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The serotonergic system has been known to play an important role in acquisition, consolidation and retrieval of memories. Specific serotonin (5-HT) receptor modulation can effectively impact the consolidation of these memories. Determining how specific 5-HT receptor modulation can impact consolidation of spatial memories has been examined, although the 5-HT6 receptor has not been a focus of such studies. The current study aims examine the impact of 5-HT6 receptor agonist EMD386088 administration on the consolidation of a probabilistic spatial discrimination. Female and male C57BL/6 J mice were trained on a probabilistic spatial discrimination then received acute systemic injections of either 0, 1 or 5 mg/kg EMD386088 immediately after reaching learning criterion for the spatial discrimination, targeting the consolidation window. During the retention test, both doses of 1 mg/kg and 5 mg/kg significantly impaired performance in both female and male C57BL/6 J mice. Although there were no significant differences between the two doses, mice treated with either dose of EMD386088 required significantly more trials to reach retention criterion compared to vehicle-treated mice. These learning impairments were independent of effects on locomotor measures due to the comparable trials per min across all treatment groups during both the acquisition and retention tests. The current findings demonstrate the potential sensitivity of treatment timing in the application of novel therapeutics aimed at stimulating 5-HT6 receptors and their impact on memory., (Copyright © 2025. Published by Elsevier B.V.)

Selective serotonin reuptake inhibitors (SSRIs) are medications commonly used by pregnant women. While SSRIs have been considered safe during pregnancy, there is limited understanding of the long-term consequences of prenatal SSRI exposure on adult behavioral processes. Recent human studies have demonstrated prenatal exposure to some SSRIs in humans may increase susceptibility to autism spectrum disorder (ASD) and developmental delays. While escitalopram is one of the most effective antidepressants, it is also one of the newer available SSRIs, resulting in less information on its safety profile during pregnancy. The current study administered escitalopram (0 or 10 mg/kg, s.c.) to nulliparous female Long-Evans rats for the first (G1-10) or last half (G11-20) of the gestational period. Young adult male and female offspring were subsequently tested on a battery of behavioral tasks consisting of probabilistic reversal learning task, open field conflict, marble burying and social approach tasks. Results demonstrate that escitalopram exposure during the first half of pregnancy resulted in reduced anxiety-like behavior (disinhibition) on the modified open field and enhanced flexibility on the probabilistic reversal learning task. Exposure to escitalopram later in pregnancy resulted in an increase in marble burying behavior, but no differences were found with the other measures. These results suggest that exposure to escitalopram during the first half of prenatal development can have long lasting changes on adult behavior demonstrating better behavioral flexibility and lower anxiety-like behavior compared to non-exposed controls., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) presents with two core symptoms, impairments in social communication and the presence of restricted, repetitive behaviors (RRBs). RRBs are commonly linked to a lack of behavioral flexibility, having a significant negative impact on daily functioning for ASD individuals and their caregivers. Commonly utilized tests of behavioral flexibility employ a traditional deterministic reward approach where choices are either correct or incorrect throughout testing. The incorporation of an 80 %/20 % probabilistic reversal learning paradigm allows for the examination of flexible behavior in the face of variable outcomes, a more ecologically relevant approach. In this task, one specific choice is reinforced on 80 % of trials and the opposite or incorrect choice is reinforced on 20% of trials. Upon successful discrimination learning, the reward contingencies are switched so that the correct choice is now reinforced 20% of trials and the incorrect choice reinforced 80 % of trials, making it the new optimal choice. This translational task has been previously validated in ASD individuals and animal models of ASD, including the BTBR T + tf/J strain. Our lab and others have demonstrated that male BTBR T + tf/J mice have higher expression of lower order RRBs and display deficits in spatial probabilistic reversal learning tasks using a T-maze apparatus. Instead, female BTBR mice do not express the same lower order RRBs and results are mixed on whether females demonstrate similar probabilistic reversal learning deficits in a T-maze. Therefore, the purpose of this study was to assess the validity of using operant chambers to examine BTBR mouse performance on an 80 %/20 % probabilistic reversal learning task and to also examine the sex-specific differences in reversal learning performance in both mouse strains. Results show that BTBR mice, irrespective of sex, were impaired on the reversal learning, requiring more days and trials to reach reversal criterion