Deep Brain Stimulation Reveals a Dissociation of Consummatory and Motivated Behaviour in the Medial and Lateral Nucleus Accumbens Shell of the Rat

Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa

P2 receptors are involved in the mediation of motivation-related behavior

The importance of purinergic signaling in the intact mesolimbic–mesocortical circuit of the brain of freely moving rats is reviewed. In the rat, an endogenous ADP/ATPergic tone reinforces the release of dopamine from the axon terminals in the nucleus accumbens as well as from the somatodendritic region of these neurons in the ventral tegmental area, as well as the release of glutamate, probably via P2Y1 receptor stimulation. Similar mechanisms may regulate the release of glutamate in both areas of the brain. Dopamine and glutamate determine in concert the activity of the accumbal GABAergic, medium-size spiny neurons thought to act as an interface between the limbic cortex and the extrapyramidal motor system. These neurons project to the pallidal and mesencephalic areas, thereby mediating the behavioral reaction of the animal in response to a motivation-related stimulus. There is evidence that extracellular ADP/ATP promotes goal-directed behavior, e.g., intention and feeding, via dopamine, probably via P2Y1 receptor stimulation. Accumbal P2 receptor-mediated glutamatergic mechanisms seem to counteract the dopaminergic effects on behavior. Furthermore, adaptive changes of motivation-related behavior, e.g., by chronic succession of starvation and feeding or by repeated amphetamine administration, are accompanied by changes in the expression of the P2Y1 receptor, thought to modulate the sensitivity of the animal to respond to certain stimuli

Dopamine–Glutamate Interplay in the Ventral Striatum Modulates Spatial Learning in a Receptor Subtype-Dependent Manner

The ventral striatum (VS) is characterized by a distinctive neural architecture in which multiple corticolimbic glutamatergic (GLUergic) and mesolimbic dopaminergic (DAergic) afferents converge on the same output cell type (the medium-sized spiny neuron, MSN). However, despite the gateway function attributed to VS and its involvement in action selection and spatial navigation, as well as the evidence of physical and functional receptor–receptor interaction between different members of ionotropic GLUergic and DAergic receptors, there is no available knowledge that such reciprocal interaction may be critical in shaping the ability to learn novel spatial and non-spatial arrangement of stimuli. In this study, it was evaluated whether intra-VS bilateral infusion of either N-methyl-D-aspartate (NMDA) or a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-selective antagonists may suppress the ability to detect spatial or non-spatial novelty in a non-associative behavioral task. In a second set of experiments, we further examined the hypothesis that VS-mediated spatial information processing may be subserved by some preferential receptor–receptor interactions among specific GLUergic and DAergic receptor subtypes. This was assessed by concomitant intra-VS infusion of the combination between subthreshold doses of either NMDA or AMPA receptor antagonists with individual D1 or D2 receptor blockade. The results of this study highlighted the fact that NMDA or AMPA receptors are differentially involved in processing of spatial and non-spatial novelty, and showed for the first time that preferential NMDA/D1 and AMPA/D2 receptor–receptor functional communication, but not NMDA/ D2 and AMPA/D1, is required for enabling learning of novel spatial information in the VS