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 α6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The α6-selective blocker, α-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 α6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of α6 nAChRs 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 α6-containing nAChRs to drive inhibitory GABA tone on dopamine release.

During adolescence, chemicals and cells in the brain undergo significant reorganization. These changes are thought to be why teenagers are often more vulnerable to developing drug addictions and psychiatric disorders. However, it is not fully understood how the brain transforms during this transitional period. Most of this reorganization takes place in the dopamine system which is responsible for triggering pleasurable sensations, including the feeling of reward after taking drugs. In 2020, a group of researchers found that adolescent male rats released less of the chemical dopamine in a part of the brain involved in the reward pathway than adult rats. But it was unclear what was causing this age-related effect. To investigate, Iacino et al. ­ including some of the researchers involved in the 2020 study ­blocked a family of receptors called nAChRs (short for nicotinic acetylcholine receptors) in the brain cells of male rats. These receptors bind to a neurotransmitter called acetylcholine which stimulates cells to release dopamine. Iacino et al. found that inhibiting a specific type of nAChR led to a decrease in dopamine in adult rats, but an increase in early adolescent rats. However, this effect was not observed when other types of nAChRs were inhibited. Iacino et al. found that the adolescent male rats also had higher levels of another neurotransmitter called GABA which blocks the release of dopamine. This led them to hypothesize that the reduced levels of dopamine in early adolescence may be due to increased levels of GABA, which is secreted by specialized cells which also have nAChRs on their surface. To investigate, Iacino et al. blocked two receptors for GABA that are found on dopamine-releasing neurons before exposing the rats to the nAChR inhibitor. This caused the adolescent rats to release less dopamine following nAChR inhibition, similar to the levels observed in adult rats. These findings suggest that the nAChR inhibitor leads to a rise in dopamine by stopping cells from releasing GABA ­ but only in adolescent rats. The work of Iacino et al. demonstrates how the dopamine system differs in adolescence, which may provide new insights in to why teenagers are often more susceptible to addiction. For instance, nicotine, the addictive substance in cigarettes, can also bind to nAChRs and make them less sensitive to acetylcholine. This may reduce the release of GABA, resulting in more dopamine being released which is then sensed as a reward by the teenage brain. However, more research is needed to fully understand how this brain circuit is modulated by nicotine intake.

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.