compared to C57BL/6J mice. These results parallel previous strain findings in the spatial dependent T-maze task in male mice. Further error analysis showed that the impaired behavioral flexibility was due to elevated regressive errors and lose-shift probabilities. BTBR mice have more difficulty maintaining new choice patterns compared to C57BL/6J mice, which supports findings utilizing a spatial T-maze task. Together, these findings further support the use of the BTBR mouse as preclinical models of ASD due to their validity as an ASD model., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower-order and higher-order RRBs. Individuals displaying lower-order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. Higher-order RRBs most commonly cover the behavior inflexibility and cognitive rigidity commonly found in disorders such as autism spectrum disorder and obsessive-compulsive disorder. Various neuropsychiatric disorders are plagued by RRBs yet no FDA-approved treatments have been identified. In rodents, lower-order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower-order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A, and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A receptor activation RRB expression, whereas blockade generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less but show promise as potential targets for regulating RRBs. Although it is less clear due to the involvement of 5-HT1D, 5-HT1A activation increases RRBs, and blocking 5-HT1A tends to decrease RRBs. 5-HT2B activation could reduce RRBs, while inhibiting 5-HT2B does not impact RRBs. Increasing 5-HT3 has not been shown to affect RRBs. Yet, increases in RRBs have been observed in Htr3a KO mice. 5-HT6 receptor activation can increase RRBs, while blocking 5-HT6 activity tends to decrease RRBs. Lastly, neither increasing or blocking 5-HT7 activity can reduce RRBs. In sum, there is no uniform pattern in whether all specific 5-HT receptors affect RRBs in either direction, instead, there is evidence suggesting that different 5-HT receptors can modulate RRBs in different directions. Further researching the less explored receptors and aiming to understand why these receptors can differently modulate RRBs, may play a key role in developing therapeutics that treat RRBs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alvarez, Cavazos, Morales, Lopez and Amodeo.)

Pharmacological activation of the serotonin (5-HT) 1B and 5-HT1A receptors has been shown to induce OCD-like perseverative circling and locomotor stereotypy in rodents. Although, several studies have examined how activation of these receptors facilitates these motor-associated OCD-like behaviors, it is not known how acute 5-HT1B and 5-HT1A activation impacts behavioral inflexibility, a common trait related to OCD. The current study examined how acute 5-HT1B/1A receptor agonist RU24969 treatment at 0.01, 0.1, and 1.0 mg/kg impacted behavioral flexibility in both female and male C57BL/6J mice. Behavioral flexibility was tested using a spatial reversal learning task, with probabilistic reward contingencies. In addition, locomotor activity and anxiety-like behaviors were also measured. RU24969 at 0.1 and 1.0 mg/kg impaired behavioral flexibility in both female and male C57BL/6J mice. RU24969 treatment at 1.0 mg/kg reduced locomotor activity in male mice, although RU24969 treatment did not significantly reduce locomotor activity in female mice. In the open field, 1.0 mg/kg elevated anxiety-like behavior in male mice only. Overall, these results demonstrate that acute 5-HT1B and 5-HT1A receptor activation leads to impairments in behavioral flexibility, a common trait associated with OCD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Serotonin (5-HT) is known to play a critical role in regulation of essential neural processes, whereas more recent research highlights serotonin's modulatory effects on cognition and executive functioning. Current examinations have identified specific serotonin receptors for their direct impact on behavioral flexibility. Providing definitive evidence for the impact of specific receptor targets on behavioral flexibility is difficult, due to the range of behavioral tests used. Due to limited studies and the sheer amount of different serotonin receptor targets, beginning to bring these studies together is important for the field. Our current review of the literature aims to differentiate how modulation of specific 5-HT receptors affects behavioral flexibility. Although more studies have examined 5-HT 2A , 5-HT 2C , and 5-HT 6 receptors, it is unclear why this is the case. Above all, there are some paradoxical results pertaining to these receptor targets. There is a clear distinction between 5-HT 2A and 5-HT 2C , which conveys that these two receptor subtypes have inverse effects when compared to each other. In addition, some findings support one another, such as upregulation of 5-HT 6 receptors impairs flexibility, while blockade alleviates this impairment in both drug-induced and disease model rodent studies. Further understanding how modulatory effects of specific 5-HT receptors impact behavioral flexibility is imperative to advance the development of new therapeutics for neuropsychiatric disorders afflicted by behavioral inflexibility., (Published by Elsevier Inc.)

