhanced locomotor activity, responding for a CRf, and NAc DA release, although higher doses of SB206553 produced opposite behavioral effects. Pretreatment with the non-selective DA receptor antagonist α-flupenthixol prevented SB242084 from enhancing responding for a CRf. Thus blocking tonic 5-HT2C receptor signaling can release serotonergic inhibition of mesolimbic DA activity and enhance reward-related behavior. The observed bidirectional effects of 5-HT2C receptor ligands may have important implications when considering the 5-HT2C receptor as a therapeutic target for psychiatric disorders, particularly those presenting with motivational dysfunctions.

The 5-HT(2C) receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity.

Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction.

The effect of acute morphine on delay discounting in dependent and non-dependent rats.

RATIONALE: Chronic opiate use is associated with increased impulsivity in both humans and animals, and previous studies suggest that acute morphine can increase impulsivity in non-dependent rats. However, the extent to which chronic opiate usage modulates the effect of acute morphine is unknown. METHODS: Rats were trained to delay discount 20 % sucrose solution and then randomly assigned to either a dependent group that received a nightly 30 mg/kg subcutaneous dose of morphine or a non-dependent group that received a nightly saline injection. Once dependence was established, rats were then assigned to one of four acute morphine doses (0, 1.25, 2.5, 5 mg/kg). For 5 days, delay discounting curves were determined 22.5 h after maintenance doses and 1 h after their prescribed acute injections. RESULTS: In non-dependent rats, 2.5 and 5 mg/kg doses of morphine caused decreased preference for the large reward at all delays. Acute morphine had no effect on discounting curves in dependent rats. CONCLUSIONS: Morphine dependence can cause tolerance to the effects of acute morphine on delay discounting.

Delay discounting of oral morphine and sweetened juice rewards in dependent and non-dependent rats.

RATIONALE: Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats METHODS: We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose. RESULTS: Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly. CONCLUSIONS: These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.

The effect of morphine dependence on impulsive choice in rats.

RATIONALE: In the human opiate-dependent population, the most consistently reported deficit in executive functioning is impulsivity. Previous research has shown that acute and chronic exposure to drugs of abuse can increase impulsive choice; however, the extent to which opiate dependence contributes to increased impulsivity has not been examined. We report here the effects of morphine dependence on rats' delay discounting (DD) of a sucrose reward. METHODS: We assigned rats randomly to either a dependent group that received a nightly 30 mg/kg subcutaneous dose of morphine or a morphine-naive group that received a nightly saline injection. DD of a sucrose reward was examined in rats prior to initiation of the dosing regimen, 22.5 h after the daily maintenance dose, and after a 14-day abstinence period. RESULTS: The groups did not differ at baseline, but rats showed accelerated DD while dependent on morphine. After withdrawal from morphine, DD in previously dependent rats was not significantly different from that of naive rats. Since dependent rats also showed reduced motivation to acquire the sucrose reinforcer, we performed a separate experiment to test whether such a decrease in motivation could cause an increase in impulsivity. We found that food-deprived rats switched to a free-feeding diet did not differ in DD from rats maintained at 85 % of free-feeding weight. CONCLUSIONS: An increase in impulsivity can result from physical dependence on morphine and cannot be attributed to changes in motivation to acquire sucrose-reinforced responses.

Varying perceived social threat modulates pain behavior in male mice.

UNLABELLED: We previously demonstrated that male mice display significantly reduced pain behavior on the acetic acid abdominal constriction test when confined in close proximity to a stranger male mouse. We show here the testosterone-dependence (via castration and testosterone propionate replacement) of this phenomenon, likely a form of (social) stress-induced analgesia. However, when similar male dyads are separated by vertical metal bars, allowing only partial physical contact, we find that the mice exhibit hyperalgesia, not analgesia, in response to both acetic acid injection and noxious radiant heat, relative to testing in isolation. This finding is specific to same-sex male dyads, and no change in nociceptive sensitivity is observed when males are tested in the presence of a female conspecific. We propose that pain sensitivity varies with respect to the severity of the social threat: mild social threat produces hyperalgesia and more severe social threat produces analgesia. PERSPECTIVE: This work highlights the importance of social threat in modulating pain behavior in a sex-specific manner. The findings add to a growing body of evidence that social factors affect pain behavior in mice, thus allowing the study of the mechanistic underpinnings of social modulation of pain in humans.