Compulsive-like Behavior Research Articles

Effects of Morphine and Maternal Care on Behaviors and Protein Expression of Male Offspring

Genes and environment interact during development to alter gene expression and behavior. Parental morphine exposure before conception has devastating effects on the offspring. In the present study, we evaluated the role of maternal care in the intergenerational effect of maternal morphine exposure. Female rats received morphine or saline for ten days and were drugfree for another ten days. Thereafter, they were allowed to mate with drug-naïve male rats. When pups were born, they were cross-fostered to assess the contribution of maternal care versus morphine effects on the offspring. Adult male offspring were examined for anxiety-like behavior, spatial memory, and obsessive–compulsive-like behavior. To determine the mechanisms underlying the observed behavioral changes, protein levels of acetylated histone H3, BDNF, Trk-B, NMDA subunits, p-CREB, and 5-HT3R were measured in the brain. Our results indicate that maternal caregiving is impaired in morphine-abstinent mothers. Interestingly, maternal care behaviors were also affected in drug-naïve mothers that raised offspring of morphine-exposed mothers. In addition, the offspring of morphine abstinent and non-drug dependent mothers, when raised by morphine abstinent mothers, exhibited more anxiety, obsessive–compulsive behaviors and impaired spatial memory. These altered behaviors were associated with alterations in the levels of the above-mentioned proteins. These data illustrate the intergenerational effects of maternal morphine exposure on offspring behaviors. Moreover, exposure to morphine before gestation not only affects maternal care and offspring behavior, but also has negative consequences on behaviors and protein expression in adoptive mothers of affected offspring.

Sign Tracking in an Enriched Environment: A Potential Ecologically Relevant Animal Model of Adaptive Behavior Change.

When an object conditioned stimulus (CS) is paired with a food unconditioned stimulus (US), anticipatory goal-directed action directed at the US location (goal tracking) is accompanied by behavior directed at the object CS (sign tracking). Sign-tracking behavior appears to be compulsive and habit-like and predicts increased vulnerability to the addictive potential of drugs in animal models. A large body of the literature also suggests that environmental enrichment protects against the development of addiction-prone phenotypes. Thus, we investigated whether compulsive-like sign tracking develops in environmentally enriched rats trained directly in their enriched home environment. We demonstrate that adolescent enriched-housed male Sprague-Dawley rats readily sign track a 5% ethanol bottle CS in their home environment and at a rate higher than adolescent standard-housed rats. We also show that enriched adolescent rats sign track less than enriched adult-trained rats and that acute isolation stress affects sign- and goal-tracking performance of adolescents and adults differently. Sign tracking increased more in the adult than the adolescent rats. Whereas the younger rats showed a decrease in goal tacking after the final stressor manipulation, the adults showed increased goal tracking. Our results are consistent with recent studies, which suggest that although sign tracking performance is compulsive-like, it is not as inflexible and habit-like as previously assumed. Testing in an enriched home environment with object CSs having greater affordance than “neutral” lever CSs may provide greater ecological relevance for investigating the development and expression of adaptive and compulsive-like behaviors in translational research.

Subthalamic low-frequency oscillations predict vulnerability to cocaine addiction

Identifying vulnerable individuals before they transition to a compulsive pattern of drug seeking and taking is a key challenge in addiction to develop efficient prevention strategies. Oscillatory activity within the subthalamic nucleus (STN) has been associated with compulsive-related disorders. To study compulsive cocaine-seeking behavior, a core component of drug addiction, we have used a rat model in which cocaine seeking despite a foot-shock contingency only emerges in some vulnerable individuals having escalated their cocaine intake. We show that abnormal oscillatory activity within the alpha/theta and low-beta bands during the escalation of cocaine intake phase predicts the subsequent emergence of compulsive-like seeking behavior. In fact, mimicking STN pathological activity in noncompulsive rats during cocaine escalation turns them into compulsive ones. We also find that 30 Hz, but not 130 Hz, STN deep brain stimulation (DBS) reduces pathological cocaine seeking in compulsive individuals. Our results identify an early electrical signature of future compulsive-like cocaine-seeking behavior and further advocates the use of frequency-dependent STN DBS for the treatment of addiction.

