Biology subjects

Arriaga, M.

Publications and source records attributed to Arriaga, M..

3 recordsLinked to original sources

bioRxiv2024

Nor-LAAM loaded PLGA Microparticles for Treating Opioid Use Disorder

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo--acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt.%) and an average diameter (19 {micro}m) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD.

bioengineering↗

bioRxiv2019

Structured Inhibitory Activity Dynamics During Learning

Hippocampal network activity is tightly regulated by local inhibitory interneurons. Suppression of inhibition has been proposed to accelerate learning by enhancing network activity and plasticity; however, the activity dynamics of hippocampal interneurons during learning remain poorly understood. Furthermore, it is unknown if individual interneurons are stochastically suppressed across different learning episodes, mirroring the random remapping of place cells, or if instead they exhibit consistent patterns of activity suppression. These critical properties define how inhibition shapes and controls learning at a network level. To uncover the functional circuit dynamics of inhibition during novelty-induced learning, we recorded calcium activity from hippocampal CA1 interneurons using two-photon imaging as mice learned a virtual reality (VR) goal-directed spatial navigation task in new visual contexts. Here we focused on dendrite-targeting somatostatin-expressing interneurons (SOM-ints), which powerfully control burst firing and synaptic plasticity in excitatory neurons. We found robust activity suppression in SOM-ints upon exposure to novel virtual environments; activity then recovered over repeated exposures to the novel environment as the animal learned goal locations. At a population level, we found a continuum of activity suppression, from interneurons strongly suppressed to moderately activated during learning. Surprisingly, each interneuron exhibited a stable level of activity modulation: when animals were switched into a second novel environment, the magnitude of activity suppression was strongly correlated across remapping sessions. This work reveals dynamic inhibition suppression triggered by novel environments and the gradual return of inhibition with learning. Furthermore, unlike the stochastic remapping of place cells, inhibitory networks display a stable activity structure across learning episodes. This functional inhibitory circuit architecture suggests that individual interneurons play specialized and stereotyped roles during learning, perhaps by differentially regulating pyramidal subnetworks specialized for plasticity and stability.

neuroscience↗

bioRxiv2019

Hippocampal Activity Dynamics During Contextual Reward Association in Virtual Reality Place Conditioning

Exposure to environmental contexts associated with drug use can induce cravings that promote continued use and/or relapse. Opioid abuse is marked by high relapse rates, suggesting that contextual memories formed during opioid use may be particularly strong. While it is known that reward-seeking behavior is controlled by the mesolimbic reward circuit, little is understood about how contextual memories are altered by drug use. The dorsal hippocampus (dHPC) is necessary for multiple types of contextual learning and the place-specific activity of CA1 place cells map out space in a given environment. Here we examined the neuronal representation of context as animals developed morphine-paired environmental associations using a conditioned place preference (CPP) paradigm. To investigate changes in the hippocampal encoding before, during, and after drug-pairing, we developed a virtual reality (VR) morphine CPP (Mor-CPP) paradigm and used in vivo two-photon calcium imaging to record the activity of CA1 pyramidal neurons. We found increased activity in rewarded contexts following real-time operant conditioning with water rewards, but not after Mor-CPP training, suggesting different neural encoding mechanisms for natural reinforcers and morphine.

neuroscience↗