The serotonin 6 receptor (5-HT6) is a more recently identified therapeutic target for several neuropsychiatric disorders. While the 5-HT6 receptor has gained interest as a target for novel therapeutics, determining the basic sex differences is lacking in the literature. To address this, the present study examined the effects of 5-HT6 receptor modulation on locomotor activity and open field measures of anxiety in C57BL/6J mice. Female and male mice were tested after acute treatment with either 5-HT6 receptor antagonist SB 271046 or 5-HT6 receptor agonist EMD 386088. Acute 5-HT6 receptor blockade with SB 271046 attenuated locomotor activity in C57BL6/J mice, irrespective of sex. When locomotor activity was analyzed for six 10 min time blocks, 0.1, 5, or 15 mg/kg of SB 271046 reduced locomotor activity for the initial 40 min of testing, but only 5 and 15 mg/kg SB 271046 exhibited a reduction in locomotor activity for at least 60 min. EMD 386088 only attenuated locomotor activity when mice were treated with the high dose of 15 mg/kg EMD 386088. This was true for all time blocks except for the 40-50 min time block. In addition, EMD 386088 at the 15 mg/kg dose reduced locomotor activity in female mice more than males during the 20-30 and 30-40 minute time blocks. Analysis of the anxiolytic properties of 5-HT6 receptor modulation via the open field, showed that SB 271046 did not demonstrate anxiogenic properties in either sex at the doses tested. Instead, 15 mg/kg EMD 386088 produced an anxiogenic effect in both female and male mice. Together these findings highlight the differing impact of specific 5-HT6 receptor modulation on locomotor activity in C57BL/6J mice., (Published by Elsevier B.V.)

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Previous studies have found that specific serotonin (5-HT) receptor modulation can attenuate repetitive behaviors expressed in specific mouse strains. The present study examined how 5-HT6 receptor blockade impacts the expression of repetitive behaviors in two different mouse strains that demonstrate elevated restricted, repetitive behavior and impairments in social behavior. BTBR T+ Itpr3tf /J (BTBR), C58/J (C58) and control C57BL/6J strains were behaviorally tested after acute treatment with the 5-HT6 receptor antagonist BGC 20-761 (BGC) or vehicle. BTBR mice express high levels of self-grooming behavior while C58 mice display high rates of repetitive jumping behavior. Similarly, the effect of 5-HT6 receptor blockade was also tested on social approach behaviors in both strains. BGC significantly reduced repetitive grooming in both female and male BTBR mice compared to vehicle-treated BTBR mice. BGC treatment did not attenuate social approach impairments in either female or male BTBR mice compared to vehicle-treated BTBR mice. Follow-up dose response studies were conducted on repetitive grooming and locomotor activity in BTBR mice. All doses reduced repetitive grooming in female and male BTBR mice. Acute treatment with BGC only reduced locomotor activity with the lower doses. In C58 mice, BGC treatment did not significantly attenuate flipping or general social approach behaviors. Instead, BGC significantly increased social sniff time in female C58 mice. While 5-HT6 receptor blockade did not attenuate the social impairments found in BTBR mice, this treatment did increase sniff time in female C58 mice. Although the lower doses of BGC deduced locomotion, the higher dose attenuated repetitive grooming in BTBR mice while sparing locomotor activity. Together these findings suggest the therapeutic effects of 5-HT6 receptor blockade are complex and may be specific to the types of repetitive behaviors expressed., (Published by Elsevier Inc.)