A cross-species assessment of behavioral flexibility in compulsive disorders

Lack of behavioral flexibility has been proposed as one underlying cause of compulsions, defined as repetitive behaviors performed through rigid rituals. However, experimental evidence has proven inconsistent across human and animal models of compulsive-like behavior. In the present study, applying a similarly-designed reversal learning task in two different species, which share a common symptom of compulsivity (human OCD patients and Sapap3 KO mice), we found no consistent link between compulsive behaviors and lack of behavioral flexibility. However, we showed that a distinct subgroup of compulsive individuals of both species exhibit a behavioral flexibility deficit in reversal learning. This deficit was not due to perseverative, rigid behaviors as commonly hypothesized, but rather due to an increase in response lability. These cross-species results highlight the necessity to consider the heterogeneity of cognitive deficits in compulsive disorders and call for reconsidering the role of behavioral flexibility in the aetiology of compulsive behaviors.

Altered mRNA Levels of Stress-Related Peptides in Mouse Hippocampus and Caudate-Putamen in Withdrawal after Long-Term Intermittent Exposure to Tobacco Smoke or Electronic Cigarette Vapour.

Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive–compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.

NOX1/NADPH oxidase regulates compulsive-like repetitive behaviors through promoting D<sub>2</sub> receptor-mediated synaptic facilitation in the striatum

NOX1/NADPH oxidase regulates compulsive-like repetitive behaviors through promoting D<sub>2</sub> receptor-mediated synaptic facilitation in the striatum

Investigating the role of 5-HT2A and 5-HT2C receptor activation in the effects of psilocybin, DOI, and citalopram on marble burying in mice

Psychedelic drugs acting as 5-hydroxyptryptamine 2A receptor (5-HT2AR) agonists have shown promise as viable treatments of psychiatric disorders, including obsessive-compulsive disorder. The marble burying test is a test of compulsive-like behavior in mice, and psychedelics acting as 5-HT2AR agonists can reduce digging in this test. We assessed the 5-HT2R contribution to the mechanisms of two 5-HT2A agonists on digging behavior in female NMRI mice, using citalopram as a reference compound. While the 5-HT2AR antagonist M100907 blocked the effect of DOI and the 5-HT2CR antagonist SB242084 blocked the effect of citalopram, neither antagonist blocked the effect of psilocybin. This study confirms 5-HT2AR agonism as a mechanism for reduced compulsive-like digging in the MB test and suggests that 5-HT2A and 5-HT2CRs can work in parallel on this type of behavior. Our results with psilocybin suggest that a 5-HT2R-independent mechanism also contributes to the effect of psilocybin on repetitive digging behavior.

Arbitration of Approach-Avoidance Conflict by Ventral Hippocampus

When environmental cues or stimuli that represent both rewarding and aversive outcomes are presented, complex computations must be made in order to determine whether approach or avoidance is the better behavioral strategy. In many neuropsychiatric illnesses these computations can be skewed. In some instances, circumstances that may normally warrant avoidance instead promote approach, thus producing compulsive-like behavioral strategies that are inflexible in response to new or conflicting information. Alternatively, high sensitivity to aversion or low sensitivity to reward can result in the failure to achieve goals and loss of resilience that characterizes depressive disorders. Increases in compulsive-like behavior have been found to be associated with disrupted signaling in regions that regulate response to conflicting stimuli, including the hippocampus. Classic behavioral inhibition theories of hippocampus function in anxiety suggest that the hippocampus blocks aberrant behavior in response to anxiety related cues or stimuli. The hippocampus may act to block approach in the face of conflicting stimuli. Dysregulations of hippocampal function, as may be present in neuropsychiatric disorders, may therefore promote aberrant approach behavior. The ventral hippocampus (vHPC) subregion is key for coordinating this approach/avoidance conflict resolution, likely through its participation with cortico-striatal and mesolimbic circuits. We revisit Gray's behavioral inhibition theory of HPC function, first posited in the 1980s, and interpret in the context of new knowledge on vHPC function gained through modern technology. Taken together with the extant, classical literature on hippocampal function, we propose that these new findings suggest that vHPC circuits balance behavioral response to conflicting stimuli in a manner that is both state- and context-dependent and, further, that disruption of specific vHPC circuits tips the balance in favor of biased approach or avoidance behavioral strategies.

