The puzzle of spontaneous alternation and inhibition of return: How they might fit together.

Two isolated spatial phenomena share a similar "been there; done that" effect on spatial behavior. Originally discovered in rodent learning experiments, spontaneous alternation is a tendency for the organism to visit a different arm in a T-maze on subsequent trials. Originally discovered in human studies of attention, inhibition of return is a tendency for the organism to orient away from a previously attended location. Whereas spontaneous alternation was identified by O'Keefe & Nadel as dependent on an intact hippocampus, inhibition of return is dependent on neural structures that participate in oculomotor control (the superior colliculus, parietal and frontal cortex). Despite the isolated literatures, each phenomenon has been assumed to reflect a basic novelty-seeking process, avoiding places previously visited or locations attended. In this commentary, we explore and compare the behavioral manifestations and neural underpinnings of these two phenomena, and suggest what is still needed to determine whether they operate in parallel or serial.

Neuron and neuroblast numbers and cytogenesis in the dentate gyrus of aged APPswe/PS1dE9 transgenic mice: Effect of long-term treatment with paroxetine.

Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess the longitudinal changes in the number of doublecortin-expressing neuroblasts and number of granular neurons in the dentate gyrus of APPswe/PS1dE9 transgenic mice. Furthermore, we investigated the effect of long-term paroxetine treatment on the number of neuroblasts and granular neurons, hippocampal amyloidosis, and spontaneous alternation behaviour, a measure of spatial working memory, in transgenic mice. We observed no difference in granular neurons between transgenic and wild type mice up till 18months of age, and no differences with age in wild type mice. The number of neuroblasts and the performance in the spontaneous alternation task was reduced in aged transgenic mice. Paroxetine treatment from 9 to 18months of age reduced hippocampal amyloidosis without affecting the number of neuroblasts or granular neurons. These findings suggest that the amyloidosis affects the differentiation of neuroblasts and spatial working memory, independent of changes in total granular neurons. Furthermore, while long-term paroxetine treatment may be able to reduce hippocampal amyloidosis, it appears to have no effect on total number of granular neurons or spatial working memory.

Spontaneous alternation: A potential gateway to spatial working memory in Drosophila.

Despite their ubiquity in biomedical research, Drosophila have yet to be widely employed as model organisms in psychology. Many complex human-like behaviors are observed in Drosophila, which exhibit elaborate displays of inter-male aggression and female courtship, self-medication with alcohol in response to stress, and even cultural transmission of social information. Here, we asked whether Drosophila can demonstrate behavioral indices of spatial working memory in a Y-maze, a classic test of memory function and novelty-seeking in rodents. Our data show that Drosophila, like rodents, alternate their visits among the three arms of a Y-maze and spontaneously favor entry into arms they have explored less recently versus ones they have just seen. These findings suggest that Drosophila possess some of the information-seeking and working memory facilities mammals depend on to navigate through space and might be relevant models for understanding human psychological phenomena such as curiosity.

Cellular activation of hypothalamic hypocretin/orexin neurons facilitates short-term spatial memory in mice.

The hypothalamic hypocretin/orexin (HO) system holds a central role in the regulation of several physiological functions critical for food-seeking behavior including mnemonic processes for effective foraging behavior. It is unclear however whether physiological increases in HO neuronal activity can support such processes. Using a designer rM3Ds receptor activation approach increasing HO neuronal activity resulted in improved short-term memory for novel locations. When tested on a non-spatial novelty object recognition task no significant difference was detected between groups indicating that hypothalamic HO neuronal activation can selectively facilitate short-term spatial memory for potentially supporting memory for locations during active exploration.

Win-stay and win-shift lever-press strategies in an appetitively reinforced task for rats.

Two experiments examined acquisition of win-stay, win-shift, lose-stay, and lose-shift rules by which hungry rats could earn food reinforcement. In Experiment 1, two groups of rats were trained in a two-lever operant task that required them to follow either a win-stay/lose-shift or a win-shift/lose-stay contingency. The rates of acquisition of the individual rules within each contingency differed: lose-shift and lose-stay rules were acquired faster than win-stay and win-shift rules. Contrary to a number of previous reports, the win-shift rule was acquired less rapidly than any of the other rules. In Experiment 2, the four rules were taught separately, but subjects still acquired the win-shift rule more slowly than any of the other rules.

