Biology subjects

Espana, R. A.

Publications and source records attributed to Espana, R. A..

7 recordsLinked to original sources

bioRxiv2026

Restoration of Rapid-Eye Movement Sleep During Cocaine Abstinence Reduces Incubation of Cocaine Seeking and Normalizes Dopamine Transporter Function

Progressive increases in cocaine craving or seeking during abstinence from cocaine are thought to contribute to relapse. Recent observations suggest that sleep disruptions during abstinence from cocaine may have a significant influence on cocaine seeking. While the neural mechanisms underlying the association between sleep disruptions and increases in cocaine seeking during abstinence continue to be investigated, alterations in mesolimbic dopamine transmission may be a common factor. In these studies, we assessed whether sleep disruptions during abstinence are associated with incubation of cocaine seeking and dopamine terminal adaptations in the nucleus accumbens core of female and male rats. We observed that intermittent access to cocaine followed by abstinence reduced rapid-eye movement sleep, intensified cue-induced cocaine seeking, and enhanced dopamine uptake and dopamine transporter sensitivity to cocaine. Notably, a sleep restoration procedure that restricted sleep to the light phase (active period) restored rapid-eye movement sleep, prevented incubation of cocaine seeking, and normalized baseline dopamine uptake and dopamine transporter sensitivity to cocaine. These findings indicate that rapid-eye movement sleep disruptions during abstinence contribute to exaggerated cocaine seeking and that dopamine transporter adaptations are a potential molecular substrate through which these changes occur. Thus, interventions that restore sleep during cocaine abstinence may serve as effective behavioral therapies for reducing cocaine craving and preventing subsequent relapse.

neuroscience↗

bioRxiv2025

Dual Hypocretin Receptor Antagonism Reduces Oxycodone Seeking During Abstinence

A major barrier in the treatment of opioid use disorder is persistent drug craving during abstinence. While opioid-based medications have been used to treat opioid use disorder for decades, there is an urgent need for novel, non-opioid-based pharmacotherapies. The hypocretin/orexin (hypocretin) system is a promising target for treating opioid use disorder due to its influence on motivation for drugs of abuse through actions on dopamine transmission. We recently showed that intermittent access (IntA) to oxycodone promoted sustained oxycodone seeking and alterations in dopamine transmission during abstinence. In the current studies, we investigated to what extent suvorexant, an FDA-approved dual hypocretin receptor antagonist, reduces oxycodone seeking and restores dopamine function during abstinence. Results indicated that IntA to oxycodone produced sustained cue-induced oxycodone seeking after a 14-day abstinence period, which was associated with reduced dopamine uptake in the nucleus accumbens core as we have previously shown. Treatment with suvorexant 24 h prior to a cue-induced seeking test significantly reduced oxycodone seeking and normalized aberrant dopamine uptake. These findings suggest that targeting hypocretin receptors may be a promising strategy for reducing opioid craving and associated neuroadaptations, thus lowering the risk of relapse.

neuroscience↗

bioRxiv2024

Hypocretin Receptor 1 Blockade Early in Abstinence Prevents Incubation of Cocaine Seeking and Normalizes Dopamine Transmission

Abstinence from cocaine use has been shown to elicit a progressive intensification or incubation of cocaine craving/seeking that is posited to contribute to propensity for relapse. While the mechanisms underlying incubation of cocaine seeking remain elusive, considerable evidence suggests that abstinence from cocaine promotes mesolimbic dopamine adaptations that contribute to exaggerated cocaine seeking. Consequently, preventing these dopamine adaptations may reduce incubation of cocaine seeking and thereby reduce the likelihood of relapse. In the present studies, we first examined if incubation of cocaine seeking was associated with aberrant dopamine transmission in the nucleus accumbens after seven days of abstinence from intermittent access to cocaine. Given the extensive evidence that hypocretins/orexins regulate motivation for cocaine, we then examined to what extent hypocretin receptor 1 antagonism on the first day of abstinence prevented incubation of cocaine seeking and dopamine adaptations later in abstinence. Results indicated that abstinence from intermittent access to cocaine engendered robust incubation of cocaine seeking in both female and male rats. We also observed aberrant dopamine transmission, but only in rats that displayed incubation of cocaine seeking. Further, we showed that a single injection of the hypocretin receptor 1 antagonist, RTIOX-276, on the first day of abstinence prevented incubation of cocaine seeking and aberrant dopamine transmission. These findings suggest that hypocretin receptor 1 antagonism may serve as a viable therapeutic for reducing cocaine craving/seeking, thus reducing the likelihood of relapse.

