Street drugs known as `bath salts' represent an emergent danger to public health. Chemicals present in formulations of bath salts elicit neurochemical actions and behavioral responses that resemble the combined effects of other illegal stimulants, hallucinogens and empathogenic agents. Hours after the euphorigenic effects of bath salts wane, there is an onset of a `crash' that in many cases include a strong negative affective state with excited delirium, major depression and violent aggressive behavior. These effects last hours, days and even weeks after ceasing intake. There is still a knowledge gap with regards to the sites of action within the brain that may cause these effects. There is also a need for preclinical data to help understand the onset of aggressive behavior and negative affective states that may lead to violence and suicide, even in individuals with no prior history of psychiatric illness. To begin to investigate the neural actions of bath salt drugs we carried out a preliminary experiment to examine blood oxygen level dependent (BOLD) signal changes in rats treated with various doses of 3,4-methylenedioxypyrovalerone (MDPV), one of the most harmful agents present in bath salts. Consistent with previous reports by other pioneering groups, MDPV elicited a robust activation of the reward system, including nucleus accumbens and ventral tegmental area, and areas of the prefrontal cortex such as insular and orbital cortices. Elevated doses of MDPV also caused a dramatic global reduction in resting state functional connectivity (rsFC) at 1 hour after administration. However, at the very highest dose tested a selective increase in rsFC emerged between the amygdala and regions of the prefrontal cortex. Our central hypothesis is that following bath salt exposure there is a progressive, time-dependent increase in anxiety and aggressive behavior with diminished cognitive function that is characterized centrally by a dramatic reduction in the brain's intrinsic functional connectivity. T test this hypothesis, in aim 1 we will determine the temporal progression of social, affective and cognitive behaviors following MDPV administration.
In aim 2 we will determine MDPV-evoked BOLD signal changes and alterations in rsFC. The overall reduction in synchronous brain BOLD activity along with greater BOLD synchrony between prefrontal areas and amygdala might be associated with the negative affective states elicited by binge consumption, especially at higher doses. This might represent an important signature of MDPV's mechanism of action to be exploredin the present proposal. From a public health perspective, the present series of experiments will provide the urgently needed data that will help develop strategies to treat acute bath salts intoxication. This will be possible with a better understanding of the temporal progression of the negative behavioral effects and the sites of actions of these agents within the central nervous system.
There are a growing number of cases of intoxication following consumption of a class of synthetic street drugs known as `bath salts'. Brain regions mediating the negative affective outcomes of bath salt abuse need further investigation. The proposed experiments test a novel hypothesis on the mechanism of action of a major constituent of bath salts, which could subsequently offer strategies for acute treatment.
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