Involvement of Glutamate NMDA Receptors in the Acute, Long-Term, and Conditioned Effects of Amphetamine on Rat 50 kHz Ultrasonic Vocalizations.

BACKGROUND: Rats emit 50 kHz ultrasonic vocalizations (USVs) in response to either natural or pharmacological pleasurable stimuli, and these USVs have emerged as a new behavioral measure for investigating the motivational properties of drugs. Earlier studies have indicated that activation of the dopaminergic system is critically involved in 50 kHz USV emissions. However, evidence also exists that non-dopaminergic neurotransmitters participate in this behavioral response. METHODS: To ascertain whether glutamate transmission plays a role in 50 kHz USV emissions stimulated by amphetamine, rats received five amphetamine (1-2mg/kg, i.p.) administrations on alternate days in a test cage, either alone or combined with the glutamate N-methyl-D-aspartate receptor antagonist MK-801 (0.1-0.5mg/kg, i.p.). Seven days after treatment discontinuation, rats were re-exposed to the test cage to assess drug conditioning, and afterwards received a drug challenge. USVs and locomotor activity were evaluated, along with immunofluorescence for Zif-268 in various brain regions and spontaneous alternation in a Y maze. RESULTS: Amphetamine-treated rats displayed higher 50 kHz USV emissions and locomotor activity than vehicle-treated rats, and emitted conditioned vocalizations on test cage re-exposure. Rats co-administered amphetamine and MK-801 displayed lower and dose-dependent 50 kHz USV emissions, but not lower locomotor activity, during repeated treatment and challenge, and scarce conditioned vocalization compared with amphetamine-treated rats. These effects were associated with lower levels of Zif-268 after amphetamine challenge and spontaneous alternation deficits. CONCLUSIONS: These results indicate that glutamate transmission participates in the acute, long-term, and conditioned effects of amphetamine on 50 kHz USVs, possibly by influencing amphetamine-induced long-term neuronal changes and/or amphetamine-associated memories.

Interactions between chronic ethanol consumption and thiamine deficiency on neural plasticity, spatial memory, and cognitive flexibility.

BACKGROUND: Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition, and many alcoholics are thiamine deficient. Thus, thiamine deficiency (TD) has emerged as a key factor underlying alcohol-related brain damage (ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol (EtOH)- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction. METHODS: Adult rats were randomly assigned to 1 of 6 treatment conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH over 6 months; severe pyrithiamine-induced TD (PTD-moderate acute stage); moderate PTD (PTD-early acute stage); moderate PTD followed by CET (PTD-CET); moderate PTD during CET (CET-PTD); and pair-fed (PF) control. After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain-derived neurotrophic factor (BDNF) and thalamic pathology. RESULTS: Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility, and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone, and the synergistic effects of moderate TD with CET lead to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD. CONCLUSIONS: These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD.

Brain and behavioral perturbations in rats following Western diet access.

Energy dense "Western" diets (WD) are known to cause obesity as well as learning and memory impairments, blood-brain barrier damage, and psychological disturbances. Impaired glucose (GLUT1) and monocarboxylate (MCT1) transport may play a role in diet-induced dementia development. In contrast, ketogenic diets (KD) have been shown to be neuroprotective. We assessed the effect of 10, 40 and 90 days WD, KD and Chow maintenance on spontaneous alternation (SA) and vicarious trial and error (VTE) behaviors in male rats, then analyzed blood glucose, insulin, and ketone levels; and hippocampal GLUT1 and MCT1 mRNA. Compared to Chow and KD, rats fed WD had increased 90 day insulin levels. SA was decreased in WD rats at 10, but not 40 or 90 days. VTE was perturbed in WD-fed rats, particularly at 10 and 90 days, indicating hippocampal deficits. WD rats had lower hippocampal GLUT1 and MCT1 expression compared to Chow and KD, and KD rats had increased 90 day MCT1 expression compared to Chow and WD. These data suggest that WD reduces glucose and monocarboxylate transport at the hippocampus, which may result in learning and memory deficits. Further, KD consumption may be useful for MCT1 transporter recovery, which may benefit cognition.

Multimodal Gamma Stimulation Improves Activity but not Memory in Aged Tgf344-AD Rats.