Serotonin 2A (5-HT 2A ) receptors are the primary site of action of hallucinogenic drugs and the target of atypical antipsychotics. 5-HT 2A receptors are also implicated in executive function, including behavioral flexibility. Previous studies showed that 5-HT 2A receptor blockade improved behavioral flexibility in rodent models related to autism spectrum disorder and schizophrenia. The current study instead was conducted to examine the impact of acute 5-HT 2A receptor activation on behavior flexibility in the control C57BL/6 J strain. Because of the therapeutic potential of serotonergic hallucinogens and the unknown impact of many of these compounds on cognition, the present study examined how the 5-HT 2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the more selective 5-HT 2A agonist 25CN-NBOH impacted behavioral flexibility in C57BL/6 J mice. Male mice were tested on a probabilistic spatial discrimination and reversal learning task after an intraperitoneal injection of vehicle, 2.5 mg/kg DOI, 1.0 mg/kg 25CN-NBOH, 1.0 mg/kg of the 5-HT 2C receptor antagonist SER-082 or combined treatment with SER-082 (1.0 mg/kg) and 2.5 mg/kg DOI before testing of probabilistic reversal learning. All groups demonstrated comparable performance on the initial spatial discrimination, i.e. similar trials to criterion. DOI alone did not impair reversal learning, whereas 25CN-NBOH increased the number of trials to criterion during reversal learning. Because 5-HT 2A and 5-HT 2C receptors have been shown to functionally antagonize each other in several behavioral paradigms, we also tested whether blockade of 5-HT 2C receptors would unmask 5-HT 2A receptor activation by DOI and impair reversal learning. Mice treated with SER-082 in combination with DOI required significantly more trials to reach criterion. In an additional experiment, a dose response experiment with 25CN-NBOH revealed that the 1.0 mg/kg dose tested in reversal learning did not affect locomotor activity. Together, these findings indicate that activation of 5-HT 2A receptors impairs probabilistic reversal learning and that 5-HT 2A and 5-HT 2C receptors exert opposing effects on behavioral flexibility in male mice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Epidemiological studies demonstrate males are three times more likely than females to be affected. Although this is the case, more recent studies suggest females may be underrepresented in these numbers due to standard clinical measures of RRBs and social behaviors. In addition, many studies examining mouse models of ASD exclude females due to the sex disparity in diagnoses. The present study examined how female and male BTBR T + Itpr3tf /J (BTBR) compare to control C57BL/6J mice on tests of RRBs (probabilistic reversal learning, repetitive grooming, spontaneous alternation, and marble burying) and social behaviors (three chambered social approach task). Utilizing a spatial reversal learning test with 80/20 probabilistic feedback, in which ASD individuals have exhibited deficits, we find that female BTBR mice do not show the same impairment found in male BTBR mice. Interestingly, control female C57BL/6J mice required more trials to reach criterion. Female BTBR mice expressed comparable rates of repetitive grooming, marble burying and spontaneous alternation compared to female C57BL/6J mice. Male BTBR mice expressed higher rates of grooming behavior and locomotor activity compared to male C57BL/6J mice, as found in previous studies. Similarly, male BTBR mice showed a reduction in both measures of social approach compared to controls. Both male and female BTBR mice showed a reduction in sniff time for the stranger mouse compared to controls. Together these findings demonstrate how female BTBR mice do not display the RRB profile expressed by male BTBR mice. Testing of repetitive behaviors in ASD needs to better reflect the sex differences in how RRBs manifest in females compared to their extensively researched male counterparts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Epidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes., Methods: The current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams., Results: Exposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations., Conclusions: These findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Serotonin 6 (5-HT6) receptors are primarily expressed in the central nervous system and to an even further extent brain regions responsible for learning and memory. Recent studies have demonstrated 5-HT6 receptor involvement in pathophysiological processes highlighting their therapeutic possibilities. Most research concerning the effects of 5-HT6 receptor modulation has focused on blockade despite paradoxical findings that 5-HT6 agonists and antagonists can both have pro-cognitive effects. The current experiments examine the effects of the 5-HT6 receptor agonist EMD386088 on behavioral flexibility and working memory. C57BL/6J mice received systemic injections of either 0, 2, or 4 mg/kg EMD386088 before being tested on probabilistic reversal learning, spontaneous alternation, and locomotor activity. In the probabilistic reversal learning task, the high dose