A unique multi-synaptic mechanism involving acetylcholine and GABA regulates dopamine release in the nucleus accumbens through early adolescence in male rats.

Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent stimulated dopamine release in male rats, as well as opposite effects of the a6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The a6-selective blocker, a-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this a6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of a6 nAChR and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at a6-containing nAChRs to drive inhibitory GABA tone on dopamine release.

Diurnal rhythms in cholinergic modulation of rapid dopamine signals and associative learning in the striatum.

Dysregulation of biological rhythms plays a role in a wide range of psychiatric disorders. We report mechanistic insights into the rhythms of rapid dopamine signals and cholinergic interneurons (CINs) working in concert in the rodent striatum. These rhythms mediate diurnal variation in conditioned responses to reward-associated cues. We report that the dopamine signal-to-noise ratio varies according to the time of day and that phasic signals are magnified during the middle of the dark cycle in rats. We show that CINs provide the mechanism for diurnal variation in rapid dopamine signals by serving as a gain of function to the dopamine signal-to-noise ratio that adjusts across time of day. We also show that conditioned responses to reward-associated cues exhibit diurnal rhythms, with cue-directed behaviors observed exclusively midway through the dark cycle. We conclude that the rapid dopamine signaling rhythm is mediated by a diurnal rhythm in CIN activity, which influences learning and motivated behaviors across the time of day.

Design, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability.

The sphingomyelin pathway is important in cell regulation and determining cellular fate. Inhibition of sphingosine kinase isoform 1 (SK1) within this pathway, leads to a buildup of sphingosine and ceramide, two molecules directly linked to cell apoptosis, while decreasing the intracellular concentration of sphingosine-1-phosphate (S1P), a molecule linked to cellular proliferation. Recently, an inhibitor capable of inhibiting SK1 in vitro was identified, but also shown to be ineffective in vivo. A set of compounds designed to assess the impact of synthetic modifications to the hydroxynaphthalene ring region of the template inhibitor with SK1 to obtain a compound with increased efficacy in vivo. Of these fifteen compounds, 4A was shown to have an IC50 = 6.55 µM with improved solubility and in vivo potential.