Astronauts on interplanetary missions-such as to Mars-will be exposed to space radiation, a spectrum of highly-charged, fast-moving particles that includes 56 fe and 28 Si. earth-based preclinical studies show space radiation decreases rodent performance in low-and some high-level cognitive tasks. Given astronaut use of touchscreen platforms during training and space flight and given the ability of rodent touchscreen tasks to assess functional integrity of brain circuits and multiple cognitive domains in a non-aversive way, here we exposed 6-month-old C57BL/6J male mice to whole-body space radiation and subsequently assessed them on a touchscreen battery. Relative to Sham treatment, 56 fe irradiation did not overtly change performance on tasks of visual discrimination, reversal learning, rule-based, or object-spatial paired associates learning, suggesting preserved functional integrity of supporting brain circuits. Surprisingly, 56 fe irradiation improved performance on a dentate gyrus-reliant pattern separation task; irradiated mice learned faster and were more accurate than controls. Improved pattern separation performance did not appear to be touchscreen-, radiation particle-, or neurogenesisdependent, as 56 fe and 28 Si irradiation led to faster context discrimination in a non-touchscreen task and 56 fe decreased new dentate gyrus neurons relative to Sham. these data urge revisitation of the broadly-held view that space radiation is detrimental to cognition. Interplanetary missions-such as to Mars-are a high priority for many space agencies. The crew of future missions will face hazards 1-3 , such as exposure to galactic cosmic radiation 4-7 a spectrum of low and high-(H) atomic number (Z) and high-energy (E) particles such as 56 Fe and 28 Si. Fast-moving HZE particles cannot be effectively blocked by modern spacecraft shielding 8-11. Therefore, it is concerning that studies with laboratory animals generally conclude HZE particles are detrimental to brain and behavior 12-14. Such preclinical data suggest HZE particle exposure may be harmful to astronaut cognition and impede mission success.

Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Most preclinical studies with mature, “astronaut-aged” rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As there are conflicting results on whether the female rodent brain is preferentially injured by or resistant to charged particle exposure, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to fractionated whole-body 56Fe irradiation (3 × 6.7cGy 56Fe over 5 days, 600 MeV/n) would improve performance vs. Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function [e.g., location discrimination reversal (LDR) and extinction, respectively]. In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal stimulus-response rule-based habit learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASA’s risk assessments from being based on a single cognitive domain.

Abuse of synthetic psychostimulants like synthetic cathinones has risen in recent years. 3,4-Methylenedioxypyrovalerone (MDPV) is one such synthetic cathinone that demonstrates a mechanism of action similar to cocaine. Compared to cocaine, MDPV is more potent at blocking dopamine and norepinephrine reuptake and is readily self-administered by rodents. The present study compared the rewarding and reinforcing properties of MDPV and cocaine using systemic injection dose-response and self-administration models. Fifty kilohertz ultrasonic vocalizations (USVs) were recorded as an index of positive affect throughout experiments. In Experiment 1, MDPV and cocaine dose-dependently elicited 50-kHz USVs upon systemic injection, but MDPV increased USVs at greater rates and with greater persistence relative to cocaine. In Experiment 2, latency to begin MDPV self-administration was shorter than latency to begin cocaine self-administration, and self-administered MDPV elicited greater and more persistent rates of 50-kHz USVs versus cocaine. MDPV-elicited 50-kHz USVs were sustained over the course of drug load-up whereas cocaine-elicited USVs waned following initial infusions. Notably, we observed a robust presence of context-elicited 50-kHz USVs from both MDPV and cocaine self-administering rats. Collectively, these data suggest that MDPV has powerfully rewarding and reinforcing effects relative to cocaine at one-tenth doses. Consistent with prior work, we additionally interpret these data in supporting that MDPV has significant abuse risk based on its potency and subjectively positive effects. Future studies will be needed to better refine therapeutic strategies targeted at reducing the rewarding effects of cathinone analogs in efforts to ultimately reduce abuse liability.