of 4 mg/kg significantly impaired performance requiring more trials to reach criterion. The same dose significantly increased perseverative type errors, suggesting that the probabilistic reversal learning impairment was due to an inability to inhibit the previously learned choice pattern, rather than maintaining the new optimal choice pattern. Acute EMD386088 administration at 2 mg/kg significantly impaired spontaneous alternation performance, while the high dose of 4 mg/kg did not reach significance. These learning impairments were not due to an overall locomotor impairment as evidenced by comparable locomotor activity scores. Acute systemic 5-HT6 receptor activation with EMD386088 led to impaired behavior flexibility and working memory performance. Current findings support previous research suggesting that novel therapeutics directed at down regulation of 5-HT6 receptors may be effective in attenuating working memory and behavioral flexibility impairments commonly found in neuropsychiatric disorders such as Alzheimer's and schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Restricted interests and repetitive behaviors (RRBs) are a defining feature of autism spectrum disorder (ASD). To date there are limited options for treating this core symptomology. Treatments that stimulate adenosine A 2A receptors may represent a promising approach for reducing RRBs in ASD. This is because A 2A receptors are expressed on striatal neurons of the basal ganglia indirect pathway. Under activation of this pathway has been associated with RRBs while activation of A 2A receptors leads to increased activity of the indirect basal ganglia pathway. The present studies investigated whether acute, systemic treatment with CGS21680, an A 2A receptor agonist attenuates elevated self-grooming and a probabilistic reversal learning deficit in the BTBR T+ Itpr3 tf /J (BTBR) mouse model of idiopathic autism. The effects of this treatment were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, comparable to one in which ASD individuals exhibit deficits, CGS 21680 (0.005 and 0.01mg/kg) attenuated a reversal learning deficit in BTBR mice. Enhancement in probabilistic reversal learning performance resulted from CGS 21680 improving the consistent maintenance of new adaptive behavioral choice patterns after reversal. CGS 21680 at 0.01 mg, but not 0.005 mg, also reduced self-grooming behavior in BTBR mice. CGS 21680 did not affect self-grooming or reversal learning in B6 mice. These findings demonstrate that A 2A receptor agonists may be a promising receptor target in the treatment of RRBs in ASD. Autism Res 2018, 11: 223-233. © 2017 International Society for Autism Research, Wiley Periodicals, Inc., Lay Summary: The present experiments determined whether the drug, CGS 21680, that facilitates activation of adenosine A 2A receptors in the brain, would reduce repetitive and inflexible behaviors in the BTBR mouse model of idiopathic autism. CGS 21680 treatment in BTBR mice reduced repetitive and inflexible behaviors. In the control C57BL/6J (B6) mouse strain, CGS 21680 did not affect performance. These findings suggest that stimulation of brain adenosine A 2A receptors may be a promising therapeutic strategy in ASD., (© 2017 International Society for Autism Research, Wiley Periodicals, Inc.)

Central infusion of the Na+/K+-ATPase inhibitor, ouabain in rats serves as an animal model of mania because it leads to hyperactivity, as well as reproduces ion dysregulation and reduced brain-derived neurotrophic factor (BDNF) levels similar to that observed in bipolar disorder. Bipolar disorder is also associated with cognitive inflexibility and working memory deficits. It is unknown whether ouabain treatment in rats leads to similar cognitive flexibility and working memory deficits. The present study examined the effects of an intracerebral ventricular infusion of ouabain in rats on spontaneous alternation, probabilistic reversal learning and BDNF expression levels in the frontal cortex. Ouabain treatment significantly increased locomotor activity, but did not affect alternation performance in a Y-maze. Ouabain treatment selectively impaired reversal learning in a spatial discrimination task using an 80/20 probabilistic reinforcement procedure. The reversal learning deficit in ouabain-treated rats resulted from an impaired ability to maintain a new choice pattern (increased regressive errors). Ouabain treatment also decreased sensitivity to negative feedback during the initial phase of reversal learning. Expression of BDNF mRNA and protein levels was downregulated in the frontal cortex which also negatively correlated with regressive errors. These findings suggest that the ouabain model of mania may be useful in understanding the neuropathophysiology that contributes to cognitive flexibility deficits and test potential treatments to alleviate cognitive deficits in bipolar disorder., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT 2A receptor activity is altered in autism, while recent work indicates that systemic 5HT 2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT 2A receptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT 2A receptor blockade in the dorsomedial striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT 2A receptor antagonist, M100907 into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT 2A receptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. 