Dopamine release, diffusion and uptake: A computational model for synaptic and volume transmission.

Computational modeling of dopamine transmission is challenged by complex underlying mechanisms. Here we present a new computational model that (I) simultaneously regards release, diffusion and uptake of dopamine, (II) considers multiple terminal release events and (III) comprises both synaptic and volume transmission by incorporating the geometry of the synaptic cleft. We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies. Further, although synaptic dopamine diffuses into extra-synaptic space, our model reflects a very localized signal occurring on the synaptic level, i.e. synaptic dopamine release is negligibly recognized by neighboring synapses. Moreover, increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data (e.g. BOLD). Signal variability in target areas of dopaminergic neurons (striatum, cortex) may arise from dopamine concentration variability. On that account we compared spatio-temporal variability in a simulation mimicking normal dopamine transmission in striatum to scenarios of enhanced dopamine release and dopamine uptake inhibition. We found different variability characteristics between the three settings, which may in part account for differences in empirical observations. From a clinical perspective, differences in striatal dopaminergic signaling contribute to differential learning and reward processing, with relevant implications for addictive- and compulsive-like behavior. Specifically, dopaminergic tone is assumed to impact on phasic dopamine and hence on the integration of reward-related signals. However, in humans DA tone is classically assessed using PET, which is an indirect measure of endogenous DA availability and suffers from temporal and spatial resolution issues. We discuss how this can lead to discrepancies with observations from other methods such as microdialysis and show how computational modeling can help to refine our understanding of DA transmission.

Blockade of Orexin Receptors in the Posterior Paraventricular Nucleus of the Thalamus Prevents Stress-Induced Reinstatement of Reward-Seeking Behavior in Rats With a History of Ethanol Dependence.

Neural systems involved in processing natural rewards and drugs of abuse overlap and exposure to drugs of abuse induce neuroadaptations that can cause compulsive-like behavior. For example, the recruitment of the orexin (Orx) system by drugs of abuse has been proposed to induce neuroadaptations that in turn alter its function, reflected by maladaptive, compulsive, and addictive behavior. Orexin neurons project to the paraventricular nucleus of the thalamus (PVT)—particularly the posterior part (pPVT), a structure that plays a key role in stress regulation. This study investigated whether Orx transmission in the pPVT plays a role in stress-induced reinstatement of reward-seeking behavior toward ethanol (EtOH) and a highly palatable food reward [sweetened condensed milk (SCM)] in rats and whether this role changes with EtOH dependence. After being trained to orally self-administer EtOH or SCM, the rats were made dependent (EtOHD and SCMD) by chronic intermittent EtOH vapor exposure. The control nondependent groups (EtOHND and SCMND) were exposed to air. Following extinction, the rats were tested for stress-induced reinstatement of EtOH- and SCM-seeking behavior. Stress reinstated EtOH- and SCM-seeking behavior in all groups (EtOHD/ND and SCMD/ND). Administration of the dual Orx receptor (OrxR) antagonist TCS1102 (15 μg) in the pPVT prevented stress-induced reinstatement only in dependent rats (EtOHD and SCMD). In parallel, the qPCR analysis showed that Orx mRNA expression in the hypothalamus and OrxR1/R2 mRNA expression in the pPVT were increased at the time of testing in the EtOHD and SCMD groups. These results are the first to implicate Orx transmission in the pPVT in the stress-induced reinstatement of reward-seeking behavior in EtOH dependent rats and indicate the maladaptive recruitment of Orx transmission in the pPVT by EtOH dependence.

Studies on CRMP2 SUMOylation-deficient transgenic mice identify sex-specific Nav1.7 regulation in the pathogenesis of chronic neuropathic pain.

The sodium channel Nav1.7 is a master regulator of nociceptive input into the central nervous system. Mutations in this channel can result in painful conditions and produce insensitivity to pain. Despite being recognized as a "poster child" for nociceptive signaling and human pain, targeting Nav1.7 has not yet produced a clinical drug. Recent work has illuminated the Nav1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Among the regulators of Nav1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound Nav1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2) mice in which Lys374 was replaced with Ala. CRMP2 mice had reduced Nav1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2 mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2 mice to inflammatory, acute, or visceral pain. By contrast, in a neuropathic model, CRMP2 mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral Nav1.7 is a hallmark of chronic, but not physiological, neuropathic pain.

