Nye, J. A. | Search bioRxiv

bioRxiv2026

Long-term Effects of Early Life Adversity On Brain Dopamine and Serotonin Receptor Systems Involved In Cocaine Reinforcement In Adult Macaques: a Positron Emission Tomography study

Early life adverse (ELA) experiences such as child maltreatment (MALT) are associated with physical and mental illness, including substance use disorders (SUDs), but underlying neurobiological mechanisms remain unclear. This study examined long-term effects of infant MALT on adult brain serotonin (5HT) and dopamine (DA) receptors in corticolimbic regions involved in reward and emotional control, using positron emission tomography (PET) imaging, a translational infant MALT macaque model of cocaine use disorder (CUD) risk and a COC self-administration (SA) paradigm. The study focused on regional serotonin 5HT1A, 5HT2A, and dopamine D2/D3 receptor availability (BP) differences between MALT and Control animals using PET, both at baseline (pre-COC SA) and following chronic COC SA (once they reached a total of 100 mg/kg intake). We also examined whether levels of these neurochemical receptors predicted COC SA measures, including reinforcing effects and potency using fixed-ratio (FR) peak response rates and progressive-ratio (PR) peak breakpoint. Our findings showed long-term effects of infant MALT on 5HT, but not DA, receptors in corticolimbic circuits. Specifically, MALT animals showed lower 5HT1A BP in the anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and hippocampus compared to Controls. A MALT by Sex interaction effect was detected in 5HT2A BP in the OFC, with lower levels in MALT than Control males, but not in females. In addition, upregulation of 5HT1A and 5HT2A receptors was detected following chronic COC SA in most PFC subregions, hippocampus, and NAcc, particularly in the Control group. These findings suggest long-term effects of ELA on adult 5HT, but not DA, receptors in corticolimbic regions involved in emotional and reward processes. We also found associations between PET baseline (pre-COC SA) receptor BP data and COC SA measures. In particular, a positive correlation between 5HT1A receptor BP in caudate and peak FR Response Rates, whereas amygdala 5HT1A receptor levels were positively correlated with peak PR breakpoint and negatively correlated with peak FR Response Rates. Overall, these findings suggest an important role of 5HT1A and 5HT2A PFC receptors in early COC-related changes in reward circuitry and of amygdala 5HT receptors on cocaine-maintained behaviors. The dynamic change of these 5HT1A and 5HT2A receptors following chronic COC exposure was blunted in animals with ELA. It would be important to understand the biological consequences of these dynamic changes in 5HT receptors and whether they are associated with other stages of the addiction cycle, for example COC relapse, which could inform future pharmacological interventions that target 5HT receptors for treatment of CUD. Simple SummaryWe studied the long-term effects of early life adversity (ELA) on adult brain dopamine (DA) and serotonin (5HT) signaling in corticolimbic regions involved in emotional and reward regulation. We used specific PET radioligands that bind to the DA D2/D3, 5HT1A and 5HT2A receptors, finding lower levels of 5HT, but not DA, receptors binding potential (BP) in animals that experienced ELA. We also found associations between PET receptor BP measures and reinforcing effects of cocaine in i.v. self-administration paradigms using fixed- and progressive-ratio reinforcement schedules. In addition, a strong upregulation of 5HT, but not DA, receptors was identified following chronic cocaine exposure in prefrontal cortex (PFC). Our findings suggest long-term effects of ELA on adult PFC 5HT1A and 5HT2A receptors. The findings also suggest an important role of 5HT1A and 5HT2A, more so than D2/D3, receptors in early cocaine-related changes in reward circuitry. The early dynamic changes of these 5HT receptors could serve as biomarkers for cocaine use disorder (CUD) and inform future pharmacological interventions.

neuroscience↗

bioRxiv2020

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson's disease

Inflammation has been linked to the development of nonmotor symptoms in Parkinsons disease (PD), which greatly impact patients quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

neuroscience↗