neuroscience↗

bioRxiv2021

Effectiveness and relationship between biased and unbiased measures of dopamine release and clearance

Fast-scan cyclic voltammetry (FSCV) is an effective tool for measuring dopamine (DA) release and clearance throughout the brain, including the ventral and dorsal striatum. Striatal DA terminals are abundant with signals heavily regulated by release machinery and the dopamine transporter (DAT). Peak height is a common method for measuring release but can be affected by changes in clearance. The Michaelis-Menten model has been a standard in measuring DA clearance, but requires experimenter fitted modeling subject to experimenter bias. The current study presents the use of the first derivative (velocity) of evoked DA signals as an alternative approach for measuring dopamine release and clearance and can be used to distinguish the two measures. Maximal upwards velocity predicts reductions in DA peak height due to D2 and GABAB receptor stimulation and by alterations in calcium concentrations. The Michaelis-Menten maximal velocity (Vmax) measure, an approximation for DAT numbers, predicted maximal downward velocity in slices and in vivo. Dopamine peak height and upward velocity were similar between wildtype C57 (WT) and DAT knock out (DATKO) mice. In contrast, downward velocity was considerably reduced and exponential decay (tau) was increased in DATKO mice, supporting use of both measures for changes in DAT activity. In slices, the competitive DAT inhibitors cocaine, PTT and WF23 increased peak height and upward velocity differentially across increasing concentrations, with PTT and cocaine reducing these measures at high concentrations. Downward velocity and tau values decreased and increased respectively across concentrations, with greater potency and efficacy observed with WF23 and PTT. In vivo recordings demonstrated similar effects of WF23 and PTT on measures of release and clearance. Tau was a more sensitive measure at low concentrations, supporting its use as a surrogate for the Michaelis-Menten measure of apparent affinity (Km). Together, these results inform on the use of these measures for DA release and clearance.

neuroscience↗

bioRxiv2021

Dopaminergic axon tracts within a hyaluronic acid hydrogel encasement for implantation to restore the nigrostriatal pathway

Parkinsons disease (PD) affects 10 million patients worldwide, making it the second most prevalent neurodegenerative disease. Motor symptoms emerge from the loss of dopamine in the striatum after the death of dopaminergic neurons and the long-projecting axons of the nigrostriatal pathway. Current treatments, such as dopamine replacement, deep brain stimulation or cell therapies, disregard the loss of this pathway at the core of symptoms. We sought to address this by improving our tissue-engineered nigrostriatal pathway (TE-NSP) technology, which consists of a tubular hydrogel with a collagen/laminin core that encases an aggregate of dopaminergic neurons and their axons in a way that resembles the nigrostriatal pathway. These constructs can be implanted to replace the lost neurons and axons with fidelity to the pathway, and thus provide dopamine according to feedback from the host circuitry. While TE-NSPs have been traditionally fabricated with agarose, here we utilized a hyaluronic acid (HA) hydrogel to expand the functionality of the encasement and our control over its properties. Using rat ventral midbrain neurons, we found that TE-NSPs exhibited longer and faster neurite growth with HA relative to agarose, with no differences observed in electrically-evoked dopamine release. When transplanted, HA hydrogels reduced host neuron loss and inflammation around the implant compared to agarose, and the cells and axons within TE-NSPs survived and maintained their cytoarchitecture for at least 2 weeks. HighlightsO_LIWe fabricated engineered dopaminergic axons encased in a tubular hydrogel. C_LIO_LIWe made hydrogels from methacrylated hyaluronic acid and compared them to agarose. C_LIO_LIAxons in HA hydrogels had longer and faster axon growth and displayed evoked dopamine release. C_LIO_LIHA hydrogels reduced the host inflammatory response and supported neuron and axon survival in vivo. C_LIO_LIThis platform may be used to reconstruct the nigrostriatal pathway to treat Parkinsons disease. C_LI

bioengineering↗

bioRxiv2020

Striatal low-threshold spiking interneurons locally gate dopamine during learning

Low-threshold spiking interneurons (LTSIs) in the dorsomedial striatum are potent modulators of goal-directed learning. Here, we uncover a novel function for LTSIs in locally and directly gating striatal dopamine, using in vitro fast scan cyclic voltammetry as well as in vivo GRAB-DA sensor imaging and pharmacology during operant learning. We demonstrate that LTSIs, acting via GABAB signaling, attenuate dopamine release, thereby serving as local coordinators of striatal plasticity.

neuroscience↗

bioRxiv2018

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaines reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction.\n\nSignificance StatementG-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamines complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

neuroscience↗