5HT 2A receptor signaling in the orbitofrontal cortex may be critical for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors., (© 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Individuals with autism spectrum disorder (ASD) exhibit social-communication deficits along with restricted interests and repetitive behaviors (RRBs). To date, there is a lack of effective treatments to alleviate RRBs. A recent study found that treatment with the 5HT2A receptor antagonist M100907 attenuates a reversal learning deficit in the BTBR mouse model of autism. The BTBR mouse also exhibits elevated grooming behavior which may model stereotyped motor behaviors also observed in ASD. The present study examined whether 5HT2A receptor blockade with M100907 at either 0.01 or 0.1mg/kg can reduce repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR and C57BL6/J (B6) mice. M100907 at 0.1mg/kg, but not 0.01mg/kg, significantly attenuated repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR mice. M100907 at either dose did not affect grooming behavior in B6 mice. To determine whether 0.1mg/kg M100907 had a more general effect on activity in BTBR mice, a second experiment determined whether M100907 at 0.1mg/kg affected locomotor activity in BTBR mice. M100907 treatment in BTBR and B6 mice did not alter locomotor activity compared to that of vehicle-treated BTBR and B6 mice. The present findings taken together with past results suggest that treatment with a 5HT2A receptor antagonist may be effective in ameliorating RRBs in ASD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Study Objectives: To determine whether learning deficits occur during acute exacerbation of spontaneous sleep related breathing disorder (SRBD) in rats with high (Brown Norway; BN) and low (Zucker Lean; ZL) apnea propensity., Design: Spatial acquisition (3 days) and reversal learning (3 days) in the Morris water maze (MWM) with polysomnography (12:00-08:00): (1) with acute SRBD exacerbation (by 20-h hyperoxia immediately preceding reversal learning) or (2) without SRBD exacerbation (room air throughout)., Setting: Randomized, placebo-controlled, repeated-measures design., Participants: 14 BN rats; 16 ZL rats., Interventions: 20-h hyperoxia., Measurements and Results: Apneas were detected as cessation of respiration ≥ 2 sec. Swim latency in MWM, apnea indices (AI; apneas/hour of sleep) and percentages of recording time for nonrapid eye movement (NREM), rapid eye movement (REM), and total sleep were assessed. Baseline AI in BN rats was more than double that of ZL rats (22.46 ± 2.27 versus 10.7 ± 0.9, P = 0.005). Hyperoxia increased AI in both BN (34.3 ± 7.4 versus 22.46 ± 2.27) and ZL rats (15.4 ± 2.7 versus 10.7 ± 0.9) without changes in sleep stage percentages. Control (room air) BN and ZL rats exhibited equivalent acquisition and reversal learning. Acute exacerbation of AI by hyperoxia produced a reversal learning performance deficit in BN but not ZL rats. In addition, the percentage of REM sleep and REM apnea index in BN rats during hyperoxia negatively correlated with reversal learning performance., Conclusions: Acute exacerbation of sleep related breathing disorder by hyperoxia impairs reversal learning in a rat strain with high apnea propensity, but not a strain with a low apnea propensity. This suggests a non-linear threshold effect may contribute to the relationships between sleep apnea and cognitive dysfunctions, but strain-specific differences also may be important.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD. Risperidone, an atypical antipsychotic, is approved to treat irritability in ASD, but less is known about whether it is effective in treating "higher order" RRBs, for example cognitive inflexibility. Risperidone also has multiple receptor targets in which only a subset may be procognitive and others induce cognitive impairment. 5HT2A receptor blockade represents one promising and more targeted approach, as various preclinical studies have shown that 5HT2A receptor antagonists improve cognition. The present study investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist, improved probabilistic reversal learning performance in the BTBR T + tf/J (BTBR) mouse model of autism. The effects of these treatments were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, similar to one in which ASD individuals exhibit impairments, both risperidone (0.125 mg) and M100907 (0.01 and 0.1 mg) improved reversal learning in BTBR mice. Risperidone (0.125 mg) impaired reversal learning in B6 mice. Improvement in probabilistic reversal learning performance resulted from treatments enhancing the maintenance of the newly correct choice pattern. Because risperidone can lead to unwanted side effects, treatment with a specific 5HT2A receptor antagonist may improve cognitive flexibility in individuals with ASD while also minimizing unwanted side effects., (© 2014 International Society for Autism Research, Wiley Periodicals, Inc.)