27.2 Selective Overexpression of EAAT3 in Midbrain Dopamine Neurons Leads to Increased OCD-like Behaviors

OCD is a severe, chronic condition that affects 2% to 3% of the population. Genetic findings have pointed to SLC1A1, encoding the neuronal glutamate transporter EAAT3/EAAC1, with evidence suggesting that increased expression may contribute to risk. We previously reported that a loss of Slc1a1 in mice leads to decreased amphetamine (AMPH)-induced dopamine (DA) release, locomotion, and stereotypic movements, as well as decreased SKF-38393 (D1-agonist)-induced grooming behavior. Viral rescue of midbrain Slc1a1 expression partially restored the behavioral response to AMPH, suggesting an impact on DA neuron function. Here, to test more directly the developmental impact of DA neuron EAAT3 overexpression on compulsive-like behaviors, we generated mice with DA neuron–selective overexpression of EAAT3. We hypothesized that increased expression in DA neurons would lead to increased OCD-like behaviors.

Novel Highly Potent and Selective Sigma1 Receptor Antagonists Effectively Block the Binge Eating Episode in Female Rats.

In this paper, the benzo-cracking approach was applied to the potent sigma1 (σ1) receptor antagonist 1 to afford the less conformationally constrained 1,3-dioxane derivatives 2 and 3. To evaluate the effect of the increase in the distance between the two hydrophobic structural elements that flank the basic function, the cis and trans diastereomers of 4 and 5 were also prepared and studied. Compounds 2 and 3 showed affinity values at the σ1 receptor significantly higher than that of the lead compound 1. In particular, 3 displayed unprecedented selectivity over the σ2 receptor, the phencyclidine site of the NMDA receptor, and opioid receptor subtypes, as well as over the dopamine transporter. Docking results supported the structure–activity relationship studies. Due to its interesting biological profile, derivative 3, selected for an in vivo study in a validated preclinical model of binge eating, was able to counteract the overeating of palatable food only in binging rats, without affecting palatable food intake in the control group and anxiety-like and depression-related behaviors in female rats. This result strengthened the involvement of the σ1 receptor in the compulsive-like eating behavior and supported the σ1 receptor as a promising target for the management of eating disorders.

Large nest building and high marble-burying: Two compulsive-like phenotypes expressed by deer mice (Peromyscus maniculatus bairdii) and their unique response to serotoninergic and dopamine modulating intervention

This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50 mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9 mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5 mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorders.

Naturalistic operant responses in deer mice (Peromyscus maniculatus bairdii) and its response to outcome manipulation and serotonergic intervention.

Investigating the motivational triggers underlying naturalistic compulsive-like behavior is generally regarded as challenging. To this extent, the current study aimed to establish a proof-of-concept for future investigation by probing unconditioned and naturalistic operant responses aimed at obtaining nesting material by normal (NNB) and large (LNB) nest building deer mice (Peromyscus maniculatus bairdii). LNB mice and NNB controls were individually placed in cages equipped with a lever-operated nesting material (cotton rope) dispenser and allowed to become accustomed to the response (lever press)-outcome (obtaining cotton rope) contingency over seven nights. Subsequently, the contingency was manipulated by withdrawing the nesting material (experiment 1) or punishing the lever-press response with a mild electrical foot shock (experiment 2). Mice were then treated for 28 days with escitalopram (50 mg/kg/d) and retested. Our results indicate that (1) LNB mice generally made more operant responses compared to NNB controls, (2) withdrawal of nesting material and institution of punishment bolstered responding in LNB but not NNB mice and (3) escitalopram treatment tended to reduce increased responding in LNB mice following experimental manipulation, while normalizing the total number of lever-press counts in the LNB cohort. Therefore, LNB seems to diverge from NNB, not only as a spontaneous phenotype, but also in terms of the motivation to obtain nesting material, despite demotivating feedback. That such differences were abrogated by chronic escitalopram intervention, indicates that the uniquely motivated operant interactions displayed by LNB mice, may be founded upon serotonergic mechanisms, a finding in line with the neurobiological theory of obsessive-compulsive disorder.

