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Astronauts will encounter extended exposure to galactic cosmic radiation (GCR) during deep space exploration, which could impair brain function. Here, we report that in male mice, acute or chronic GCR exposure did not modify reward sensitivity but did adversely affect attentional processes and increased reaction times. Potassium (K+)-stimulation in the prefrontal cortex (PFC) elevated dopamine (DA) but abolished temporal DA responsiveness after acute and chronic GCR exposure. Unlike acute GCR, chronic GCR increased levels of all other neurotransmitters, with differences evident between groups after higher K+-stimulation. Correlational and machine learning analysis showed that acute and chronic GCR exposure differentially reorganized the connection strength and causation of DA and other PFC neurotransmitter networks compared to controls which may explain space radiation-induced neurocognitive deficits.

The response of the human body to multiple spaceflight stressors is complex, but mounting evidence implicate risks to CNS functionality as significant, able to threaten metrics of mission success and longer-term behavioral and neurocognitive health. Prolonged exposure to microgravity, sleep disruption, social isolation, fluid shifts, and ionizing radiation have been shown to disrupt mechanisms of homeostasis and neurobiological well-being. The overarching goal of this review is to document the existing evidence of how the major spaceflight stressors, including radiation, microgravity, isolation/confinement, and sleep deprivation, alone or in combination alter molecular, neurochemical, neurobiological, and plasma metabolite/lipid signatures that may be linked to operationally-relevant behavioral and cognitive performance. While certain brain region-specific and/or systemic alterations titrated in part with neurobiological outcome, variations across model systems, study design, and the conspicuous absence of targeted studies implementing combinations of spaceflight stressors, confounded the identification of specific signatures having direct relevance to human activities in space. Summaries are provided for formulating new research directives and more predictive readouts of portending change in neurobiological function.

Introduction The high comorbidity between schizophrenia and cigarette smoking points to a possible shared heritable factor predisposing individuals with schizophrenia to nicotine addiction. The N -methyl- d -aspartate (NMDA) receptor has been highly implicated in both schizophrenia and nicotine addiction. Methods In the present study, we used mice with a null mutation on the serine racemase gene (srr), an established risk gene for schizophrenia, which encodes the enzyme to produce the NMDA receptor co-agonist d -serine, to model the pathology of schizophrenia and to determine whether NMDA receptor hypofunction reduced the ability of srr −/− mice to identify nicotine's subjective effects. Established nicotine discrimination procedures were used to train srr −/− and wild-type (WT) mice to discriminate 0.4 mg/kg nicotine under a 10-response fixed-ratio (FR10) schedule of food reinforcement. Results Results show that WT mice reliably acquired 0.4 mg/kg nicotine discrimination in about 54 training sessions, whereas srr −/− mice failed to acquire robust 0.4 mg/kg nicotine discrimination even after extended (>70) training sessions. These results show that NDMA receptor hypofunction in srr −/− mice decreased sensitivity to the interoceptive effects of nicotine. Conclusions Projected to humans, NMDA receptor hypofunction caused by mutations to the serine racemase gene in schizophrenia may reduce sensitivity to nicotine's subjective effects leading to increased nicotine consumption to produce the same effects as those unaffected by schizophrenia. Implications There is high comorbidity between schizophrenia and nicotine dependence as well as possible shared genetic risk factors between the two. The serine racemase knockout mouse (srr −/− ) with NMDA receptor hypofunction has been developed as a model for schizophrenia. We found that srr −/− mice were unable to acquire 0.4 mg/kg nicotine discrimination, while WT mice readily discriminated nicotine. These results show that decreased NMDA receptor function present in srr −/− mice and patients with schizophrenia may result in reduced sensitivity to nicotine's interoceptive effects, leading to increased nicotine consumption to produce the same subjective effects as those unaffected by schizophrenia. [ABSTRACT FROM AUTHOR]