BACKGROUND: Multimodal sensory gamma stimulation is a treatment approach for Alzheimer's disease that has been shown to improve pathology and memory in transgenic mouse models of Alzheimer's. Because rats are closer to humans in evolution, we tested the hypothesis that the transgenic rat line bearing human APP and PS1, line TgF344-AD, would be a good supplemental candidate to test the efficacy of this treatment. Current therapy approaches under investigation seek to utilize the immune response to minimize or degrade the accumulation of ß-amyloid plaque load in mouse models designed to overexpress Aß. However, many of these models lack some of the hallmarks of Alzheimer's disease, such as hyperphosphorylated tau and neuronal cell loss. The TgF344-AD transgenic rat model is a good candidate to bridge the gap between mouse models and clinical efficacy in humans. OBJECTIVE: The objective of this study was to use multimodal gamma stimulation at light and auditory modalities simultaneously to test whether this enhances memory performance as measured by the object location task and the spontaneous alternation task. METHOD: In our study, we designed and built a low-cost, easy-to-construct multimodal light and sound gamma stimulator. Our gamma stimulation device was built using an Arduino microcontroller, which drives lights and a speaker at the gamma frequency. We have included in this paper our device's parts, hardware design, and software architecture for easy reproducibility. We then performed an experiment to test the effect of multimodal gamma stimulation on the cognitive performance of fourteen-month-old TgF344-AD rats. Rats were randomly assigned to either an experimental group that received gamma stimulation or a control group that did not. Performance in a Novel Object Location (NOL) task and spontaneous alternation task was evaluated in both groups before and after the treatment. RESULT: Multimodal gamma stimulation did not improve memory compared to unstimulated TgF344-AD rats. However, the gamma-stimulated rats did spend significantly more time exploring objects in the novel location task than the unstimulated rats. In the spontaneous alternation task, gamma-stimulated rats exhibited significantly greater exploratory activity than unstimulated controls. CONCLUSION: Multimodal gamma stimulation did not enhance memory performance in the object location task or the spontaneous alternation task. However, in both tasks, the treatment group had improved measures of exploratory activity relative to the untreated group. We conclude that several limitations could have contributed to this mixed effect, including aging complications, different animal models, or light cycle effects.

Ameliorative effect of the oil components derived from sweet potato shochu on impaired short-term memory in mice after amyloid ß25-35 injection.

Sweet potato shochu oil is a by-product of shochu production and usually discarded although some physiological functions are considered. In this study, we investigated the effects of shochu oil on short-term memory using a murine model of spontaneous alternating behavior induced by the intracerebroventricular (ICV) administration of amyloid ß25-35 (Aß25-35). Mice were orally administered shochu oil for 15 days. Experiments with a Y-maze model revealed that the Aß25-35 caused a significant decrease in spontaneous alternation behavior, and supplementation with shochu oil significantly improved this behavior. DNA microarray analysis revealed that the administration of shochu oil downregulated the expression of S100a9 and Ptgs2, which reportedly exacerbate amyloid ß deposition in Alzheimer's disease. The administration of shochu oil upregulated the expression of Dnaja1 and PP2A, which is typically downregulated in Alzheimer's disease. These data suggest that shochu oil possible ameliorates on impaired short-term memory in mice after amyloid ß25-35 injection, as indicated by its effects on improving spontaneous alternation behavior and modulating the expressions of related genes.

Chronic seizures induce sex-specific cognitive deficits with loss of presenilin 2 function.

Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p < 0.02; females: p < 0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p = 0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p = 0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.

Effects of ELF-PEMF exposure on spontaneous alternation, anxiety, motor co-ordination and locomotor activity of adult wistar rats and viability of C6 (Glial) cells in culture.

The effects of ELF-PEMF exposure on spontaneous alternation, anxiety, motor coordination, and locomotor activity have been discussed in various pre-clinical and clinical settings. Several epidemiological and experimental studies have demonstrated the potential effects of ELF-PEMF when exposed > âˆ¼1 h/day; however, very few studies have focused on understanding the influence of ELF-PEMF exposure of 1-3 mT with an exposure duration of < 1 h/day on spontaneous alternation, anxiety, motor coordination, and locomotor activity. Hence, we attempted to study the effects of ELF-PEMF exposure of 1-3 mT, 50 Hz with an exposure duration of 20 min each with a 4 h gap (2 times) on the cellular proliferation and morphologies of C6 (Glial) cells and spontaneous alternation, anxiety, motor coordination and locomotor activity of Wistar rats under in vitro and in vivo conditions, respectively. The results showed that ELF-PEMF exposure did not induce any significant levels of cellular fragmentation and changes in the morphology of glial cells. Also, the outcomes revealed no noticeable effects on spontaneous alternation, anxiety, motor coordination, and locomotor activity in PEMF-exposed groups compared with the control. No undesirable side effects were observed at the highest dose (B=3 mT). We also performed histological analysis of the selected brain sections (hippocampus and cortex) following ELF-PEMF exposure. Incidentally, no significant changes were observed in cortical cell counts, tissue structure, and morphology.