Persistent cognitive and affective alterations at late withdrawal stages after long-term intermittent exposure to tobacco smoke or electronic cigarette vapour: Behavioural changes and their neurochemical correlates

Smoking cessation induces a withdrawal syndrome associated with anxiety, depression, and impaired neurocognitive functions, but much less is known about the withdrawal of e-cigarettes (e-CIG).We investigated in Balb/c mice the behavioural and neurochemical effects of withdrawal for up to 90 days after seven weeks’ intermittent exposure to e-CIG vapour or cigarette smoke (CIG).The withdrawal of e-CIG and CIG induced early behavioural alterations such as spatial memory deficits (spatial object recognition task), increased anxiety (elevated plus maze test) and compulsive-like behaviour (marble burying test) that persisted for 60–90 days. Notably, attention-related (virtual object recognition task) and depression-like behaviours (tail suspension and sucrose preference tests) appeared only 15–30 days after withdrawal and persisted for as long as up to 90 days.At hippocampal level, the withdrawal-induced changes in the levels of AMPA receptor GluA1 and GluA2/3 subunits, PSD 95 protein, corticotropin-releasing factor (Crf) and Crf receptor 1 (CrfR1) mRNA were biphasic: AMPA receptor subunit and PSD95 protein levels initially remained unchanged and decreased after 60–90 days, whereas Crf/CrfR1 mRNA levels initially increased and then markedly decreased after 60 days. These late reductions correlated with the behavioural impairments, particularly the appearance of depression-like behaviours.Our findings show that major behavioural and neurochemical alterations persist or even first appear late after the withdrawal of chronic CIG smoke or e-CIG vapour exposure, and underline importance of conducting similar studies of humans, including e-CIG vapers.

Motor impulsivity and delay intolerance are elicited in a dose-dependent manner with a dopaminergic agonist in parkinsonian rats.

Impulse control disorders (ICD) and other impulsive-compulsive behaviours are frequently found in Parkinson's disease (PD) patients treated with dopaminergic agonists. To date, there are no available animal models to investigate their pathophysiology and determine whether they can be elicited by varying doses of dopaminergic drugs. In addition, there is some controversy regarding the predispositional pattern of striatal dopaminergic depletion. To study the effect of two doses of pramipexole (PPX) on motor impulsivity, delay intolerance and compulsive-like behaviour. Male rats with mild dopaminergic denervation in the dorsolateral striatum (bilateral injections of 6-hydroxidopamine (6-OHDA)) treated with two doses of PPX (0.25 mg/kg and 3 mg/kg) and tested in the variable delay-to-signal paradigm. Partial (50%) dopaminergic depletion did not induce significant changes in motor impulsivity or delay intolerance. However, 0.25 mg/kg of PPX increased motor impulsivity, while 3 mg/kg of PPX increased both motor impulsivity and delay intolerance. These effects were independent of the drug's antiparkinsonian effects. Importantly, impulsivity scores before and after dopaminergic lesion were positively associated with the impulsivity observed after administering 3 mg/kg of PPX. No compulsive-like behaviour was induced by PPX administration. We described a rat model, with a moderate dorsolateral dopaminergic lesion resembling that suffered by patients with early PD, that develops different types of impulsivity in a dose-dependent manner dissociated from motor benefits when treated with PPX. This model recapitulates key features of abnormal impulsivity in PD and may be useful for deepening our understanding of the pathophysiology of ICD.

Prenatal nicotine exposure in mice induces sex-dependent anxiety-like behavior, cognitive deficits, hyperactivity, and changes in the expression of glutamate receptor associated-genes in the prefrontal cortex

