The neural mechanisms that underlie responses to drugs of abuse are complex, and impacted by a number of neuromodulatory peptides. Within the past 10 years it has been discovered that several of the receptors for neuromodulators are enriched in the primary cilia of neurons. Primary cilia are microtubule‐based organelles that project from the surface of nearly all mammalian cells, including neurons. Despite what we know about cilia, our understanding of how cilia regulate neuronal function and behavior is still limited. The primary objective of this study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to amphetamine. To test the consequences of cilia loss on amphetamine‐induced locomotor activity we selectively ablated cilia from dopaminergic or GAD2‐GABAergic neurons in mice. Cilia loss had no effect on baseline locomotion in either mouse strain. In mice lacking cilia on dopaminergic neurons, locomotor activity compared to wild‐ type mice was reduced in both sexes in response to acute administration of 3.0 mg/kg amphetamine. In contrast, changes in the locomotor response to amphetamine in mice lacking cilia on GAD2‐GABAergic neurons were primarily driven by reductions in locomotor activity in males. Following repeated amphetamine administration (1.0 mg kg−1 day−1 over 5 days), mice lacking cilia on GAD2‐GABAergic neurons exhibited enhanced sensitization of the locomotor stimulant response to the drug, whereas mice lacking cilia on dopaminergic neurons did not differ from wild‐type controls. These results indicate that cilia play neuron‐specific roles in both acute and neuroplastic responses to psychostimulant drugs of abuse.

The mesocorticolimbic dopamine pathway is generally considered to be a reward pathway. While shortsighted, there is a strong basis for this view of dopamine function. Here, we first describe the role of phasic dopamine release events in reward seeking. We then explain why these release events are being reconsidered as value signals and how we applied behavioral economics to confirm they play a causal role in the valuation of reward. Just because dopamine release can function as a dopamine reward value signal however, does not imply that dopamine is solely a reward molecule. Rather, mesocorticolimbic dopamine appears to mediate many adaptive behaviors, including: reward seeking, avoidance, escape and fear-associated conditioned freezing. While more studies are needed before a consensus is reached on when, where and how dopamine mediates aversively-motivated behavior, its involvement is almost irrefutable. Thus, we next describe the role dopamine plays in these ethologically-relevant defensive behaviors. We conclude by describing our recent behavioral economics results that reveal a causal role for dopamine in the valuation of avoidance.

Alcohol exposure alters the signaling of the serotoninergic system, which is involved in alcohol consumption, reward, and dependence. In particular, dysregulation of serotonin receptor type 1A (5‐HT1AR) is associated with alcohol intake and withdrawal‐induced anxiety‐like behavior in rodents. However, how ethanol regulates 5‐HT1AR activity and cell surface availability remains elusive. Using neuroblastoma 2a cells stably expressing human 5‐HT1ARs tagged with hemagglutinin at the N‐terminus, we found that prolonged ethanol exposure (18 h) reduced the basal surface levels of 5‐HT1ARs in a concentration‐dependent manner. This reduction is attributed to both enhanced receptor internalization and attenuated receptor recycling. Moreover, constitutive 5‐HT1AR internalization in ethanol naïve cells was blocked by concanavalin A (ConA) but not nystatin, suggesting clathrin‐dependent 5‐HT1AR internalization. In contrast, constitutive 5‐HT1AR internalization in ethanol‐treated cells was blocked by nystatin but not by ConA, indicating that constitutive 5‐HT1AR internalization switched from a clathrin‐ to a caveolin‐dependent pathway. Dynasore, an inhibitor of dynamin, blocked 5‐HT1AR internalization in both vehicle‐ and ethanol‐treated cells. Furthermore, ethanol exposure enhanced the activity of dynamin I via dephosphorylation and reduced myosin Va levels, which may contribute to increased internalization and reduced recycling of 5‐HT1ARs, respectively. Our findings suggest that prolonged ethanol exposure not only alters the endocytic trafficking of 5‐HT1ARs but also the mechanism by which constitutive 5‐HT1AR internalization occurs.

The mesolimbic dopamine (DA) system has traditionally been examined under a reward based context. While accumulating evidence supports that DA release events represent the value of predicted rewards, there is little known about its role in avoidance. To investigate dopamine's role in the valuation of signaled operant avoidance, we developed an economics‐based shock avoidance task in which rats were given the opportunity to avoid (signaled by the presentation of a cue light) electrical foot‐shock across epochs wherein the unit price (response requirement over mA shock) to avoid or escape increases. After developing this task, we first used fast‐scan cyclic voltammetry (FSCV) to measure DA release events in vivo as the animals performed across a range of prices. We observed that the concentration of DA decreased with price, though both DA and avoidance were initially suppressed at session onset. To establish a causal role, we then used optogenetics to augment DA release at either the presentation of the cue signal or upon successful avoidance of the foot‐shock. Increasing release at the cue made avoidance more sensitive to price; whereas increasing release at successful avoidance made it less sensitive to price. We conclude that this is likely because the neural representation of the value to avoid is greater than predicted at successful avoidance, and worse than expected at the cue on trials in which foot‐shock is administered. We will next assess the role of the rostromedial tegmental nucleus (RMTg), a neural structure known to cause prediction errors, in the valuation of avoidance.Support or Funding InformationFunding for the project was provided by NSF grant IOS‐1557755, NIH grant R03DA038734, Boettcher Young Investigator Award and NARSAD Young Investigator Award to EBO and an institutional UROP to KJP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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