MPTP-Treated Zebrafish Recapitulate 'Late-Stage' Parkinson's-like Cognitive Decline.

The zebrafish is a promising model species in biomedical research, including neurotoxicology and neuroactive drug screening. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes degeneration of dopaminergic neurons and is commonly used to model Parkinson's disease (PD) in laboratory animals, including zebrafish. However, cognitive phenotypes in MPTP-evoked experimental PD models remain poorly understood. Here, we established an LD50 (292 mg/kg) for intraperitoneal MPTP administration in adult zebrafish, and report impaired spatial working memory (poorer spontaneous alternation in the Y-maze) in a PD model utilizing fish treated with 200 µg of this agent. In addition to conventional behavioral analyses, we also employed artificial intelligence (AI)-based approaches to independently and without bias characterize MPTP effects on zebrafish behavior during the Y-maze test. These analyses yielded a distinct cluster for 200-µg MPTP (vs. other) groups, suggesting that high-dose MPTP produced distinct, computationally detectable patterns of zebrafish swimming. Collectively, these findings support MPTP treatment in adult zebrafish as a late-stage experimental PD model with overt cognitive phenotypes.

Extract of Xylopia aethiopica and its kaurene diterpene, xylopic acid, improve learning and memory in mice.

Background: Cognitive dysfunction, presenting as learning and memory impairment, is a common manifestation in many chronic diseases of the nervous system. Some of these diseases include depression, epilepsy, and Alzheimer's disease. To date, few drugs or medicinal products have shown ability to improve learning and memory deficits. Neuroprotection is one of the mechanisms by which memory could be improved. The extract of Xylopia aethiopica and its kaurene derivative, xylopic acid, have previously demonstrated neuroprotective effects in animal models. The aim of the present study was to investigate the effect of an extract of Xylopia aethiopica fruit and xylopic acid, on learning and memory using murine models. Materials and methods: Unripe Xylopia aethiopica fruits were collected, dried, and extracted using 70% v/v ethanol. Xylopic acid was isolated from the fruits using petroleum ether, concentrated with ethyl acetate and then recrystallized with petroleum ether before purifying with ethanol (96%v/v). Institute of Cancer Research (ICR) mice received oral doses of the extract of Xylopia aethiopica (XAE; 30, 100 and 300 mg/kg), xylopic acid (XA; 30, 100 and mg/kg), citicoline (300 mg/kg), piracetam (300 mg/kg) or ketamine (30 mg/kg) and saline (vehicle). The animals were then taken through the Morris water maze test (MWM), spontaneous alternation Y-maze test (Y-maze), and novel object recognition test (NOR), to assess learning and memory. Results: In the NOR test, XAE (30, 100 and 300 mg/kg) and XA (30, 100 and 300 mg/kg) increased the percentage exploration and recognition index (p = 0.0005 and p < 0.0001, respectively) when compared to both vehicle and ketamine groups. Similarly, doses of XAE and XA as used in the NOR test increased the percentage alternation in the Y-maze test. Although XAE and XA treatments decreased the latencies to find hidden platform in the MWM test, it was not significantly different from the vehicle group. However, this decrease in latency differed significantly when compared to the ketamine group. Interestingly, both XAE and XA treatments increased the percentage frequency to the target quadrant in the probe trial of the MWM. It is noteworthy that in all the three models used, both the extract and xylopic acid performed better than piracetam and citicoline, the reference drugs. Conclusion: The ethanolic extract of Xylopia aethiopica fruit and xylopic acid improved exploratory learning and recognition memory, spatial working, recognition, and reference memories in the behavioral tests.

The 5-hydroxytryptamine 2A receptor agonists DOI and 25CN-NBOH decrease marble burying and reverse 8-OH-DPAT-induced deficit in spontaneous alternation.

