Biology subjects

Toddes, C.

Publications and source records attributed to Toddes, C..

4 recordsLinked to original sources

bioRxiv2024

Mu opioid receptor expression by nucleus accumbens inhibitory interneurons promotes affiliative social behavior

Mu opioid receptors in the nucleus accumbens regulate motivated behavior, including pursuit of natural rewards like social interaction as well as exogenous opioids. We used a suite of genetic and viral strategies to conditionally delete mu opioid receptor expression from all major neuron types in the nucleus accumbens. We pinpoint inhibitory interneurons as an essential site of mu opioid receptor expression for typical social behavior, independent from exogenous opioid sensitivity.

neuroscience↗

bioRxiv2021

Angiotensin-converting enzyme governs endogenous opioid signaling and synaptic plasticity in nucleus accumbens

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is expressed at uniquely high levels in the striatonigral pathway, but its central function remains poorly understood. We find that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced mu opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but decreased the conditioned place preference caused by fentanyl administration, and enhanced reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit, while mitigating risk of addiction.

neuroscience↗

bioRxiv2020

Mu Opioid Receptor Gene Dosage Influences Reciprocal Social Behaviors and Nucleus Accumbens Microcircuitry

The mu opioid receptor regulates reward derived from both drug use and natural experiences, including social interaction. Homozygous genetic knockout of the mu opioid receptor (Oprm1-/-) causes social deficits in mice, whereas partial dysregulation of mu opioid signaling has been documented in several neuropsychiatric disorders. Here, we investigated the social behavior of male and female mice with heterozygous genetic knockout of the mu opioid receptor (Oprm1+/-), modeling partial reduction of mu opioid signaling. Reciprocal social interaction and social conditioned place preference were diminished in Oprm1+/- and Oprm1-/- mutants of both sexes. Interaction with Oprm1 mutants also altered the social behavior of genotypical test partners. We corroborated this latter result using a social preference task, in which genotypical mice preferred interactions with another typical mouse over Oprm1 mutants. We also analyzed inhibitory synapses in the nucleus accumbens, a key brain region for mu opioid regulation of social behavior, using methods that differentiate between medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. Inhibitory synaptic transmission was increased in D2-MSNs of male mutants, but not female mutants, while the density of inhibitory synaptic puncta at the cell body of D2-MSNs was increased in both male and female mutants. These changes in nucleus accumbens microcircuitry were more robust in Oprm1+/- mutants than Oprm1-/- mutants, demonstrating that partial reductions of mu opioid signaling can have large effects on brain function and behavior. Our results support a role for partial dysregulation of mu opioid signaling in social deficits associated with neuropsychiatric conditions.

neuroscience↗

bioRxiv2019

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in Brain Function and Behavior

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may therefore represent a strategy to minimize iatrogenic effects on brain reward circuits.

neuroscience↗