Repetitive behaviors with restricted interests is one of the core criteria for the diagnosis of autism spectrum disorder (ASD). Current pharmacotherapies that target the dopaminergic or serotonergic systems have limited effectiveness in treating repetitive behaviors. Previous research has demonstrated that administration of muscarinic cholinergic receptor (mAChR) antagonists can exacerbate motor stereotypies while mAChR agonists reduce stereotypies. The present study determined whether the mAChR agonist, oxotremorine affected repetitive behaviors in the BTBR T+ tf/J (BTBR) mouse model of autism. To test the effects of oxotremorine on repetitive behaviors, marble burying and grooming behavior were measured in BTBR mice and compared to that in C57BL/6J (B6) mice. The effects of oxotremorine on locomotor activity was also measured. Thirty minutes before each test, mice received an intraperitoneal (ip) injection of saline, 0.001 mg or 0.01 mg of oxotremorine methiodide. Saline- treated BTBR mice exhibited increased marble burying and self-grooming behavior compared to that of saline-treated B6 mice. Oxotremorine significantly reduced marble burying and self-grooming behavior in BTBR mice, but had no significant effect in B6 mice. In addition, oxotremorine did not affect locomotor activity in BTBR mice, but significantly reduced locomotor activity in B6 mice at the 0.01 mg dose. These findings demonstrate that activation of mAChRs reduces repetitive behavior in the BTBR mouse and suggest that treatment with a mAChR agonist may be effective in reducing repetitive behaviors in ASD.

Study Objectives: Circadian rhythms influence many biological systems, but there is limited information about circadian and diurnal variation in sleep related breathing disorder. We examined circadian and diurnal patterns in sleep apnea and ventilatory patterns in two rat strains, one with high sleep apnea propensity (Brown Norway [BN]) and the other with low sleep apnea propensity (Zucker Lean [ZL])., Design/setting: Chronically instrumented rats were randomized to breathe room air (control) or 100% oxygen (hyperoxia), and we performed 20-h polysomnography beginning at Zeitgeber time 4 (ZT 4; ZT 0 = lights on, ZT12 = lights off). We examined the effect of strain and inspired gas (twoway analysis of variance) and analyzed circadian and diurnal variability., Measurements and Results: Strain and inspired gas-dependent differences in apnea index (AI; apneas/h) were particularly prominent during the light phase. AI in BN rats (control, 16.9 ± 0.9; hyperoxia, 34.0 ± 5.8) was greater than in ZL rats (control, 8.5 ± 1.0; hyperoxia, 15.4 ± 1.1, [strain effect, P < 0.001; gas effect, P = 0.001]). Hyperoxia reduced respiratory frequency in both strains, and all respiratory pattern variables demonstrated circadian variability. BN rats exposed to hyperoxia demonstrated the largest circadian fluctuation in AI (amplitude = 17.9 ± 3.7 apneas/h [strain effect, P = 0.01; gas effect, P < 0.001; interaction, P = 0.02]; acrophase = 13.9 ± 0.7 h; r (2) = 0.8 ± 1.4)., Conclusions: Inherited, environmental, and circadian factors all are important elements of underlying sleep related breathing disorder. Our method to examine sleep related breathing disorder phenotypes in rats may have implications for understanding vulnerability for sleep related breathing disorder in humans.

Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 min prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with an SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally biased response pattern or a learned choice pattern.