5-Hydroxytryptamine 2A receptor (5-HT2AR) agonist psychedelics are increasingly recognized as potentially useful treatments of psychiatric disorders, such as obsessive-compulsive disorder, depression, anxiety, and drug dependence. There is limited understanding of the way they exert their therapeutic action, but inhibition of rigid behavior and cognition has been suggested as a key factor. To examine the role of 5-HT2ARs in modulating repetitive behavior, we tested two 5-HT2AR agonists, DOI, and the selective 25CN-NBOH, in two mouse tests of compulsive-like behavior. Using adult C57BL/6JOlaHsd male mice, we examined the effects of the two compounds on digging behavior in the marble burying test and on 8-OH-DPAT-disrupted spontaneous alternation behavior in the Y-maze. Both compounds dose-dependently decreased digging behavior in the marble burying test, indicating anti-compulsivity effects, which were not related to non-specific locomotor inhibition. Both 5-HT2AR agonists also reversed 8-OH-DPAT-reduced alternation ratio in the spontaneous alternation behavior test, although the effects were less pronounced than in the marble burying test. This suggests that the 5-HT2AR promotes exploratory behavior, but that the deficit produced by 8-OH-DPAT is too excessive to be fully reversed by 5-HT2AR agonists. This study shows that agonism of 5-HT2AR reduces repetitive behavioral patterns, supporting the theory that this is a potential new treatment approach to disorders of cognitive or behavioral inflexibility. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Adolescent administration of Δ9-THC decreases the expression and function of muscarinic-1 receptors in prelimbic prefrontal cortical neurons of adult male mice.

Long-term cannabis use during adolescence has deleterious effects in brain that are largely ascribed to the activation of cannabinoid-1 receptors (CB1Rs) by delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive compound in marijuana. Systemic administration of ∆9-THC inhibits acetylcholine release in the prelimbic-prefrontal cortex (PL-PFC). In turn, PL-PFC acetylcholine plays a role in executive activities regulated by CB1R-targeting endocannabinoids, which are generated by cholinergic stimulation of muscarinic-1 receptors (M1Rs). However, the long-term effects of chronic administration of increasing doses of ∆9-THC in adolescent males on the distribution and function of M1 and/or CB1 receptors in the PL-PFC remains unresolved. We used C57BL\6J male mice pre-treated with vehicle or escalating daily doses of ∆9-THC to begin filling this gap. Electron microscopic immunolabeling showed M1R-immunogold particles on plasma membranes and in association with cytoplasmic membranes in varying sized dendrites and dendritic spines. These dendritic profiles received synaptic inputs from unlabeled, CB1R- and/or M1R-labeled axon terminals in the PL-PFC of both treatment groups. However, there was a size-dependent decrease in total (plasmalemmal and cytoplasmic) M1R gold particles in small dendrites within the PL-PFC of mice receiving ∆9-THC. Whole cell current-clamp recording in PL-PFC slice preparations further revealed that adolescent pretreatment with ∆9-THC attenuates the hyperpolarization and increases the firing rate produced by local muscarinic stimulation. Repeated administration of ∆9-THC during adolescence also reduced spontaneous alternations in a Y-maze paradigm designed for measures of PFC-dependent memory function in adult mice. Our results provide new information implicating M1Rs in cortical dysfunctions resulting from adolescent abuse of marijuana.

Catha edulis Forsk (khat) reduces spontaneous and rewarded alternation in female mice.

Around 10 million people chew the fresh leaves and twigs of Catha edulis Forsk (khat), which synthesize cathinone, for its psychostimulatory effect. Several studies have reported that regular khat users show executive and cognitive dysfunction, such as impaired inhibitory control and poor performance on memory tests. In this study, the effect of fresh khat extract (100 and 250 mg/kg) on spatial working memory and short-term memory in mice was assessed using spontaneous and rewarded alternation T-maze tests. In the spontaneous alternation test, mice treated with fresh khat extract decreased their spontaneous alternation level to around chance level, and it remained at this level over the 7 days of khat administration and testing. On testing after a 7-day khat free period, the previously khat treated mice showed alternation level above chance but below their pre-khat alternation level. In the rewarded alternation test, acute treatment with khat caused the mice to alternate well below chance level, and then over the next 3 days of khat treatment, the alternation level increased. After a 2 and 9-day khat-free period, the previously khat treated mice alternated above chance level but below their pre-khat level. In both these tests, the mice did not show any position preference before khat treatment; however, during the khat treatment, the mice showed a right side tendency. The results show that khat treatment causes persistent changes in alternation behavior and promotes perseverative behavior, presumably due to its effect on the neural circuits activity and the neurotransmitters and promotion of position preference.

