Frustration effects on drug taking

Although not pleasant, frustration is an important state, as it acts as a check on aberrant motivation. Conditions of high motivation (e.g. substance use disorders [SUDs]) can arise when frustration fails to decrease motivation (i.e. inelasticity of demand). We have developed a way of measuring frustration-related behavior during operant responding in rats by looking at barpress durations. Having satisfied 9 fundamental criteria for determining barpress durations as a measure of frustration-related behavior, the current project will determine fundamental neurobiological aspects of frustration as it relates to decreased motivation for drug. We hypothesize that individual differences in motivation are determined in part by frustration, with frustration having distinct early life environmental determinants and specific neurocircuitry converging on motivation pathways. We contend that frustration is istinguishable from drug motivation and plays an important role in attenuating motivation for drug. Many suffering from SUDs are insensitive to frustration, meaning that frustrating conditions do not decrease motivation appropriately. This project will utilize two well-characterized rat behavioral tests for drug motivation, namely behavioral economic assessment of demand elasticity and progressive ratio determination of drug value. The project will address key aspects of 1) early-life factors conferring individual differences in frustration behavior as determinants of susceptibility and resilience to drug motivation, 2) the role of key frustration-related neurocircuitry projecting to the shell of the nucleus accumbens (shNAc), and 3) effects on shNAc medium spiny neuron output on frustration and motivation behavior. Thus, Aim 1 of this project will investigate the development of individual differences in frustration-related behavior subsequent to adolescent exposure to risk/resilience factors such as chronic unpredictable mild stress and environmental enrichment/isolation, each known to affect motivation for drug. The question is whether the already known effects on motivation are mediated through frustration. Additionally, chronic frustration during adolescence will assess whether this manipulation inoculates against, or predisposes to, later sensitivity to frustration as it affects drug motivation. Aim 2 will utilize a combinatorial chemogenetic approach for manipulating four specific pathways for frustration and/or motivation to discern the circuitry integration of frustration with motivation to affect behavior. Aim 3 will assess effects of frustration on shNAc output neurons and the effects of shNAc output on motivation for drug. To be clear, the proposed therapeutic strategy is not high frustration itself, but rather normalizing the ability for frustration to check drug motivation. Understanding the neurobiology of frustration-attenuated motivation is the first major step in developing this novel approach.