In any non-deterministic environment, unexpected events can indicate true changes in the world (and require behavioural adaptation) or reflect chance occurrence (and must be discounted). Adaptive behaviour requires distinguishing these possibilities. We investigated how humans achieve this by integrating high-level information from instruction and experience. In a series of EEG experiments, instructions modulated the perceived informativeness of feedback: Participants performed a novel probabilistic reinforcement learning task, receiving instructions about reliability of feedback or volatility of the environment. Importantly, our designs de-confound informativeness from surprise, which typically co-vary. Behavioural results indicate that participants used instructions to adapt their behaviour faster to changes in the environment when instructions indicated that negative feedback was more informative, even if it was simultaneously less surprising. This study is the first to show that neural markers of feedback anticipation (stimulus-preceding negativity) and of feedback processing (feedback-related negativity; FRN) reflect informativeness of unexpected feedback. Meanwhile, changes in P3 amplitude indicated imminent adjustments in behaviour. Collectively, our findings provide new evidence that high-level information interacts with experience-driven learning in a flexible manner, enabling human learners to make informed decisions about whether to persevere or explore new options, a pivotal ability in our complex environment.

The study of transmitter interactions in reward and motor pathways in the brain, including the striatum, requires methodology to detect stimulus-driven neurotransmitter release events. Such methods exist for dopamine, and have contributed to the understanding of local and behavioral factors that regulate dopamine release. However, factors that regulate release of another key transmitter in these pathways, acetylcholine (ACh), are unresolved, in part because of limited temporal and spatial resolution of current detection methods. We have optimized a voltammetric method for detection of local stimulus-evoked ACh release using enzyme-coated carbon-fiber microelectrodes and fast-scan cyclic voltammetry. These electrodes are based on the detection of H2O2 generated by the actions of acetylcholine esterase and choline oxidase, and reliably respond to ACh in a concentration-dependent manner. Methods for enzyme coating were optimized for mechanical stability that allowed for their use in ex vivo brain slices. We report here the first quantitative assessment of extracellular ACh concentration after local electrical stimulation in dorsal striatum in slices from control mice. The selective detection of ACh under these conditions was confirmed by showing that the response detected in the control slices was absent in slices from mice bred to lack ACh synthesis in the forebrain. These electrodes represent a new tool to study ACh and ACh-dopamine interactions with micrometer spatial resolution.

Preclinical work indicates that adolescent rats appear more sensitive to the rewarding effects and less sensitive to the aversive effects of abused drugs. The present investigation utilized the conditioned taste aversion (CTA) design to measure the relative aversive effects of (±)3,4-methylenedioxymethamphetamine (MDMA; 0,1.0, 1.8 or 3.2 mg/kg) in adolescent and adult Sprague-Dawley rats. After behavioral testing was complete, monoamine and associated metabolite levels in discrete brain regions were quantified using high-performance liquid chromatography coupled to electrochemical detection (HPLC-ECD) to determine if adolescent animals displayed a different neurochemical profile than do adult animals after being exposed to subcutaneous low doses of MDMA. Adolescent rats displayed less robust MDMA-induced taste aversions than adults during acquisition and on a final two-bottle aversion test. MDMA at these doses had no consistent effect on monoamine levels in either age group, although levels did vary with age. The relative insensitivity of adolescents to MDMA’s aversive effects may engender an increased vulnerability to MDMA abuse in this specific population.

Despite decades of research, investigations into effective neural and pharmacological therapies for many drugs of abuse, such as cocaine, have produced no FDA-approved approaches. This difficulty derives from the complexity of substance use disorders, which encompass a variety of behavioral, psychological, and neural circuit-based changes that occur as a result of repeated experience with the drug. Dopamine signaling has been demonstrated to play a key role in several aspects of drug abuse-from mediating its reinforcing properties and drug-seeking to triggering relapse-while also mediating a number of important aspects of normal (nondrug related) motivated behaviors and actions. Real-time recording methods such as in vivo voltammetry, electrophysiology, and calcium imaging demonstrate that the signaling properties of dopamine for motivationally relevant stimuli are highly dynamic and spatiotemporally circumscribed within afferent target regions. In this review, we identify the origins and functional consequences of heterogeneous dopamine release in the limbic system, and how these properties are persistently altered in the drug-experienced brain. We propose that these spatiotemporally parallel dopaminergic signals are simultaneously available to the animal, but that these circuits are impaired following prolonged drug experience by disrupting the location and content of dopamine signals in afferent target regions. These findings are discussed in the context of relapse and pathways to discovering new treatments for addiction disorders.