Evidence for defective mesolimbic dopamine exocytosis in obesity‐prone rats

Abstract

The association between dietary obesity and mesolimbic systems that regulate hedonic aspects of feeding is currently unresolved. In the present study, we examined differences in baseline and stimulated central dopamine levels in obesity-prone (OP) and obesity-resistant (OR) rats. OP rats were hyperphagic and showed a 20% weight gain over OR rats at wk 15 of age, when fed a standard chow diet. This phenotype was associated with a 50% reduction in basal extracellular dopamine, as measured by a microdialysis probe in the nucleus accumbens, a projection site of the mesolimbic dopamine system that has been implicated in food reward. Similar defects were also observed in younger animals (4 wk old). In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.

Western diet increases wheel running in mice selectively bred for high voluntary wheel running

“…In addition to the many effects high-fat diet has on muscles, it has also been shown to stimulate certain brain areas (for example, hypothalamus) and signaling by certain neurotransmitters (for example, dopamine), putatively involved in reward 5,[48][49][50][51] and possibly involved with the 'activitystat'. 52 Voluntary wheel running is also well known for its impact on the central nervous system, and is considered to be a classic self-rewarding behavior.…”

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

“…These include reduced DA concentrations, impaired response to electrically evoked accumbal DA release, decreased basal tyrosine hydroxylase and DAT expression, as well as lower levels of D 2 receptor binding (Pothos et al, 1998;Geiger et al, 2008). Correspondingly, striatal D 2 receptor binding is inversely correlated to the degree of obesity in humans (Volkow and Wise, 2005), and D 2 receptor agonists produce hypophagia and weight loss in animal models of obesity (Scislowski et al, 1999;Davis et al, 2008).…”

“…Correspondingly, there are several indices of defective central monoaminergic neurotransmission in preclinical models of obesity, including reduced hypothalamic a 1 adrenoceptor binding (Wilmot et al, 1988), enhanced electrophysiological responsiveness to intrahypothalamic NE application (Kraszewski and Cincotta, 2000), decreased basal hypothalamic 5-HT and DA levels (Meguid et al, 2000a), as well as reduced mesolimbic DA activity (Geiger et al, 2008).…”

Central lipid detection and the regulation of feeding behavior

“…Thus suggests that an enhanced activity of regions that process palatability could make obese subjects favor food over other natural reinforcers (Volkow et al, 2011). Taken together, rats and humans data suggest that an attenuated activity of dopaminergic would reduce the hedonic response associated with feeding, a deficit that obese individuals might strive to compensate by overeating (Geiger et al, 2008;Stice et al, 2008;Volkow et al, 2011).…”