Biphasic effects of Δ9-tetrahydrocannabinol on brain stimulation reward and motor activity.

Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the main psychoactive ingredient of marijuana, has led to equivocal results when tested with the intracranial self-stimulation (ICSS) procedure or the open-field test for motor activity, two behavioural models for evaluating the reward-facilitating and locomotor stimulating effects of drugs of abuse, respectively. Therefore, in the present study, the effects of high and low doses of Δ(9)-THC were compared in the ICSS procedure and the open-field test. Moreover, the involvement of CB(1) receptors in tentative Δ(9)-THC-induced effects was investigated by pre-treating the animals with the CB(1) receptor antagonist SR141716A (rimonabant). The results obtained show that low doses of Δ(9)-THC induce opposite effects from high doses of Δ(9)-THC. Specifically, 0.1 mg/kg Δ(9)-THC decreased ICSS thresholds and produced hyperactivity, whereas 1 mg/kg increased ICSS thresholds and produced hypoactivity. Both effects were reversed by pre-treatment with SR141716A, indicating the involvement of CB(1) receptors on these actions. Altogether, our results indicate that Δ(9)-THC can produce acute activating effects in locomotion that coincide with its reward-facilitating effects in the ICSS paradigm. The present findings provide further support that Δ(9)-THC induces behaviours typical of abuse and substantiate the notion that marijuana resembles other drugs of abuse.

Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus.

Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.

Differential effects of chronic voluntary wheel-running on morphine induced brain stimulation reward, motor activity and striatal dopaminergic activity.

Physical exercise could be a protective factor against the development of substance use disorders; however, a number of preclinical studies report reward-enhancing effects of exercise for various drugs of abuse. We examined the effects of chronic wheel-running on brain reward sensitivity, reaction to novelty, reward-facilitating and locomotor-stimulating effects of morphine, using the intracranial self-stimulation (ICSS) and the open field test (OFT). Male Sprague-Dawley rats were randomly assigned to a sedentary or exercised group. For the ICSS procedure, rats were implanted with electrodes and trained to respond for electrical stimulation. Several indices were recorded in the training phase to estimate brain reward sensitivity. Once responding was stable, the animals of both groups received systemic injections of morphine and their ICSS thresholds were measured with the curve-shift paradigm. Employing the OFT, basal and morphine-induced locomotor activity was measured. Finally, basal and morphine-evoked tissue levels of dopamine and its metabolites were determined in the striatum using gas chromatography/mass spectrometry. Chronic wheel-running decreased brain reward sensitivity and subsequently increased the reward-facilitating effect of morphine. Exercised animals demonstrated a decreased reaction to novelty and reduced morphine-induced locomotion. Lastly, dopaminergic activity was decreased in the striatum of exercised animals under basal conditions, whereas morphine administration led to an increase in dopamine turnover. These findings indicate that chronic voluntary exercise exerts divergent effects on reward function, psychomotor activity and the reward-facilitating and locomotor-activating effects of opioids during adulthood. Our results provide insights into the increased non-medical use of opioids among young athletes reported in the literature.

Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit morphine's rewarding effect in rats.

RATIONALE: Recent animal studies reported that curcumin, the active constituent of Curcuma longa, has several central actions and may attenuate morphine tolerance. OBJECTIVES: In the present study, we utilized the intracranial self-stimulation (ICSS) paradigm to examine the effects of the commercially available curcuminoid mixture and each one of its components, individually, on brain stimulation reward and on the reward-facilitating effect of morphine. METHODS: Male Sprague-Dawley rats were implanted with an electrode into the medial forebrain bundle and trained to respond for electrical stimulation using a rate-frequency paradigm. In the first study, rats were injected with graded doses either of the curcuminoid mixture, or curcumin I, or II, or III. In the second study, we examined whether a low dose of the curcuminoid mixture or each individual curcumin analogue composing it could counteract the reward-facilitating effect of morphine. RESULTS: At low doses, both the curcuminoid mixture and curcumin I did not affect brain stimulation reward, whereas, higher doses increased ICSS thresholds. Curcumin II and curcumin III did not affect brain stimulation reward at any doses. Subthreshold doses of the curcuminoid mixture and curcumin I inhibited the reward-facilitating effect of morphine. CONCLUSION: Both the curcuminoid mixture and curcumin I lack hedonic properties and moderate the reward-facilitating effect of morphine. Our data suggest that curcumin interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids and provide evidence that curcumin may be a promising adjuvant for attenuating morphine's rewarding effects in patients who are under long-term opioid therapy.

Role of serotonin 5-HT2A and 5-HT2C receptors on brain stimulation reward and the reward-facilitating effect of cocaine.

RATIONALE: The serotonin 5-HT(2A) and 5-HT(2C) receptors, which are found in abundance in the mesolimbocortical dopaminergic system, appear to modulate the behavioral effects of cocaine. OBJECTIVES: The present series of studies set out to investigate the role of 5-HT(2A) and 5-HT(2C) receptors on brain reward and on the reward-facilitating effect of cocaine and localize the neural substrates within the mesolimbocortical dopaminergic system that are responsible for these effects. METHODS: Male Sprague-Dawley rats were implanted with stimulating electrodes and bilateral cannulae for the experiments involving microinjections and were trained to respond to electrical stimulation. In the first study, we examined the effects of systemic administration of selective 5-HT(2A) and 5-HT(2C) receptor agonists (TCB-2 and WAY-161503) and antagonists (R-96544 and SB-242084) on intracranial self-stimulation (ICSS). In the second study, we examined the effectiveness of TCB-2, WAY-161503, R-96544, and SB-242084 in blocking the reward-facilitating effect of cocaine. In the third study, we examined the effects of intra-medial prefrontal cortex (mPFC), intra-nucleus accumbens (NAC), and intra-ventral tegmental area (VTA) injection of WAY-161503 on the reward-facilitating effect of cocaine. RESULTS: Acute systemic administration of TCB-2 and WAY-161503 increased ICSS threshold. Systemic WAY-161503 attenuated the reward-facilitating effect of cocaine. This effect was reversed by pretreatment with SB-242084. Intracranial microinjections of WAY-161503 into the mPFC and the NAC shell/core, but not the VTA, attenuated the reward-facilitating effect of cocaine. CONCLUSION: These data indicate that 5-HT(2C) receptors within the mPFC and the NAC modulate the reinforcing effects of cocaine and provide evidence that 5-HT(2C) receptor agonists could be a possible drug discovery target for the treatment of psychostimulant addiction.