Diet-induced obesity and diet-resistant rats: differences in the rewarding and anorectic effects of d-amphetamine

Abstract

Rationale Obesity is a leading public health problem worldwide. Multiple lines of evidence associate deficits in the brain reward circuit with obesity. Objective Whether alterations in brain reward sensitivity precede or are a consequence of obesity is unknown. This study aimed to investigate both innate and obesity-induced differences in the sensitivity to the effects of an indirect dopaminergic agonist. Methods Rats genetically prone to diet-induced obesity (DIO) and their counterpart diet-resistant (DR) were fed a chow diet and their response to D-amphetamine on intracranial self-stimulation and food intake were assessed. The same variables were then evaluated after exposing the rats to a high-fat diet, after DIO rats selectively developed obesity. Finally, gene expression levels of dopamine receptor 1 and 2 as well as tyrosine hydroxylase were measured in reward-related brain regions. Results In a pre-obesity state, DIO rats showed innate decreased sensitivity to the reward-enhancing and anorectic effects of D-amphetamine, as compared to DR rats. In a diet-induced obese state, the insensitivity to the potentiating effects of D-amphetamine on ICSS threshold persisted and became more marked in DIO rats, while the anorectic effects were comparable between genotypes. Finally, innate and obesity-induced differences in the gene expression of dopamine receptors were observed. Conclusions Our results demonstrate that brain reward deficits antedate the development of obesity and worsen after obesity is fully developed, suggesting that these alterations represent vulnerability factors for its development. Moreover, our data suggests that the reward-enhancing and anorectic effects of D-amphetamine are dissociable in the context of obesity.

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

“…Although debate still exists whether this can be Seeman, 2012;Skinbjerg et al, 2012), in theory, only agonist tracers like [ 11 C](+)PHNO would prefer these sites as D 2/3 R antagonist tracers typically bind with equal preference to both high-and low-affinity forms of the D 2/3 R. Therefore, it is possible that these differential binding characteristics could also help explain our VST findings such that the regulation of 'active' highaffinity forms vs 'inactive' low-affinity forms of the D 2/3 R may be altered in obesity. Our finding in the VST is also consistent with the previous [ 11 C](+)PHNO work in non-OB individuals (Caravaggio et al, 2013) and preclinical research that posits the nucleus accumbens, a central component of the VST, plays a key role in the formation/development of the OB phenotype (Davis et al, 2008;Geiger et al, 2009;Hryhorczuk et al, 2016;Rada et al, 2010;Valenza et al, 2015). This regional specificity, along with tracer properties, may help explain why differences were not found in the dorsal striatum.…”

Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet-induced obesity

“…We next examined intrinsic excitability of MSNs in the NAc core of obesity-prone and -resistant rats because there are basal differences in dopamine systems in obesity-prone vs. -resistant rats, dopamine-mediated transmission strongly influences MSN excitability, and cocaine sensitization is associated with alterations in intrinsic excitability, (Geiger et al 2008; Hu 2007; Kourrich et al 2015; Kourrich and Thomas 2009; Marinelli et al 2006; Rada et al 2010; Valenza et al 2015; Vollbrecht et al In Press). Recordings were made from adult and adolescent obesity-prone and obesity-resistant rats without diet manipulation or cocaine exposure (Fig.…”

“…Glutamatergic transmission provides the main excitatory drive to MSNs, whereas dopamine-mediated transmission can powerfully modulate excitability of MSNs; thus, the convergence of these inputs in the NAc can ultimately drive cue-triggered motivational responses (Everitt and Wolf 2002; Kelley 2004; Perez et al 2006). Although, basal differences in striatal dopamine levels, and mesolimbic dopamine receptor expression and function have been found (Geiger et al 2008; Geiger et al 2009; Rada et al 2010; Valenza et al 2015; Vollbrecht et al In Press; Vollbrecht et al 2015) no previous studies have examined basal differences in neurotransmission to MSNs in the NAc core of obesity-prone and obesity-resistant rats.…”

“Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats”

“…Procedures were carried out as previously published (Valenza et al 2016; Valenza et al 2015). About 30 h after the end of the last self-administration session, cocaine and yoked-saline rats were briefly anesthetized with carbon dioxide and decapitated.…”