8-OH-DPAT Induces Compulsive-like Deficit in Spontaneous Alternation Behavior: Reversal by MDMA but Not Citalopram.

Rodents exhibit natural exploratory behaviors, which can be measured by the spontaneous alternation behavior (SAB) test. Perseverance in this test induced by the 5-hydroxytryptamine 1A receptor (5-HT1AR) agonist, 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), resembles compulsive behaviors observed in humans and manifests as reduced alternation ratio. This study characterized 8-OH-DPAT-induced perseverance in the SAB test in C57BL/6JOlaHsd male mice by coadministration of WAY100635, citalopram and the 5-HT releasing agent, 3,4-methylenedioxymethamphetamine (MDMA), to deepen the understanding of 5-HT-dependent mechanisms. The 5-HT1AR mechanism of 8-OH-DPAT (1.0 mg/kg, p < 0.01) on perseverance was confirmed by coadministration of the 5-HT1AR antagonist, WAY100635 (2.0 mg/kg, p < 0.05), which attenuated the effects of 8-OH-DPAT. Such effects could also be reversed by MDMA (1.0 mg/kg, p < 0.05; 10.0 mg/kg, p < 0.001) but not citalopram. These findings confirm the importance of 5-HT in regulating perseverative behavior. Future investigations are required to determine the predictive validity of the 8-OH-DPAT-disrupted SAB test as an inducible mouse model of compulsivity.

Chronic unpredictable stress influenced the behavioral but not the neurodegenerative impact of paraquat.

The impact of psychological stressors on the progression of motor and non-motor disturbances observed in Parkinson's disease (PD) has received little attention. Given that PD likely results from many different environmental "hits", we were interested in whether a chronic unpredictable stressor regimen would act additively or possibly even synergistically to augment the impact of the toxicant, paraquat, which has previously been linked to PD. Our findings support the contention that paraquat itself acted as a systemic stressor, with the pesticide increasing plasma corticosterone, as well as altering glucocorticoid receptor (GR) expression in the hippocampus. Furthermore, stressed mice that also received paraquat displayed synergistic motor coordination impairment on a rotarod test and augmented signs of anhedonia (sucrose preference test). The individual stressor and paraquat treatments also caused a range of non-motor (e.g. open field, Y and plus mazes) deficits, but there were no signs of an interaction (neither additive nor synergistic) between the insults. Similarly, paraquat caused the expected loss of substantia nigra dopamine neurons and microglial activation, but this effect was not further influenced by the chronic stressor. Taken together, these results indicate that paraquat has many effects comparable to that of a more traditional stressor and that at least some behavioral measures (i.e. sucrose preference and rotarod) are augmented by the combined pesticide and stress treatments. Thus, although psychological stressors might not necessarily increase the neurodegenerative effects of the toxicant exposure, they may promote co-morbid behaviors pathology.

Effects of cordycepin on spontaneous alternation behavior and adenosine receptors expression in hippocampus.

Cordycepin, an adenosine analogue, has been reported to improve cognitive function. Important roles on learning and memory of adenosine and its receptors, such as adenosine A1 and A2A receptors (A1R and A2AR), also have been shown. Therefore, we assume that the improvement of learning and memory induced by cordycepin is likely related to hippocampal adenosine content and adenosine receptor density. Here we investigated the effects of cordycepin on the short-term spatial memory by using a spontaneous alternation behavior (SAB) test in Y-maze, and then examined hippocampal adenosine content and A1R and A2AR densities. We found that orally administrated cordycepin (at dosages of 5 and 10mg/kg twice daily for three weeks) significantly increased the percent of relative alternation of mice in SAB but not altered body weight, hippocampus weight and hippocampal adenosine content. Furthermore, cordycepin decreased A2AR density in hippocampal subareas; however, cordycepin only reduced the A1R density in DG but not CA1 or CA3 region. Our results suggest that cordycepin exerts a nootropic role possibly through modulating A2AR density of hippocampus, which further support the concept that it is mostly A2AR rather than A1R to control the adaptive processes of memory performance. These findings would be helpful to provide a new window into the pharmacological properties of cordycepin for cognitive promotion.