Background: There are increasing reports of the misuse of prescription psychostimulants for cognitive enhancement together with recreational cannabis. This raises a concern that chronic use of cannabis high in Δ9-THC may alter the sensitivity to amphetamines. In this exploratory study we hypothesized chronic exposure to Δ9-THC through vaporized cannabis would diminish the central nervous system (CNS) activity of Adderall. Methods: To address this issue we exposed male and female mice to inhaled vaporized cannabis (10.3% Δ9-THC) or placebo for 30 min each day for ten consecutive days. After 24 h, mice were imaged fully awake for changes in BOLD signal following an IP injection of Adderall (60 µg) during the scanning session. After a 2-week washout, without any cannabis or placebo exposure, mice were again imaged and challenged with Adderall during the scanning session. The data were registered to a mouse 3D MRI atlas with 134 brain regions providing sitespecific increases and decreases in global brain activity. Results: Mice exposed to cannabis when compared to placebo showed a decrease in brain activation to Adderall. The blunted Adderall response was characterized by a decrease in positive BOLD signal and increase in negative BOLD. The prefrontal cortex, accumbens, ventral pallidum, caudate/putamen, and thalamus were most affected. After a 2-week wash out there were no significant differences between the cannabis and placebo groups when challenged with Adderall. Summary: This exploratory study shows that short, daily exposures to inhaled cannabis, something equivalent to recreational use, affects the sensitivity to the psychostimulant Adderall. The reduced Adderall effect on brain activity, particularly circuitry associated with dopaminergic signaling raises concerns about escalation in psychostimulant use. [ABSTRACT FROM AUTHOR]

The most prevalent psychoactive chemical in tobacco smoke is nicotine, which has been shown to maintain tobacco consumption as well as cause acute adverse effects at high doses, like nausea and emesis. Recent studies in laboratory animals have suggested that many non-nicotine constituents of tobacco smoke (e.g., minor tobacco alkaloids) may also contribute to tobacco's overall reinforcing and adverse effects. Here, we used intravenous (IV) self-administration (n = 3) and observation (n = 4) procedures in squirrel monkeys to, respectively, compare the reinforcing and adverse observable effects of nicotine and three prominent minor tobacco alkaloids, nornicotine, anatabine, and myosmine. In self-administration studies, male squirrel monkeys were trained to respond under a second-order fixed-interval schedule of reinforcement and dose-effects functions for nicotine and each of the minor tobacco alkaloids nornicotine, anatabine, and mysomine were determined. Observation studies were conducted in a different group of male squirrel monkeys to quantify the ability of nicotine, nornicotine, anatabine, and mysomine to produce adverse overt effects, including hypersalivation, emesis, and tremors. Results show that nicotine and to a lesser extent nornicotine were readily self-administered, whereas anatabine and myosmine were not. In observation studies, all minor tobacco alkaloids produced adverse observable effects that were either comparable or more pronounced than nicotine. Collectively, the present results showing that nicotine and the minor tobacco alkaloids nornicotine, anatabine, and myosmine produce differential reinforcing and acute adverse observable effects in monkeys provides further evidence that these constituents may differently contribute to the psychopharmacological and adverse effects of tobacco consumption. • Nicotine and nornicotine are readily self-administered by squirrel monkeys. • Anatabine and myosmine are not self-administered by squirrel monkeys. • Nicotine/minor tobacco alkaloids produce distinct overt adverse effects in monkeys. • Tobacco alkaloids contribute differently to tobacco's reinforcing/adverse effects. [ABSTRACT FROM AUTHOR]

Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co-agonist d-serine and an established risk gene for SZ, to recreate the pathology of SZ. We determined the effect of NMDAR hypofunction resulting from the absence of d-serine on motivated behavior by using intracranial self-stimulation and neurotransmitter release in the nucleus accumbens by using in vivo microdialysis. Compared with wild-type mice, SR-/- mice exhibited similar baseline intracranial self-stimulation thresholds but were less sensitive to the threshold-lowering (rewarding) and the performance-elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR-/- mice, cocaine-induced increases in DA and glutamate release were blunted. γ-Amino-butyric acid efflux was unaffected in the SR-/- mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the drug. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction. [ABSTRACT FROM AUTHOR]