␥-Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug of abuse, although its mechanism of action is poorly understood. This study characterized the role of GABA A , GABA B , and other receptors in the discriminative stimulus effects of GHB. Eight rats reliably discriminated 200 mg/kg GHB from saline after a median of 35 (range: 23-41) training sessions. GHB, a metabolic precursor 1,4-butanediol (1,4-BDL), and the GABA B agonist (Ϯ)baclofen all occasioned greater than 83% responding on the GHB lever. The onset of action was similar for GHB and 1,4-BDL; however, 1,4-BDL exhibited a longer duration of action than GHB. The GHB precursor ␥-butyrolactone, the benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist morphine, and the Nmethyl-D-aspartate antagonist ketamine elicited substantial GHB-appropriate responding, although none occasioned greater than 66% drug-lever responding. The barbiturate pentobarbital and the GABA A receptor agonist muscimol did not occasion greater than 17% drug-lever responding at any dose tested. The benzodiazepine antagonist flumazenil attenuated GHB-lever responding occasioned by diazepam, but not GHB. The GABA B receptor antagonist CGP 35348 antagonized GHBlever responding occasioned by baclofen or GHB. Small doses of the purported GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a] [7]annulen-6-ylidene ethanoic acid (NCS-382) attenuated partially the effects of GHB, whereas larger doses of NCS-382 alone occasioned partial GHB-lever responding. These results implicate GABA B mechanisms in the discriminative stimulus effects of GHB and further suggest that the effects of 1,4-BDL under these conditions result from its conversion to GHB. That NCS-382 shares effects with GHB could explain the lack of antagonism reported for NCS-382 in some studies.

␥-Hydroxybutyrate (GHB) is an emerging drug of abuse with multiple mechanisms of action. This study is part of an effort to examine the role of GHB, GABA A , and GABA B receptors in the discriminative stimulus (DS) effects of GHB. In pigeons trained to discriminate 100 mg/kg GHB from saline, GHB and its precursors ␥-butyrolactone and 1,4-butanediol produced 80 to 100% GHB-appropriate responding, whereas other compounds such as morphine, naltrexone, cocaine, and haloperidol produced no more than 34%. Compounds interacting with GABA receptors produced different maximal levels of GHBappropriate responding. For example, the GABA A agonist muscimol produced 3%; the GABA A -positive modulators diazepam, pentobarbital, and ethanol, and the GABA B agonist baclofen produced levels ranging from 54 to 73%; and the benzodiazepine antagonist flumazenil and inverse agonist Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-␣]-[1,4]-benzodiazepine-3-carboxylate) both produced 96%. The putative GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a] [7]annulen-6-ylidene ethanoic acid (NCS-382) produced 70% GHB-appropriate responding. The GABA B antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) completely blocked the GHB-like DS effects of NCS-382 and baclofen at a dose of 56 mg/kg. CGP 35348 also blocked the DS effects of GHB, but incompletely and only at a dose of 560 mg/kg. Together, these results are consistent with a role for diazepam-sensitive and -insensitive GABA A and GABA B receptors in the DS effects of GHB. Together with previous findings, the present results suggest that diazepam-insensitive GABA A receptors are more prominently involved in the DS effects of GHB in pigeons than in rats, whereas GABA B receptors are less prominently involved. Exploring the role of GHB receptors with NCS-382 is hampered by its GABA B receptor-mediated, GHB-like agonist activity.

In the current literature, there are a number of cognitive training studies that use N-back tasks as their training vehicle; however, the interventions are often bland, and many studies suffer from considerable attrition rates. An increasingly common approach to increase participant engagement has been the implementation of motivational features in training tasks; yet, the effects of such “gamification” on learning have been inconsistent. To shed more light on those issues, here, we report the results of a training study conducted at two Universities in Southern California. A total of 115 participants completed 4 weeks (20 sessions) of N-back training in the laboratory. We varied the amount of “gamification” and the motivational features that might make the training more engaging and, potentially, more effective. Thus, 47 participants trained on a basic color/identity N-back version with no motivational features, whereas 68 participants trained on a gamified version that translated the basic mechanics of the N-back task into an engaging 3D space-themed “collection” game (Deveau et al. Frontiers in Systems Neuroscience, 8, 243, 2015). Both versions used similar adaptive algorithms to increase the difficulty level as participants became more proficient. Participants’ self-reports indicated that the group who trained on the gamified version enjoyed the intervention more than the group who trained on the non-gamified version. Furthermore, the participants who trained on the gamified version exerted more effort and also improved more during training. However, despite the differential training effects, there were no significant group differences in any of the outcome measures at post-test, suggesting that the inclusion of motivational features neither substantially benefited nor hurt broader learning. Overall, our findings provide guidelines for task implementation to optimally target participants’ interest and engagement to promote learning, which may lead to broader adoption and adherence of cognitive training.

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Although patients with γδ and αβ T-LGL leukemia show some different clinical or phenotypic features, overall survival is similar, suggesting that γδ TCR expression does not carry prognostic significance.