Dopamine Neurons That Cotransmit Glutamate, From Synapses to Circuits to Behavior.

Discovered just over 20 years ago, dopamine neurons have the ability to cotransmit both dopamine and glutamate. Yet, the functional roles of dopamine neuron glutamate cotransmission and their implications for therapeutic use are just emerging. This review article encompasses the current body of evidence investigating the functions of dopamine neurons of the ventral midbrain that cotransmit glutamate. Since its discovery in dopamine neuron cultures, further work in vivo confirmed dopamine neuron glutamate cotransmission across species. From there, growing interest has led to research related to neural functioning including roles in synaptic signaling, development, and behavior. Functional connectome mapping reveals robust connections in multiple forebrain regions to various cell types, most notably to cholinergic interneurons in both the medial shell of the nucleus accumbens and the lateral dorsal striatum. Glutamate markers in dopamine neurons reach peak levels during embryonic development and increase in response to various toxins, suggesting dopamine neuron glutamate cotransmission may serve neuroprotective roles. Findings from behavioral analyses reveal prominent roles for dopamine neuron glutamate cotransmission in responses to psychostimulants, in positive valence and cognitive systems and for subtle roles in negative valence systems. Insight into dopamine neuron glutamate cotransmission informs the pathophysiology of neuropsychiatric disorders such as addiction, schizophrenia and Parkinson Disease, with therapeutic implications.

Increased expression of 5-HT6 receptors in dorsolateral striatum decreases habitual lever pressing, but does not affect learning acquisition of simple operant tasks in rats.

Serotonin-6 (5-HT(6)) receptors are densely expressed in the dorsolateral striatum (DLS), a brain region linked to habits. Medications acting on the serotonergic system, including 5-HT(6) receptors, can diminish habitual and repetitive behaviors associated with clinical syndromes such as obsessive-compulsive disorder, and may have implications for addiction as well. To examine the role of 5-HT(6) receptors in the acquisition and persistence of habitual behavior, we manipulated 5-HT(6) receptor expression in the DLS with herpes simplex virus vectors in combination with different behavioral procedures; control rats received a vector expressing enhanced green fluorescent protein. In one set of experiments, rats were tested under conditions that favor the acquisition of either discrete action-outcome responding or repetitive responding; increased 5-HT(6) receptor expression in DLS did not alter learning in either paradigm. In the next experiment, rats were over-trained on fixed- then variable-interval schedules, resulting in an escalation of lever pressing over sessions far in excess of that necessary to receive sucrose pellets. After training, rats received viral vector infusion into the DLS. Subsequently, half of each group underwent an omission contingency training session in which they received reinforcement for refraining from pressing the lever, while the other half served as yoked controls. A probe session under extinction conditions was performed the following day. Only rats that received both the 5-HT(6) vector and omission contingency training showed reduced lever pressing during the probe session. These results suggest that increasing 5-HT(6) receptor signaling in the DLS facilitates behavioral flexibility in the face of changing contingencies.

Increased expression of the 5-HT6 receptor by viral mediated gene transfer into posterior but not anterior dorsomedial striatum interferes with acquisition of a discrete action-outcome task.

Serotonin plays a role in reinforcement learning; however, it is not known which serotonin receptors mediate these effects. Serotonin 6 (5-HT(6)) receptors are abundant in the striatum, a brain area that is involved in reinforcement learning. We previously found that 5-HT(6) receptors in the dorsomedial striatum (DMS) affect reinforcement learning or consolidation over several days. We use viral-mediated gene transfer to discern the role that 5-HT(6) receptors play in mediating post-synaptic responses in anterior versus posterior DMS. Male Long-Evans rats were used to study learning acquisition during a single session of 100 trials on a fixed interval of 20 seconds. In a discrete action-outcome learning task, rats had 10 seconds to press a lever to induce lever retraction and sucrose pellet delivery. In another group of rats, the task had a lever that was continuously extended but only active every 20 seconds, allowing for repetitive, mostly non-reinforced, lever pressing. Results demonstrate that increased expression of 5-HT(6) receptors in the posterior DMS interferes with earning sucrose pellets in only the former task. We take this to indicate that 5-HT(6) receptor signaling in the posterior DMS interferes with acquisition of discrete action-outcome responding.

Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization.

Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein-coupled receptor (hM(4)D), we found that activation of hM(4)D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM(4)D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.