In rodents, prenatal nicotine exposure (PNE) has been associated with increased risk for development of cognitive and emotional disturbances, but the findings are somewhat conflicting. Lack of behavioral alterations following PNE could be due to the variety of methods available for nicotine delivery, exposure time and species used, with inbred strains being mostly employed. Such differences suggest the need to investigate the behavioral phenotype in each PNE model available if we are to find models with enhanced translational value. In this study, we assessed sex-dependent effects of PNE on ADHD-related behaviors and on the levels of mRNA coding for glutamate receptor subunits within the prefrontal cortex in the outbred NMRI mice exposed to nicotine via maternal drinking water during gestation. Cotinine levels were assessed in newborn pups. Behaviors related to anxiety, compulsivity, working memory, and locomotion were evaluated in both sexes of young adult offspring using the elevated zero maze, marble burying, spontaneous alternation behavior, and locomotor activity tests. Expression of mRNA coding for different glutamate receptors subunits within the prefrontal cortex (PFC) was measured using RT-qPCR. Cotinine levels in the serum of newborns confirmed fetal nicotine exposure. Both male and female offspring showed ADHD-like behaviors, such as deficit in the SAB test and hyperactivity. In addition, PNE male mice displayed anxiety- and compulsive-like behaviors, effects that were absent in female offspring. Finally, PNE reduced the mRNA expression of GluN1-, GluN2B-, and mGluR2-related genes within the PFC of male offspring, whereas it reduced the expression of mRNA coding for GluA2 subunit in female mice. PNE in NMRI mice induced sex-dependent behavioral changes, which parallels clinical findings following maternal cigarette smoke exposure. Alterations detected in PFC mRNA glutamate receptor proteins could contribute to the abnormal behavioral responses observed, but other signaling pathways or brain regions are likely involved in the behavioral susceptibility of PNE individuals.

Trait specific modulatory effects of caffeine exposure on compulsive-like behaviors in a spontaneous mouse model of obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurring intrusive thoughts and repetitive compulsive behaviors, ultimately interfering with their quality of life. The complex heterogeneity of symptom dimensions across OCD patient subgroups impedes diagnosis and treatment. The core and comorbid symptomologies of OCD are thought to be modulated by common environmental exposures such as consumption of the psychostimulant caffeine. The effect of caffeine on the expression of obsessions and compulsions are unexplored. The current study utilized mouse strains (HA) with a spontaneous, predictable, and stable compulsive-like phenotype that have face, predictive, and construct validity for OCD. We demonstrate that an acute high dose (25 mg/kg) of caffeine decreased compulsive-like nest-building behavior in the HA strains in the first hour after injection. However, nest-building scores increased in hours 3, 4, and 5 after administration finally decreasing over a 24 h period. In contrast, a high dose of chronic caffeine (25 mg/kg/d) increased nest-building behavior. Interestingly for compulsive-like digging behavior, acute exposure to a high dose of caffeine decreased the number of marbles buried, while chronic exposure had little effect. An acute high dose of caffeine decreased anxiety-like and motor activity in open field behaviors whereas chronic caffeine administration did not have any overall effect on open field activity. The results, therefore, suggest a complex role of caffeine on compulsive-like, anxiety-like, and locomotor behaviors that is dependent on the duration of exposure.

Role of Long Noncoding RNA Gas5 in Cocaine Action

BackgroundLong noncoding RNAs (lncRNAs) are a class of transcribed RNA molecules greater than 200 nucleotides in length. Although lncRNAs do not encode proteins, they play numerous functional roles in gene expression regulation. lncRNAs are notably abundant in brain; however, their neural functions remain largely unknown. MethodsWe examined the expression of the lncRNA Gas5 in nucleus accumbens (NAc), a key brain reward region, of adult male mice after cocaine administration. We then performed viral-mediated overexpression of Gas5 in NAc neurons to determine its role in addiction-related behaviors. We also carried out RNA sequencing to investigate Gas5-mediated transcriptomic changes. ResultsWe demonstrated that repeated short-term or long-term cocaine administration decreased expression of Gas5 in NAc. Viral-mediated overexpression of Gas5 in NAc neurons decreased cocaine-induced conditioned place preference. Likewise, Gas5 overexpression led to decreased cocaine intake, decreased motivation, and compulsive-like behavior to acquire cocaine, and it facilitated extinction of cocaine-seeking behavior. Transcriptome profiling identified numerous Gas5-mediated gene expression changes that are enriched in relevant neural function categories. Interestingly, these Gas5-regulated gene expression changes significantly overlap with chronic cocaine-induced transcriptome alterations, suggesting that Gas5 may serve as an important regulator of transcriptional responses to cocaine. ConclusionsAltogether, our study demonstrates a novel lncRNA-based molecular mechanism of cocaine action.