Treatments for cognitive impairments associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder or narcolepsy, aim at modulating extracellular dopamine levels in the brain. CE-123 (5-((benzhydrylsulfinyl)methyl) thiazole) is a novel modafinil analog with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. We studied the neuropharmacological and behavioral effects of the S-enantiomer of CE-123 ((S)-CE-123) and R-modafinil in cognitive- and reward-related brain areas of adult male rats. In vivo single unit recordings in anesthetized animals showed that (S)-CE-123, but not R-modafinil, dose-dependently (1.25 to 10 mg/kg i.v.) reduced firing of pyramidal neurons in the infralimbic/prelimbic (IL/PrL) cortex. Neither compound the affected firing activity of ventral tegmental area dopamine cells. In freely moving animals, (S)-CE-123 (10 mg/kg i.p.) increased extracellular dopamine levels in the IL/PrL, with different patterns when compared to R-modafinil (10 mg/kg i.p.); in the nucleus accumbens shell, a low and transitory increase of dopamine was observed only after (S)-CE-123. Neither (S)-CE-123 nor R-modafinil initiated the emission of 50-kHz ultrasonic vocalizations, a behavioral marker of positive affect and drug-mediated reward. Our data support previous reports of the procognitive effects of (S)-CE-123, and show a minor impact on reward-related dopaminergic areas.

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Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence.

Rationale Sardinian alcohol-preferring (sP) rats displayed high sensitivity to time schedule and consumed intoxicating amounts of alcohol during the last portion of the dark phase of the light/dark cycle when exposed to daily drinking sessions of one hour, with concurrent availability of multiple alcohol concentrations, and unpredictability of time of alcohol access. Objectives The present study investigated whether sensitivity of sP rats to time schedule extended to operant procedures of alcohol self-administration. Methods In Experiment 1, three different alcohol solutions (10%, 20%, and 30%, v/v) were concurrently available under a Fixed Ratio 4 schedule of reinforcement and with unpredictable time schedule; water was available uncontingently. Experiments 2 and 3 assessed the sensitivity of the motivational properties of alcohol to time schedule; rats were exposed to (a) self-administration sessions under the Progressive Ratio (PR) schedule of reinforcement and (b) sessions of alcohol seeking under the extinction responding (ER) schedule. Results In Experiment 1, number of lever-responses and amount of self-administered alcohol were positively correlated with time of alcohol access during the dark phase. When the self-administration session occurred at the first and latest hours of the dark phase, the amount of self-administered alcohol averaged 0.95–1.0 and 1.55–1.65 g/kg, respectively. In Experiments 2 and 3, values of breakpoint and ER for alcohol were approximately 50% higher when the sessions occurred at the last than first hour of the dark phase. Conclusions The reinforcing and motivational properties of alcohol were sensitive to time schedule and stronger at the end of the dark phase.