Biology subjects

Farero, R. D.

Publications and source records attributed to Farero, R. D..

4 recordsLinked to original sources

bioRxiv2025

Corticotropin-Releasing Factor in the Nucleus Accumbens Does Not Drive High Levels of Cocaine Consumption

Uncovering the neurobiological processes underlying substance use disorder informs future therapeutic interventions. Prior research implicates the corticotropin releasing factor (CRF) system as a major player in a wide variety of substance use disorder-like phenotypes. However, the complexity of the CRF system in regard to brain region specific effects and experience-dependent changes in activity is poorly understood. Employing a cocaine self-administration paradigm that induces escalation of cocaine consumption in a subset of subjects, we investigated the role of CRF activity in the Nucleus Accumbens (NAc) in cocaine-taking patterns both before and after chronic cocaine experience. Our results showed that pharmacologically inhibiting CRF-R1 in the NAc did not reduce cocaine consumption following escalation and genetically deleting CRF-R1 from cells in the NAc did not prevent escalation. Overall, this suggests that any effect of CRF activity driving escalation or high levels of cocaine consumption is not through its actions on CRF-R1 in the NAc.

neuroscience↗

bioRxiv2023

Kappa Opioid Receptors in Mesolimbic Terminals Mediate Escalation of Cocaine Consumption

Increases in drug consumption over time, also known as escalation, is a key behavioral component of substance use disorder (SUD) that is related to potential harm to users, such as overdose. Studying escalation also allows researchers to investigate the transition from casual drug use to more SUD-like drug use. Understanding the neurobiological systems that drive this transition will inform therapeutic treatments in the aim to prevent increases in drug use and the development of SUD. The kappa opioid receptor (KOR) system is typically known for its role in negative affect, which is commonly found in SUD as well. Furthermore, the KOR system has also been implicated in drug use and importantly, modulating the negative effects of drug use. However, the specific neuronal subpopulation expressing KOR involved has not been identified. Here, we first demonstrated that pharmacologically inhibiting KOR in the nucleus accumbens core (NAcC), as a whole, blocks cocaine escalation under long-access self-administration conditions. We then demonstrated that KOR expressed on ventral tegmental area (VTA) neurons but not NAcC neurons is sufficient for blocking cocaine escalation by utilizing a novel virally-mediated CRISPR-SaCas9 knock-out of the oprk1 gene. Together, this suggests that activation of KOR on VTA terminals in the NAcC drives the transition to the SUD-like phenotype of escalation of cocaine consumption.

neuroscience↗

bioRxiv2023

Levodopa reduces consumption of multiple classes of addictive substances in rats

Dopamine transmission is implicated in aberrant behaviors associated with substance use disorders. Previous research revealed a causal link between excessive drug consumption and the loss of dopamine signaling to stimuli associated with psychostimulant use. The emerging change in dopamine signaling is specific to stimuli associated with the substance rather than the pharmacological properties of the drug itself. Because the change in dopamine signaling was specific to the associated stimuli and not the pharmacological properties of the substance, we examined if treatment with the dopamine precursor, L-DOPA, alters alcohol and opioid self-administration. Therefore, we trained rats to orally self-administer ethanol or the synthetic opioid fentanyl and found that treating animals with L-DOPA significantly reduced consumption of both alcohol and fentanyl. These data suggest dopamine signaling has a vital role in mediating the amount of drug animals will voluntarily take, across multiple classes of drugs. Importantly, these data are preclinical demonstrations of L-DOPA being utilized as a harm reducing treatment in substance use disorders.

animal behavior and cognition↗

bioRxiv2023

Cocaine Seeking And Taking Are Oppositely Regulated By Dopamine

In some individuals, drug-associated cues subsume potent control of behavior, such as the elicitation of drug craving1-3 and automatized drug use4. The intensity of this cue reactivity is highly predictive of relapse and other clinical outcomes in substance use disorders5, 6. It has been postulated that this cue reactivity is driven by augmentation of dopamine release over the course of chronic drug use7. Here we carried out longitudinal recording and manipulation of cue-evoked dopamine signaling across phases of substance-use related behavior in rats. We observed a subset of individuals that exhibited increased cue reactivity and escalated drug consumption, two cardinal features of substance use disorders. In these individuals, cue-evoked phasic dopamine release underwent diametrically opposed changes in amplitude, determined by the context in which the cue is presented. Dopamine evoked by non-contingent cue presentation increased over drug use, producing greater cue reactivity; whereas dopamine evoked by contingent cue presentation decreased over drug use, producing escalation of drug consumption. Therefore, despite being in opposite directions, these dopamine trajectories each promote core symptoms of substance use disorders.

neuroscience↗