Inflammation has been linked to the development of nonmotor symptoms in Parkinson's 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. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust [18F]FEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg-1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has well documented prosocial effects and is currently under clinical investigation as a treatment for patients with PTSD, autism, and other conditions. Early clinical trials have found that MDMA-assisted therapy may have robust long-lasting therapeutic effects, yet the mechanism by which acute treatments produce these long-term effects is unclear. Sensitization to certain behavioral drug effects is a common rodent model used to assess long-lasting neurobiological adaptations induced by acute drug treatments. Nine independent experiments were undertaken to investigate if and how mice sensitize to the prosocial effects of MDMA. When treated with 7.8 mg/kg MDMA and paired every other day for a week, MDMA-induced social interaction increased precipitously across treatment sessions. This previously unreported phenomenon was investigated and found to be heavily influenced by a social context and 5-HT2AR activation. Social sensitization did not appear to develop if mice were administered MDMA in isolation, and pretreatment with MDL100907, a selective 5-HT2AR antagonist, inhibited the development of social sensitization. However, when MDL100907 was administered to mice that had already been sensitized, it did not attenuate social interaction, suggesting that 5-HT2AR activity may be necessary for the development of social sensitization but not the expression of MDMA-induced social behavior. Additional investigation is warranted to further explore the phenomenon of social sensitization and to determine the underlying neurobiological mechanisms.

Objective: Alfaxalone has been used increasingly in biomedical research and veterinary medicine of large animals in recent years. However, its effects on the cerebral blood flow (CBF) physiology and intrinsic neuronal activity of anesthetized brains remain poorly understood. Methods: Four healthy adult rhesus monkeys were anesthetized initially with alfaxalone (0.125 mg/kg/min) or ketamine (1.6 mg/kg/min) for 50 min, then administrated with 0.8% isoflurane for 60 min. Heart rates, breathing beats, and blood pressures were continuously monitored. CBF data were collected using pseudo-continuous arterial spin-labeling (pCASL) MRI technique and rsfMRI data were collected using single-shot EPI sequence for each anesthetic. Results: Both the heart rates and mean arterial pressure (MAP) remained more stable during alfaxalone infusion than those during ketamine administration. Alfaxalone reduced CBF substantially compared to ketamine anesthesia (grey matter, 65 ± 22 vs. 179 ± 38 ml/100g/min, p<0.001; white matter, 14 ± 7 vs. 26 ± 6 ml/100g/min, p < 0.05); In addition, CBF increase was seen in all selected cortical and subcortical regions of alfaxalone-pretreated monkey brains during isoflurane exposure, very different from the findings in isoflurane-exposed monkeys pretreated with ketamine. Also, alfaxalone showed suppression effects on functional connectivity of the monkey brain similar to ketamine. Conclusion: Alfaxalone showed strong suppression effects on CBF of the monkey brain.The residual effect of alfaxalone on CBF of isoflurane-exposed brains was evident and monotonous in all the examined brain regions when used as induction agent for inhalational anesthesia. In particular, alfaxalone showed similar suppression effect on intrinsic neuronal activity of the brain in comparison with ketamine. These findings suggest alfaxalone can be a good alternative to veterinary anesthesia in neuroimaging examination of large animal models. However, its effects on CBF and functional connectivity should be considered.

Ketamine has been used as a pharmacological model for schizophrenia, as sub-anesthetic infusions have been shown to produce temporary schizophrenia-like symptoms in healthy humans. More recently, ketamine has emerged as a potential treatment for multiple psychiatric disorders, including treatment-resistant depression and suicidal ideation. However, the mechanisms underlying both the psychotomimetic and therapeutic effects of ketamine remain poorly understood. This review provides an overview of what is known of the neural mechanisms underlying the effects of ketamine and details what functional magnetic resonance imaging studies have revealed at a systems level focused on brain circuitry. Multiple analytic approaches show that ketamine produces robust and consistent effects at the whole-brain level. These effects are highly conserved across human and nonhuman primates, validating the use of nonhuman primate models for further investigations with ketamine. Regional analysis of brain functional connectivity suggests that the therapeutic potential of ketamine may be derived from a strengthening of executive control circuitry, making it an intriguing candidate for the treatment of drug abuse. There are still important questions about the mechanism of action and therapeutic potential of ketamine that can be addressed using appropriate functional neuroimaging techniques.

