Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; ␣) for remifentanil without affecting remifentanil consumption at low effort. Baseline ␣ values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline ␣ values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists.
For submission to the special issue: 'Orexin/hypocretin receptor antagonists for the treatment of addiction and related psychiatric disease: What are the steps from here?' (Eds. Aston-Jones and James).
Human trace amine-associated receptor subtype 1 (hTAAR1) is a G proteincoupled receptor that has therapeutic potential for multiple diseases, including schizophrenia, drug addiction, and Parkinson's disease (PD). Although several potent agonists have been identified and have shown positive results in various clinical trials for schizophrenia, the discovery of potent hTAAR1 antagonists remains elusive. Herein, we report the results of structure−activity relationship studies that have led to the discovery of a potent hTAAR1 antagonist (RTI-7470-44, 34). RTI-7470-44 exhibited an IC 50 of 8.4 nM in an in vitro cAMP functional assay, a K i of 0.3 nM in a radioligand binding assay, and showed species selectivity for hTAAR1 over the rat and mouse orthologues. RTI-7470-44 displayed good blood−brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. Finally, RTI-7470-44 increased the spontaneous firing rate of mouse VTA dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. Collectively, this work provides a promising hTAAR1 antagonist probe that can be used to study TAAR1 pharmacology and the potential therapeutic role in hypodopaminergic diseases such as PD.
The brain's endogenous opioid and endocannabinoid systems are neuromodulatory of synaptic transmission, and play key roles in pain, memory, reward, and addiction.Recent clinical and pre-clinical evidence suggests that opioid use may be reduced with cannabinoid intake. This suggests the presence of a functional interaction between these two systems. Emerging research indicates that cannabinoids and opioids can functionally interact at different levels. At the cellular level, opioid and cannabinoids can have direct receptor associations, alterations in endogenous opioid peptide or cannabinoid release, or post-receptor activation interactions via shared signal transduction pathways. At the systems level, the nature of cannabinoid and opioid interaction might differ in brain circuits underlying different behavioral phenomenon, including reward-seeking or antinociception. Given the rising use of opioid and cannabinoid drugs, a better understanding of how these endogenous signaling systems interact in the brain is of significant interest. This review focuses on the potential relationship of these neural systems in addiction-related processes.
Reward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed to mesolimbic dopamine. However, ventral tegmental area (VTA) dopamine neurons receive complex innervation and various neuromodulatory factors, including input from lateral hypothalamic (LH) orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin. Dynorphin in the VTA induces aversive conditioning through the Kappa opioid receptor (KOR) and decreases dopamine when administered intra-VTA. Exogenous application of orexin or orexin 1 receptor (oxR1) antagonists in the VTA bidirectionally modulates dopamine-driven motivation and reward-seeking behaviours, including the attribution of motivational value to primary rewards and associated conditioned stimuli. However, the effect of endogenous stimulation of LH orexin/dynorphin-containing projections to the VTA and the potential contribution of co-released dynorphin on mesolimbic dopamine and reward related processes remains uncharacterised. We combined optogenetic, electrochemical, and behavioural approaches to examine this. We found that optical stimulation of LH orexin/dynorphin inputs in the VTA potentiates mesolimbic dopamine neurotransmission in the nucleus accumbens (NAc) core, produces real time and conditioned place preference, and increases the food cue-directed orientation in a Pavlovian conditioning procedure. LH orexin/dynorphin potentiation of NAc dopamine release and real time place preference was blocked by an oxR1, but not KOR antagonist. Thus, rewarding effects associated with optical stimulation of LH orexin/dynorphin inputs in the VTA are predominantly driven by orexin rather than dynorphin.
For submission to the special issue: 'Orexin/hypocretin receptor antagonists for the treatment of addiction and related psychiatric disease: What are the steps from here?' (Eds. Aston-Jones and James). Abstract:The orexin (hypocretin) system is important for reward-seeking behavior. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of food and drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the shortacting opioid remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24h, but not on a third test at 48h. When injected locally into caudal ventral pallidum (cVP) the effects of SB were more persistent, with reduced motivation observed for up to 48h. We next made SB injections into cVP 24h prior to behavioral testing; this produced persistent effects that persisted for at least 72h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24h prior. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations might have important ramifications for the future clinical use of orexin receptor antagonists for the treatment of addiction.
The orbitofrontal cortex (OFC) is a key node in the cortico-limbic-striatal circuitry that influences decision-making guided by the relative value of outcomes. Midbrain dopamine from either the ventral tegmental area (VTA) or the dorsal raphe nucleus (DRN) has the potential to modulate OFC neurons, however it is unknown at what concentrations these terminals release dopamine. Male and female adult DATIRES-CRE-tdTomato mice were injected with AAV2/8-EF1a-DIO-eYFP into either the DRN or VTA or the retrograde label CTB 488 in the medial or lateral OFC. We quantified co-expression of CTB 488 or eYFP with tdTomato fluorescence in VTA or DRN as well as eYFP fiber density in the medial or lateral OFC. Both VTA and DRN dopamine neurons project to either the medial or lateral OFC, with greater expression of fibers in the medial OFC. Using fast-scan cyclic voltammetry, we detected optogenetically evoked dopamine from channelrhodopsin2 (ChR2)-expressing VTA or DRN dopamine terminals in either the medial or lateral OFC. Consistent with increased fiber expression in the medial OFC, dopamine was more reliably detected in this region from optical stimulation of VTA or DRN dopamine terminals. We assessed if optical stimulation of dopamine from the VTA or DRN onto the medial OFC could alter layer V pyramidal neuronal firing; however, we did not observe a change in firing at stimulation parameters which evoked dopamine release from either projection. In summary, dopaminergic neurons from the VTA or DRN project to the OFC and release submicromolar dopamine in the medial and lateral OFC.
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