Title

Forebrain neurochemical interactions regulating effort-related processes

Date of Completion

January 2007

Keywords

Biology, Neuroscience

Degree

Ph.D.

Abstract

An emerging body of evidence indicates that striatal DA systems interact with adenosine A2A receptors, and these interactions may regulate the behavioral functions of the nucleus accumbens. The following experiments were designed to characterize the effects of the adenosine A2A agonist CGS 21680 on effort-related processes known to be modulated by the nucleus accumbens. The first set of experiments (exp. 1-3) showed that of systemic or intracranial injections into the nucleus accumbens of CGS 21680 interfere with an effort-related choice procedure know as the concurrent FR5/feeding procedure. The second set of experiments (exp.4-6), the same neurochemical manipulations produced suppressant effects on operant responding that interacted with the work requirement of the task. The last experiments included anatomical, neurochemical and behavioral studies that investigated the functional relation between adenosine A2A receptors in nucleus accumbens and GABA transmission in the ventral pallidum (VP). Using immunohistochemistry and track-tracing methods it was shown that ventral striatopallidal neurons expressed A 2A receptor immunoreactivity (exp. 7). Stimulation of these receptors increased extracellular levels of GABA in the ventral pallidum, as measured my microdialysis (exp. 8). Simultaneous intracranial unilateral injections of CGS 21680 into nucleus accumbens and contralateral injections of muscimol into the VP, produced a synergistic effect that dramatically suppressed operant responding in a schedule with a high ratio requirement (exp.9). ^ In conclusion, these experiments showed that stimulation of adenosine A2A receptors alters the exertion of effort in a manner that is similar to the effects of interference with DA transmission. These studies implicated the role of adenosine A2A receptor mechanisms in activational aspects of motivation. Further research into the function of these receptors in forebrain systems may lead to a greater understanding of both normal and pathological features of motivation, promoting the development of novel treatments for effort-related disorders in humans, such as psychomotor slowing in depression. ^