Biology subjects

Martinez-Rivera, A.

Publications and source records attributed to Martinez-Rivera, A..

3 recordsLinked to original sources

bioRxiv2026

Reversible m6Am methylation of snRNA by FTO controls morphine reward and tolerance without altering analgesia

Mu opioids, such as morphine, are effective analgesics, but their reward and tolerance drive opioid use disorder. A major goal is to achieve analgesia without these harmful effects. Here we show that morphine reward and tolerance require the RNA demethylase FTO. Genetic depletion and pharmacologic inhibition of FTO each reduced morphine reward, measured by conditioned-place preference, and reduced antinociceptive tolerance to morphine and fentanyl, without altering analgesia. Although FTO is known to erase m6A on mRNA, we found no effect of FTO depletion on m6A sites, but markedly increased levels of m6Am on snRNA. The effects of FTO depletion were suppressed in mice that cannot make m6Am, supporting the role of m6Am in morphine reward and tolerance. We show that FTO depletion regulates a gene expression network linked to morphine signaling. FTO inhibitors may therefore provide useful adjuvants to mu opioids in pain management and treatment of opioid use disorder.

neuroscience↗

bioRxiv2025

Deletion of Cacna1c (CaV1.2) in D1-expressing cells elicits divergent sex-specific effects on aversive and spatial memories

Dopamine signaling is critical for cognitive and emotional regulation and is implicated in multiple neuropsychiatric disorders. One downstream effector of dopamine is the L-type calcium channel CaV1.2, encoded by the risk gene CACNA1C. Genome-wide association studies have consistently linked CACNA1C single nucleotide polymorphisms to schizophrenia, bipolar disorder, and related conditions. We previously showed that homozygous deletion of Cacna1c in dopamine receptor 1 (D1)-expressing cells enhances remote (30 days post-training) contextual fear memory in male mice. Here, we extend these findings by examining sex- and gene dosage-specific behavioral consequences of Cacna1c loss in D1 cells. We find that D1-Cacna1c deletion produces a sex- and gene dosage-dependent effect on fear memory. In males, homozygous loss of D1-Cacna1c heightens remote contextual fear at 30-days post-training, replicating prior findings, whereas partial loss had no effect. Cue-associated fear memory remained unaffected across genotypes. In contrast, females exhibited heightened contextual fear with both heterozygous and homozygous D1-Cacna1c loss at 24-hrs, 7-days, and 30-days post-training, indicating increased sensitivity to contextual aversive learning. Cue-associated fear memory was higher at 24-hrs but normalized at later time points in females. In the Water Y-maze, males with heterozygous or homozygous D1-Cacna1c loss showed impaired spatial memory at 7-days post-training, whereas females were unaffected. D1-Cacna1c deletion reduced locomotor activity selectively in females during the initial 5-mins of a 60-min session, with no genotype effects in males. Social interaction and anxiety-like behavior were unchanged across groups. Together, these findings highlight the interplay between dopamine receptor signaling and calcium channel function in shaping sex-dependent aspects of memory.

neuroscience↗

bioRxiv2024

Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia

Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184s effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.

neuroscience↗