Orexin receptor antagonism prevents transcriptional and behavioral plasticity resulting from stimulant exposure

Abstract

Orexin is a key neurotransmitter of central arousal and reward circuits in the CNS. Two receptors respond to orexin signaling, Orexin 1 Receptor (OX1R) and Orexin 2 Receptor (OX2R) with partially overlapping brain distributions. Genetic and pharmacological studies suggest orexin receptor antagonists could provide therapeutic benefit for insomnia and other disorders in which sleep/wake cycles are disrupted. Preclinical data has also emerged showing that the orexin system is involved in the behavioral and neurological effects of drugs of abuse (Aston-Jones et al., 2009, Harris et al., 2005). Here we report sleep promoting effects of a recently described small molecule dual orexin receptor OX1R and OX2R antagonist. This dual orexin receptor antagonist (DORA) also inhibits the ability of subchronic amphetamine to produce behavioral sensitization measured 10 days following pre-treatment. Transcriptional profiling of isolated reward and arousal circuits from brains of behaviorally sensitized animals showed that the DORA blocked the significant alteration of gene expression levels in response to amphetamine exposure, particularly those associated with synaptic plasticity in the VTA. Further, DORA attenuates the ability of nicotine to induce reinstatement of extinguished responding for a reinforcer, demonstrating selectivity of the effect to reward pathways and not to food intake. In summary, these data demonstrate efficacy of a dual orexin receptor antagonist for promotion of sleep and suggest that pharmacological inhibition of the orexin system may play a role in both prevention of drug-induced plasticity and drug-relapse.

Introduction

Orexin receptors are highly expressed in brain areas known to regulate sleep/wake patterns and inhibition of these orexin receptors modifies sleep/wake behaviors (Brisbare-Roch et al., 2007, Ohno and Sakurai, 2008, Saper, 2006). Orexins emerge from extensively distributed hypothalamic signaling pathways appositing neuronal groups associated with reward and behavioral response to drugs of abuse. Two G-protein coupled orexin receptors, OX1R and OX2R, are activated by orexin peptides (OX₁ and OX₂) arising from cleavage of a prepro-orexin peptide. OX₁ is a high-affinity ligand for OX1R, with an affinity for OX₂ one to two orders of magnitude lower. OX2R exhibits equally high affinity for both peptides. Orexin signaling appears crucial for response to reward stimuli including drugs of abuse, due to its influence on brain regions involved in reward processing, including the locus coeruleus (LC), basal forebrain (BF) and tuberomammillary nucleus (TMN), nucleus accumbens (NAcc), ventral tegmental area (VTA), and dorsal raphe (DR) (Marcus et al., 2001). At the level of neurotransmitters, orexin peptides interact with cholinergic, histaminergic, noradrenergic, serotonergic and dopaminergic systems highlighting the role of these neuropeptides in responding to a variety of stimuli (Ohno and Sakurai, 2008, Saper, 2006). In addition to promoting arousal, orexinergic neurons become activated by cues paired to drugs of abuse such as cocaine, and administration of orexin peptide can produce reinstatement of extinguished cocaine seeking (Aston-Jones et al., 2009, Boutrel et al., 2005). Interestingly, Zhang et al. demonstrated that chronic cocaine administration in rats causes a long-lasting upregulation of OX2R protein in the nucleus accumbens, which persisted up to 60 days after discontinuation of treatment, suggesting a link with cocaine-induced plasticity (Zhang et al., 2007). We recently reported identification of a potent dual orexin receptor antagonist, N-biphenyl-2-yl-1-{[(1-methyl-1H-benzimidazol-2-yl)sulfanyl]acetyl}-l-prolinamide, (DORA-1), with favorable pharmacological properties in preclinical species (Bergman et al., 2008). DORA-1 is here shown to promote sleep, inhibit nicotine-induced reinstatement for a conditioned reinforcer, and attenuate amphetamine sensitization-related transcriptional responses in brain nuclei involved in arousal and reward.