Autism spectrum disorders (ASD) represent a class of neurodevelopmental disorders characterized by impairments in social interaction, verbal and non-verbal communication, as well as restricted interests and repetitive behavior. This latter class of symptoms often includes features such as compulsive behaviors and resistance to change. The BTBR T+ tf/J mouse strain has been used as an animal model to investigate the social communication and restricted interest features in ASD. Less is known about whether this mouse strain models cognitive flexibility deficits also observed in ASD. The present experiment investigated performance of BTBR T+ tf/J and C57BL/6J on two different spatial reversal learning tests (100% accurate feedback and 80/20 probabilistic feedback), as well as marble burying and grooming behavior. BTBR T+ tf/J and C57BL/6J mice exhibited similar performance on acquisition and reversal learning with 100% accurate feedback. BTBR T+ tf/J mice were impaired in probabilistic reversal learning compared to that of C57BL/6J mice. BTBR T+ tf/J mice also displayed increased stereotyped repetitive behaviors compared to that of C57BL/6J mice as shown by increased marble burying and grooming behavior. The present findings indicate that BTBR T+ tf/J mice exhibit similar features related to "insistence on sameness" in ASD that include not only stereotyped repetitive behaviors, but also alterations in behavioral flexibility. Thus, BTBR T+ tf/J mice can serve as a model to understand the neural mechanisms underlying alterations in behavioral flexibility, as well as to test potential treatments in alleviating these symptoms., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Rationale: Preweanling rats, unlike adults, exhibit context-independent behavioral sensitization after a single pretreatment injection of cocaine., Objective: The purpose of this study was to examine environmental factors modulating one- and three-trial sensitization in preweanling rats., Methods: For preweanling rats, drug pretreatments occurred on postnatal day (PD) 17-PD 19 (experiment 1) or PD 19 (experiment 2). One set of rats was injected with cocaine (30 mg/kg) and placed in anesthesia ("small"), operant conditioning ("large"), or activity chambers for 30 min. Rats were returned to the home cage and injected with saline. Additional groups of rats were injected with saline and placed in small, large, or activity chambers for 30 min and then injected with cocaine after being returned to the home cage. Control groups were injected with saline at both time points. In separate experiments, rats were pretreated with cocaine or saline and restricted to the home cage. On PD 20, all rats were injected with cocaine (20 mg/kg) and placed in activity chambers where locomotor activity was assessed for 60 min. For comparison purposes, sensitization was also assessed in adult rats., Results: Adult male and female rats exhibited only context-dependent sensitization, whereas preweanling rats showed context-independent sensitization in a variety of conditions (e.g., when pretreated with cocaine in various novel chambers or the home cage)., Conclusions: These results suggest that nonassociative mechanisms underlying behavioral sensitization are functionally mature in preweanling rats, but associative processes modulating the strength of the sensitized response do not function in an adult-like manner during the preweanling period.

Rationale: Unlike adult rats, young rats exhibit context-dependent and context-independent behavioral sensitization when assessed after a single pretreatment injection of cocaine., Objective: The purpose of this study was to determine whether: (1) the context-dependent and context-independent sensitization of young rats can be dissociated based on the persistence of the sensitized response and (2) the expression of behavioral sensitization is associated with region-specific increases in Fos immunoreactivity (Fos-IR)., Materials and Methods: On postnatal day (PD) 19, rats were injected with either saline or cocaine (30 mg/kg) in a novel test chamber or the home cage. After 1, 3, 5, 7, 14, or 61 abstinence days, rats were challenged with 20 mg/kg cocaine and locomotor activity was measured for 60 min. In a separate experiment, rats pretreated on PD 19 were challenged with cocaine (10-30 mg/kg) on PD 80., Results: The sensitized responding of young rats persisted for the same length of time (5 days) regardless of whether cocaine pretreatment occurred in a novel environment or the home cage. Behavioral sensitization did not reemerge in adulthood. When assessed after three abstinence days (i.e., on PD 22), acute treatment with cocaine increased Fos-IR in various brain regions, but sensitized responding was associated with elevated Fos expression in only the caudate-putamen (CP) and prefrontal cortex (PFC)., Conclusions: Persistence of the sensitized response cannot be used to dissociate the one-trial context-dependent and context-independent sensitization of young rats. Fos data indicate that the CP and PFC may be involved in the mediation of short-term behavioral sensitization on PD 22.