Recently, multiple compounds have been synthesized that target the allosteric binding site(s) of CB 1. These CB 1 positive allosteric modulators, may capture the benefits of cannabinoid receptor activation without unwanted psychoactive effects, such as sedation. For example, ZCZ011 blocks neuropathic pain, absent the catalepsy, sedation, and hypothermia caused by CB 1 orthosteric modulators, including Δ 9-tetrahydrocannabinol (THC). The primary goal of the present study was to evaluate the potential of ZCZ011 to attenuate somatic signs of cannabinoid withdrawal in mice. Mice were repeatedly administered THC (10 mg/kg, s.c.) or vehicle, and withdrawal was either precipitated using the CB 1 antagonist rimonabant (3 mg/kg, ip) or elicited spontaneously via THC abstinence. ZCZ011 (≥10 mg/kg, i.p.) significantly attenuated somatic signs of withdrawal, including head twitches and paw tremors, but had no effect on locomotor activity or conditioned place preference. We next tested the antiulcerogenic properties of CB 1 positive allosteric modulation. Mice were fasted for 22 h, administered ZCZ011, and gastric hemorrhages were induced with the nonsteroidal anti-inflammatory drug diclofenac sodium (100 mg/kg, p.o.). ZCZ011 alone had no effect on gastric ulceration, but ZCZ011 (≥10 mg/kg) blocked ulcer formation when combined with a subthreshold MAGL inhibitor (JZL184; 1 mg/kg, i.p.). Thus, CB 1 positive allosteric modulation is a novel approach to treat cannabinoid dependence and gastric inflammation.

Physical activity (PA) is critical for a healthy lifestyle. The current study assessed heart rate (HR) as a primary measure of moderate and vigorous PA with four typically developing children. First, individualized HR assessments were conducted to determine moderate and vigorous HR zones. Next, participants engaged in various exercises at a local YMCA facility (i.e., biking, elliptical, basketball, and exergame boxing) to determine how HR during these activities aligned with their individualized HR zones. During exercise bouts, HR was typically above moderate, but below vigorous HR zones for all participants. Additionally, exercises that restricted range of motion (i.e., biking and elliptical) engendered generally lower HR than exercises with greater range of motion. Vocal instructions to exercise at vigorous levels were effective at increasing HR to vigorous levels for one participant. The advantages of using HR as a metric of PA during assessment and intervention are discussed.

Epidemiological and experimental studies have associated oral and systemic exposures to the herbicide paraquat (PQ) with Parkinson’s disease. Despite recognition that airborne particles and solutes can be directly translocated to the brain via olfactory neurons, the potential for inhaled PQ to cause olfactory impairment has not been investigated. This study sought to determine if prolonged low-dose inhalation exposure to PQ would lead to disposition to the brain and olfactory impairment, a prodromal feature of Parkinson’s disease. Adult male and female C57BL/6J mice were exposed to PQ aerosols in a whole-body inhalation chamber for 4 h/day, 5 days/week for 4 weeks. Subsets of mice were sacrificed during and after exposure and PQ concentrations in various brain regions (olfactory bulb, striatum, midbrain, and cerebellum) lung, and kidney were quantified via mass spectrometry. Alterations in olfaction were examined using an olfactory discrimination paradigm. PQ inhalation resulted in an appreciable burden in all examined brain regions, with the highest burden observed in the olfactory bulb, consistent with nasal olfactory uptake. PQ was also detected in the lung and kidney, yet PQ levels in all tissues returned to control values within 4 weeks post exposure. PQ inhalation caused persistent male-specific deficits in olfactory discrimination. No effects were observed in females. These data support the importance of route of exposure in determination of safety estimates for neurotoxic pesticides, such as PQ. Accurate estimation of the relationship between exposure and internal dose is critical for risk assessment and public health protection.

Background Air pollution has been associated with neurodevelopmental disorders in epidemiological studies. In our studies in mice, developmental exposures to ambient ultrafine particulate (UFP) matter either postnatally or gestationally results in neurotoxic consequences that include brain metal dyshomeostasis, including significant increases in brain Fe. Since Fe is redox active and neurotoxic to brain in excess, this study examined the extent to which postnatal Fe inhalation exposure, might contribute to the observed neurotoxicity of UFPs. Mice were exposed to 1 µg/m3 Fe oxide nanoparticles alone, or in conjunction with sulfur dioxide (Fe (1 µg/m3) + SO2 (SO2 at 1.31 mg/m3, 500 ppb) from postnatal days 4–7 and 10–13 for 4 h/day. Results Overarching results included the observations that Fe + SO2 produced greater neurotoxicity than did Fe alone, that females appeared to show greater vulnerability to these exposures than did males, and that profiles of effects differed by sex. Consistent with metal dyshomeostasis, both Fe only and Fe + SO2 exposures altered correlations of Fe and of sulfur (S) with other metals in a sex and tissue-specific manner. Specifically, altered metal levels in lung, but particularly in frontal cortex were found, with reductions produced by Fe in females, but increases produced by Fe + SO2 in males. At PND14, marked changes in brain frontal cortex and striatal neurotransmitter systems were observed, particularly in response to combined Fe + SO2 as compared to Fe only, in glutamatergic and dopaminergic functions that were of opposite directions by sex. Changes in markers of trans-sulfuration in frontal cortex likewise differed in females as compared to males. Residual neurotransmitter changes were limited at PND60. Increases in serum glutathione and Il-1a were female-specific effects of combined Fe + SO2. Conclusions Collectively, these findings suggest a role for the Fe contamination in air pollution in the observed neurotoxicity of ambient UFPs and that such involvement may be different by chemical mixture. Translation of such results to humans requires verification, and, if found, would suggest a need for regulation of Fe in air for public health protection.

Timing processes have been implicated as potential mechanisms that underlie self-controlled choice. To investigate the impact of an intervention that has been shown to increase self-controlled choice on timing processes, accuracy and precision of temporal discrimination were assessed in an 18-s peak procedure (18-s fixed interval trials; 54-s peak trials). During an intervention phase, mice in three treatment groups experienced differential reinforcement of low rate (DRL) schedules of reinforcement of 27 s, 18 s, or 9 s. A fourth group received continued exposure to the peak procedure. After the DRL intervention, timing was reassessed using the peak procedure. In contrast to previous reports, the DRL intervention resulted in less precise timing as indicated by increased peak spread and disrupted single-trial measures of temporal control. These effects were only detected just after the DRL intervention suggesting a transient effect of DRL exposure on timing. The increase in peak spread in the present experiment suggests delay exposure via DRL schedules may produce a "dose-dependent" effect on temporal discrimination, which may also increase self-controlled choice.