Transient release of dopamine in response to rewarding stimulation of the medial forebrain bundle

Entitled: Transient release of dopamine in response to rewarding stimulation of the medial forebrain bundle and submitted in partial fulfillment of the requirements for the degree of Master of Arts (Psychology) complies with the regulations of the University and meets the accepted standards with respect to originality and quality. _________20___ ______Brian Lewis___________________________ Dean of Faculty iii ABSTRACT Reward valuation is a core computation that guides appetitive behaviour. Intracranial self-stimulation (ICSS) is among the principal behavioural tools employed to study neural correlates of reward seeking. The current thesis investigated anatomical and functional neural components subserving ICSS of the medial forebrain bundle (MFB), with particular attention to the mesolimbic dopamine (DA) pathway. The axons of midbrain DA neurons course through the MFB, and MFB stimulation produces transient DA release in terminal fields. However, the mechanism responsible for DA activation and the precise function of phasic DA activity in ICSS are still disputed. In Experiment 1, DA transients were measured in the nucleus accumbens (NAc) shell by means of fast-scan cyclic voltammetry (FSCV). Unilateral MFB stimulation drove DA transients in both hemispheres. Given that the DA projection to the NAc is almost exclusively unilateral, the contralateral transients are attributed to trans-synaptic activation of the DA neurons. A disynaptic route entailing a pontine relay provides a plausible route by which excitation in non-DA MFB fibers can reach DA cell bodies in the contralateral hemisphere, and a combination of monosynaptic and disynaptic routes may funnel such excitation to ipsilateral DA neurons. Experiment 2 assessed the hypothesis that midbrain DA neurons either perform spatio-temporal integration of synaptic input from directly activated MFB fibers subserving ICSS or relay the results of such integration to efferent stages of the reward iv circuitry. Current-frequency trade-off functions were derived from curves relating the stimulation current to ICSS performance or to the amplitude of NAc DA transients. Whereas the behaviourally derived trade-off functions decline monotonically as a function of pulse frequency, the trade-off functions derived from DA transients driven by the same electrodes are either U-shaped or level off as the pulse-frequency is increased. The contrast between the two sets of trade-off functions is inconsistent with the hypothesis that DA neurons projecting to the NAc shell constitute an entire series stage of the neural circuit subserving self-stimulation of the MFB.