No abstract

The administration of cannabidiol has shown promising evidence in the treatment of some neuropsychiatric disorders, including cocaine addiction. However, little information is available as to the mechanisms by which cannabidiol reduces drug use and compulsive seeking. We investigated the role of adult hippocampal neurogenesis in reducing cocaine voluntary intake produced by repeated cannabidiol treatment in mice. Cocaine intake was modelled using the intravenous cocaine self‐administration procedure in CD1 male mice. Cannabidiol (20 mg/kg) reduced cocaine self‐administration behaviour acquisition and total cocaine intake and enhanced adult hippocampal neurogenesis. Our results show that a 6‐day repeated temozolomide treatment (25 mg/kg/day), a chemotherapy drug that blocks hippocampal neurogenesis, prevented cannabidiol‐induced increment in the early stages of neuronal maturation and differentiation, without altering the basal levels of BrdU/NeuN and doublecortin immunostaining. The reduction of total cocaine intake and operant behaviour acquisition observed following cannabidiol exposure was attenuated by temozolomide treatment. Our results also show a similar effect of temozolamide on a cannabidiol‐induced improvement of novel object recognition memory, a task influenced by the proneurogenic effects of cannabidiol (10 and 20 mg/kg). The anxiolytic effects of cannabidiol (10 and 20 mg/kg), however, remained unaffected after its proneurogenic effects decreased. The present study confirms that adult hippocampal neurogenesis is one of the mechanisms by which cannabidiol lowers cocaine reinforcement and demonstrates the functional implication of adult hippocampal neurogenesis in cocaine voluntary consumption in mice. Such findings highlight the possible use of cannabidiol for developing new pharmacotherapies to manage cocaine use disorders.

Early‐life stress (ELS) is associated with negative consequences, including maladaptive long‐lasting brain effects. These alterations seem to increase the likelihood of developing substance use disorders. However, the molecular consequences of ELS are poorly understood. In the present study, we tested the impact of ELS induced by maternal separation with early weaning (MSEW) in CD1 male mice at different phases of cocaine self‐administration (SA). We also investigated the subsequent alterations on GluR2, GluR1, cAMP response element‐binding (CREB), and CREB‐phosphorylation (pCREB) in ventral tegmental area (VTA) and nucleus accumbens (NAc) induced by both MSEW and cocaine SA. Our results show that MSEW animals expressed a higher cocaine intake, an increased vulnerability to the acquisition of cocaine SA, and incapacity to extinguish cocaine SA behaviour. MSEW mice showed decreased GluR2 and increased GluR1 and pCREB in NAc. Also, results displayed reduction of basal levels of GluR1 and CREB and an elevation of GluR1/GluR2 ratio in the VTA. Such results hint at an enhanced glutamatergic function in NAc and increased excitability of VTA DA neurons in maternally separated mice. Altogether, our results suggest that MSEW induces molecular alterations in the brain areas related to reward processing, increasing the vulnerability to depression and cocaine‐seeking behaviour.

Social defeat stress induces a long-lasting increase in anxiety like behavior. • Social defeat stress enhances rewarding properties of cocaine. • Social defeat stress increase BDNF levels in prefrontal cortex. • Oxytocin treatment favors the extinction of cocaine-associated memories. • Oxytocin administration counteracts stress effect in anxiety and in BDNF levels.

MDPV exposure during adolescence induced long-lasting adaptive changes related to enhanced responsiveness to cocaine in the adult mice that seems to lead to a higher vulnerability to cocaine abuse. This particular behaviour correlated with increased expression of ΔFosB.

Clindamycin is an antimicrobial agent metabolized by CYP3A4. Gender may influence the pharmacokinetics of drugs metabolized by this pathway, however, no information about differences in the pharmacokinetics of clindamycin in men and women is available. The purpose of this study was to evaluate gender differences in clindamycin oral pharmacokinetics. Twenty-four subjects (11 men and 13 women) received an oral 600 mg dose of clindamycin under fasting conditions and plasma concentrations were obtained at selected times during 12 h. Increased plasma levels were observed in women, but when the dose was normalized by the body weight of individuals, these differences disappeared, indicating that gender does not play an important role in the pharmacokinetics of this drug.

No abstract

Motivational deficits characterized by an unwillingness to overcome effortful costs are a common feature of neuropsychiatric and neurologic disorders that are insufficiently understood and treated. Dopamine (DA) signaling in the nucleus accumbens (NAc) facilitates goal-seeking, but how NAc DA release encodes motivationally salient stimuli to influence effortful investment is not clear. Using fast-scan cyclic voltammetry in male and female mice, we find that NAc DA release diametrically responds to cues signaling increasing cost of reward, while DA release to the reward itself is unaffected by its cost. Because endocannabinoid (eCB) signaling facilitates goal seeking and NAc DA release, we further investigated whether repeated augmentation of the eCB 2-arachidonoylglycerol with a low dose of a monoacylglycerol lipase (MAGL) inhibitor facilitates motivation and DA signaling without the development of tolerance. We find that chronic MAGL treatment stably facilitates goal seeking and DA encoding of prior reward cost, providing critical insight into the neurobiological mechanisms of a viable treatment for motivational deficits.