Functional Magnetic Resonance Imaging Reveals Different Neural Substrates for the Effects of Orexin-1 and Orexin-2 Receptor Antagonists

Abstract

Orexins are neuro-modulatory peptides involved in the control of diverse physiological functions through interaction with two receptors, orexin-1 (OX1R) and orexin-2 (OX2R). Recent evidence in pre-clinical models points toward a putative dichotomic role of the two receptors, with OX2R predominantly involved in the regulation of the sleep/wake cycle and arousal, and the OX1R being more specifically involved in reward processing and motivated behaviour. However, the specific neural substrates underlying these distinct processes in the rat brain remain to be elucidated. Here we used functional magnetic resonance imaging (fMRI) in the rat to map the modulatory effect of selective OXR blockade on the functional response produced by D-amphetamine, a psychostimulant and arousing drug that stimulates orexigenic activity. OXR blockade was produced by GSK1059865 and JNJ1037049, two novel OX1R and OX2R antagonists with unprecedented selectivity at the counter receptor type. Both drugs inhibited the functional response to D-amphetamine albeit with distinct neuroanatomical patterns: GSK1059865 focally modulated functional responses in striatal terminals, whereas JNJ1037049 induced a widespread pattern of attenuation characterised by a prominent cortical involvement. At the same doses tested in the fMRI study, JNJ1037049 exhibited robust hypnotic properties, while GSK1059865 failed to display significant sleep-promoting effects, but significantly reduced drug-seeking behaviour in cocaine-induced conditioned place preference. Collectively, these findings highlight an essential contribution of the OX2R in modulating cortical activity and arousal, an effect that is consistent with the robust hypnotic effect exhibited by JNJ1037049. The subcortical and striatal pattern observed with GSK1059865 represent a possible neurofunctional correlate for the modulatory role of OX1R in controlling reward-processing and goal-oriented behaviours in the rat.

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

“…Our group has recently demonstrated through a preclinical MRI approach that OX 1 R rather than OX 2 R selectively modulate mesolimbic brain region and the cortical part of the insula, areas implicated in rewarding processing (Gozzi et al, 2011). These data confirm and extend the previous findings that OX 1 R plays a role in reward processing and precipitation of drug-seeking behavior (Boutrel et al, 2005;Lawrence et al, 2006;Hollander et al, 2008;Smith et al, 2010).…”

“…Finally, the compounds were tested at the defined doses in the BE model. OX 1 R and OX 2 R antagonists are reported in the literature to be involved in the control of sleep, in particular to induce hypnotic effects (Di Fabio et al, 2011;Gozzi et al, 2011;Dugovic et al, 2009). In a preclinical hypnotic sleep model in male rats, the results obtained demonstrated that the dual OX 1 /OX 2 R antagonist, SB-649868, induced a robust hypnotic effect, both on the ability to induce and to maintain sleep, reaching a statistically significant effect at 3 mg/kg.…”

“…Drugs SB-649868 (Di Fabio et al, 2011), GSK1059865 (Gozzi et al, 2011), andJNJ-10397049 (McAtee et al, 2004) were synthesized in GSK laboratories. OXA was supplied by California Peptides CA).…”

“…Therefore, this study was aimed at investigating the effect of the dual OX 1 /OX 2 R antagonist SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide) (Di Fabio et al, 2011), the selective OX 1 R antagonist GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine) (Gozzi et al, 2011), and the selective OX 2 R antagonist JNJ-10397049 (N-(2,4-dibromophenyl) (McAtee et al, 2004;Dugovic et al, 2009) in the BE model described by Cifani et al (2009), in which BE episodes for HPF is evoked in female rats by cycles of food restriction/re-feeding and acute stress. The three antagonists were first evaluated in vitro in rat recombinant OX 1 R and OX 2 R to determine their potency and to confirm their selectivity for the two receptor subtypes.…”

Neuroimaging Evidence of Altered Fronto-Cortical and Striatal Function after Prolonged Cocaine Self-Administration in the Rat

“…D-amphetamine (0.5 mg/kg) was administered intravenously 25 min after contrast agent injection, and MRI data were acquired over a period of 25 min following the challenge. The dose of D-amphetamine was chosen based on previous in vivo studies Gozzi et al, 2011). The dose ensures robust brain activation, does not produce 'ceiling' rCBV responses (Micheli et al, 2007), and elicits transient MABP responses that are homeostatically compensated under halothane anesthesia (Gozzi et al, 2007;Zaharchuk et al, 1999).…”