Recently, there has been a lot of interest in the neuroimaging community in exploring fMRI time-series measures of local neuronal activity and excitation/inhibition (E/I) balance in the brain. In this preliminary study we probed the sensitivity of widely used sample entropy (SE) measure at multiple scales to controlled alteration of the brain's E/I balance in non-human primates (NHPs) with a well-characterized sub-anesthetic ketamine infusion fMRI model. We found that SE failed to detect the expected changes in E/I balance induced by ketamine. Subsequently, noticing that the complexity in the time series contributing SE could be dominated by non-neuronal noise in this experimental setting, we developed a new time-series measure called restricted sample entropy (RSE) by restricting SE estimations to regular portions of the fMRI time-series. RSE was able to adequately reflect the increased excitatory activity engendered by disinhibition of glutamergic neurons, through sub-anesthetic ketamine infusion. These results show that RSE is potentially a powerful tool for examining local neural activity, E/I balance, and alterations in brain state.

Adolescence represents a developmental stage in which initiation of drug use typically occurs and is marked by dynamic neurobiological changes. These changes present a sensitive window during which perturbations to normative development lead to alterations in brain circuits critical for stress and emotional regulation as well as reward processing, potentially resulting in an increased susceptibility to psychopathologies. The occurrence of early life stress (ELS) is related to a greater risk for the development of substance use disorders (SUD) during adolescence. Studies using nonhuman primates (NHP) are ideally suited to examine how ELS may alter the development of neurobiological systems modulating the reinforcing effects of drugs, given their remarkable neurobiological, behavioral, and developmental homologies to humans. This review examines NHP models of ELS that have been used to characterize its effects on sensitivity to drug reinforcement, and proposes future directions using NHP models of ELS and drug abuse in an effort to develop more targeted intervention and prevention strategies for at risk clinical populations.

The N-(E)-fluorobutenyl-3β-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as 18F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [18F]9-[18F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [18F]9. PET imaging with [18F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min post-injection of [18F]9 the ratio of uptake in the putamen and caudate vs. cerebellum uptake was ≥ 4.

The meta-vinylhalide fluoroalkyl ester nortropanes 1-4 were synthesized as ligands of the serotonin transporter (SERT) for use as positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that 1-4 have a high affinity for the SERT (Ki's = 0.3 - 0.4 nM) and are selective for the SERT over the dopamine and norepinephrine transporters (DAT and NET). MicroPET imaging in anesthetized cynomolgus monkeys with [18F]1-[18F]4 demonstrated that all four tracers behave similarly with peak uptake in the SERT-rich brain regions achieved after 45-55 min followed by a steady washout. An awake monkey study was performed with [18F]1 which demonstrated that the uptake of [18F]1 was not influenced by anesthesia. Chase studies with the SERT ligand 15 displaced [18F]1-[18F]4 but chase studies with the DAT ligand 16 did not displace [18F]1-[18F]4 thus indicating that the tracers were binding specifically to the SERT.

Background: Cocaine and methamphetamine (METH) are two commonly abused drugs that have behavioral-stimulant properties. These stimulant effects are partially mediated by the dopaminergic system. Recent evidence has suggested that the histamine H3 receptor (H3R) may modulate the release of dopamine induced by METH. The aim of the present study was to examine the role of H3R in the behavioral-stimulant effects of cocaine and METH in mice and monkeys. Methods: Nonhabituated, experimentally naïve mice (n = 5–6) were pretreated with the H3R agonist imetit 30 min before METH or cocaine, and activity was measured for 90 min. The behavioral-stimulant effects of METH and cocaine were also studied in squirrel monkeys (n = 3) under a fixed-interval schedule of stimulus termination. Monkeys were pretreated with imetit 30 min before the peak behavioral-stimulant doses of METH or cocaine derived from individual subjects. Results: Pretreatment with imetit did not affect basal activity in mice. Imetit significantly attenuated the behavioral-stimulant effects of METH, but not cocaine. In monkeys, no dose of imetit tested significantly altered the behavioral-stimulant effects of METH or cocaine. Conclusion: These results suggest a role of H3R in the behavioral-stimulant effects of METH, but not cocaine, in mice and no role in monkeys.