Although clinical studies identify traumatic brain injury (TBI) as a risk factor for the development of substance use disorder, much remains unknown about the possible underlying pathogenesis and age-specific effects. Thus, the aim of this study is to test the hypothesis that at an age of ongoing maturation, adolescent TBI alters elements of the reward pathway, resulting in increased sensitivity to the rewarding effects of a subthreshold dose of cocaine that does not induce significant behavioral changes in naı ¨ve, non-injured mice. Specifically, these results were derived from the combination of the controlled cortical impact model of TBI, performed on either adolescent (6 weeks) or young adult (8 weeks) mice, followed by the cocaine-induced conditioned place preference assay 2 weeks later. Using three-dimensional isosurface rendering and volumetric image analysis, TBI was found to induce neuromorphological changes such as decreased dendritic complexity and reduced spine density in brain regions essential for reward perception and processing of druginduced euphoria. Further, we demonstrated that these neuronal changes may affect the differential expression of dopamine-associated genes. Our analysis also provided evidence for age-related differences in immune response and the distinct involvement of augmented microglial phagocytic activity in the remodeling of neuronal structures in the adolescent TBI brain. Our studies suggest that TBI during adolescence, a period associated with ongoing maturation of dopaminergic systems, may subsequently enhance the abuse liability of cocaine in adulthood.

Rationale Synthetic psychostimulant abuse, including cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV), continues to increase in many countries. Similar to cocaine but with greater potency, MDPV elicits a transient sympathomimetic response by blocking cellular uptake of dopamine (DA) and norepinephrine (NE)—administration in some users is reported as euphoria-inducing much like cocaine and amphetamine. Pharmacological agents that disrupt excitatory transmission onto midbrain DA-producing neurons, including hypothalamic hypocretin/orexin (hcrt/ox) receptor antagonists, present attractive targets to aide abstinence maintenance by reducing psychostimulant-associated reward and reinforcement. Objective The present study sought to assess the degree to which suvorexant, a dual hcrt/ox receptor antagonist, influences drug-taking as well as ultrasonic vocalizations (USVs) associated with MDPV self-administration. Methods Rats were trained to self-administer MDPV (~0.03 mg/kg/inf, 3-s) for 14 days under a fixed-ratio 1 schedule of reinforcement, and effects of suvorexant (0, 3, 10, 30 mg/kg, i.p.) on drug-taking was assessed. USVs were recorded during a 30-minute pre-lever period as well as during 2-hours of MDPV self-administration. Results We observed that suvorexant modestly suppressed the number of MDPV infusions earned. Notably, we observed that suvorexant reduced 50-kHz USVs associated with pre- and post-lever time-points but did not noticeably alter call type profiles. Upon comparison of the two measures, we observed trending positive associations between suvorexant-induced changes in drug-taking and 50-kHz USVs. Conclusions Results from this exploratory study provide support for: (1) studying how suvorexant may provide benefit to humans with stimulant use disorders, (2) identifying a potential role for orexin transmission in cathinone abuse, and (3) further interrogating the potential utility of rat USVs to predict drug consumption in preclinical models of substance use disorders.

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Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a chemogenetic tool commonly-used to manipulate rodent brain circuit activity. The most widely-used synthetic ligand for DREADDs is Clozapine-N-oxide (CNO). However, CNO is back-metabolized to clozapine, which itself activates numerous endogenous receptors and therefore may influence rodent behavior. To eliminate potential off-target effects of CNO, a new DREADD agonist, Compound 21 (C21), has been proposed as an alternative as it lacks active metabolites. The literature is mixed on whether acute administration of CNO or C21 changes mouse behavior. In contrast, there is no substantial literature on whether chronic administration of CNO or C21 changes mouse behavior. Here we tested whether chronic injections of these two distinct DREADD agonists change key behaviors in non-designer receptor-expressing mice relative to Vehicle (Veh)-injected control mice. Mice (CamKIIα-icre males) were injected i.p. with Veh (0.5% dimethyl sulfoxide in 0.9% saline, 5ml/kg), CNO (0.2mg/ml, 1mg/kg), or C21 (0.2mg/ml, 1mg/kg) 5 days a week for 16 weeks. All three groups had similar weight gain over the 16 week-experiment, and showed similar measures in behaviors assessed during week 3 (beam breaks in a 30-min locomotion task, time in center of open field or open arms of elevated plus maze) and week 14-16 (ambulatory distance during 240-min activity monitoring, percent marbles buried, grooming time during the sucrose splash test). These data show chronic injections of CNO or C21 do not affect key behaviors as compared to chronic injections of Veh, and may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists. Highlights Acute injection of CNO changes behavior of non-DREADD-expressing mice It’s not known if chronic CNO or alternative agonist C21 also changes mouse behavior DREADD agonists or Veh were given chronically to non-DREADD-expressing mice Mice given Veh, CNO, or C21 were similar in regard to locomotion and other behaviors Thus CNO and C21 can be injected repeatedly without non-specific behavior effects