Psychedelics such as psilocybin and lysergic acid diethylamide (LSD) exert hallucinogenic effects through stimulation of serotonin 5-HT2A receptors (5-HT2ARs) in the cerebral cortex. In recent years, numerous reports have demonstrated that psychedelics are effective in treating various psychiatric disorders such as major depressive disorder (MDD), treatment-resistant depression (TRD), and anxiety-related disorders. We have previously reported that administration of psilocin, the active metabolite of psilocybin, produces antidepressant-like effects in mice. Furthermore, we found that this effect is mediated by 5-HT2AR activation. Since depression and other psychiatric disorders often lead to impairments in social behavior (e.g., social avoidance), the present study examined the effects of psilocin on social avoidance behavior in mice subjected to chronic social defeat stress (CSDS), a widely used model that closely models human psychosocial stress. Mice exposed to CSDS exhibited social avoidance behavior, whereas psilocin administration before the onset of CSDS had little effect on this behavior. In contrast, psilocin administration after the completion of CSDS ameliorated social avoidance in CSDS-exposed mice. This effect was blocked by pretreatment with a 5-HT2AR antagonist, indicating that psilocin exerts its therapeutic effects through 5-HT2AR activation. Taken together, psilocin exerts therapeutic effects on social avoidance behavior after stress through activation of 5-HT2AR, but not preventive effects when administered before stress, suggesting that psilocin may promote stress resilience rather than resistance.

Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Recent studies have reported altered expression of early growth response 1 (Egr1), an activity-inducible immediate early gene, and histone deacetylase 2 (HDAC2), a regulator of gene transcription through the removal of acetyl groups from histone tails, in the hippocampus of epilepsy patients and animal models. Here, we investigated the roles of EGR1 and HDAC2 in pentylenetetrazol (PTZ)-induced seizures in kindled mice. Chronic PTZ treatment increased EGR1 and decreased HDAC2 expression in the hippocampus. Furthermore, EGR1 bound to the Hdac2 promoter and repressed its activity, but it had no effect when the predicted EGR1 binding site was deleted. Subsequently, we investigated the role of the HDAC2 in chemically induced kindling in mice with Hdac2 deletion. Hdac2 deletion suppressed PTZ-induced kindled seizures in mice compared with control mice. The upregulation of brain-derived neurotrophic factor (BDNF), a neurotrophin crucial for brain development, was observed in the hippocampi of control mice chronically treated with PTZ, but this increase was absent in mice with Hdac2 deletion. Additionally, continuous microinjection of recombinant BDNF protein into the ventricle accelerated kindling in mice with Hdac2 deletion, suggesting that HDAC2 contributes to the development of kindled seizures by regulating BDNF expression. In summary, HDAC2, which is negatively regulated by EGR1, induces BDNF expression in the hippocampus of PTZ-treated mice, resulting in the development of kindled seizures. These findings indicate that the EGR1-HDAC2-BDNF molecular pathway may serve as a therapeutic target in epilepsy.

Systemic immune challenge can also cause neuropsychiatric abnormalities. Interferon-induced transmembrane protein 3 (IFITM3) plays a crucial role in cellular immune defense. Previously, we have demonstrated that IFITM3 affects neurodevelopment during the early developmental stage in mice, acting through innate immune activation. However, the pathophysiological significance of IFITM3 in immune system activation in adulthood remains unclear. To address this issue, we aimed to analyze the expression level of IFITM3 in the brain and the behavioral abnormalities in polyriboinosinic-polyribocytidylic acid (polyI:C)-treated adult male C57/BL6J wild-type (WT) and Ifitm3-/- mice. The expression levels of Ifitm3 mRNA and protein were significantly upregulated in the medial prefrontal cortex (mPFC), striatum, and hippocampus 24 h after polyI:C treatment in WT mice compared to saline-treated control mice. Furthermore, behavioral experiments revealed that polyI:C treatment induced cognitive dysfunction and anhedonia in WT mice, whereas Ifitm3-/- mice were resistant to these disorders. In conclusion, our results demonstrated that in adult mice, immune activation following polyI:C treatment may induce cognitive dysfunction and anhedonia through IFITM3 upregulation in the brain. These results suggest that IFITM3 is an attractive therapeutic target for neuropsychiatric dysfunction following immune activation in adulthood.

Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), ketamine, and psilocybin, are effective for treating depression despite their distinct modes of action. We hypothesized that their underlying mechanisms of action are shared. Mice were administered escitalopram (15 mg/kg daily for 3 weeks, 21 mice), R/S/racemic ketamine (10 mg/kg, single injection, 22 mice), or psilocin (1 mg/kg, single injection, 22 mice). Electroconvulsive stimulation (9 times for 3 weeks, 12 mice) and saline were used as controls. After structural magnetic resonance imaging (MRI) of fixed brains, voxel based morphometry was conducted to assess brain wide volumetric changes. A single dose of ketamine or psilocin was sufficient to induce MRI detectable volume changes. All antidepressants increased the volume in the nucleus accumbens, ventral pallidum, and external globus pallidus and decreased the volume in the mediodorsal thalamus, which is distinct from the changes observed with electroconvulsive stimulation. We identified microstructural and molecular changes using super-resolution microscopy and imaging mass spectrometry, respectively. Pallidal volumetric increases were associated with hypertrophy of striatal medium spiny neuron terminals and increased GABA content. We experimentally addressed whether the overexpression of the vesicular GABA transporter (VGAT) reproduced these changes. The overexpression of striatal VGAT reproduced these structural changes. R ketamine, SR ketamine, and psilocin induced more pronounced ventral pallidum hypertrophy, and SSRIs and S ketamine induced globus pallidus hypertrophy. We discovered shared pallidum centered structural and molecular changes among various antidepressants, which possibly potentiate the striato pallidial inhibition associated with antidepressant action. Our data support visualizing antidepressant responses using pallidum centered GABA MR spectroscopy or structural MRI. ### Competing Interest Statement Dr. Hashimoto is the inventor of and has filed patent applications for The use of R-ketamine in the treatment of psychiatric diseases, (S)-norketamine and salt thereof as a pharmaceutical, R-ketamine and derivatives thereof as prophylactic or therapeutic agents for neurodegenerative disease or recognition function disorder, Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases, R-ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder, and TGF-β1 in the treatment of depression by Chiba University. The other authors declare that they have no competing interests.

Major Depressive Disorder (MDD) poses a significant global health burden, with 30-40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a "breakthrough medicine" for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229-232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.

Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic- and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice 24 h post-treatment. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than anxiolytic effects.

Major depressive disorder presents a substantial global health burden, and at least 30-40% of patients exhibit treatment resistance to antidepressants. Ketamine, an NMDA receptor antagonist, is used as an anesthetic agent. In 2019, the U.S. Food and Drug Administration (FDA) approved esketamine (the S-enantiomer of ketamine) as a therapeutic agent for treatment-resistant depression; however, this drug has reportedly been associated with serious side effects such as dissociative symptoms, thus limiting its clinical use as an antidepressant. Recently, various clinical studies have reported that psilocybin, the psychoactive substance found in magic mushrooms, has a fast-acting and long-lasting antidepressant effect in patients with major depressive disorder, including those resistant to conventional treatment. Furthermore, psilocybin is a psychoactive drug that is relatively harmless compared to ketamine and other similar substances. Accordingly, the FDA has designated psilocybin as a "breakthrough therapy approach" for the treatment of major depressive disorder. Additionally, serotonergic psychedelics such as psilocybin and lysergic acid diethylamide show some potential in the treatment of depression, anxiety, and addiction. The increased attention the use of psychedelics has attracted as a psychiatric disorder treatment approach is referred to as the "psychedelic renaissance". Pharmacologically, psychedelics cause hallucinations by stimulating cortical serotonin 5-HT2A receptors (5-HT2A), although whether 5-HT2A is responsible for the manifestation of their therapeutic effects remains unclear. Furthermore, it is unclear whether the hallucinations and "mystical experience" that the patients go through because of 5-HT2A activation by psychedelics is essential for the therapeutic effect of these substances. Future research should elucidate the molecular and neural mechanisms underlying the therapeutic effects of psychedelics. This review summarizes the therapeutic effects of psychedelics on psychiatric disorders such as major depressive disorder in clinical and pre-clinical studies, and discusses the possibility of 5-HT2A as a novel therapeutic target.

Depression is a common psychiatric disorder affecting around 300 million people worldwide. Serum cortisol and glucocorticoid levels in humans are reportedly higher in patients with depression compared to controls. Furthermore, rodents repeatedly treated with exogenous corticosterone (CORT), a glucocorticoid in rodents, exhibit deficits in emotional behaviors. To confirm the availability of mice with chronic CORT treatment as an animal model of depression, we investigated the effect of chronic CORT treatment on depression-like behavioral and neuropathological phenotypes in C57BL/6N male mice. Behavioral studies showed depression- and anxiety-like behaviors in mice treated with CORT compared with control mice in the forced-swim and elevated-plus maze tests. Additionally, treated mice represented anhedonia and social behavior impairments in the sucrose preference and social interaction tests, respectively. Brains of depression patients have altered expression of reelin, an extracellular matrix protein involved in neuronal development and function. Likewise, in the present study, mice with chronic CORT treatment also exhibited reelin downregulation in cells of the hippocampus. Hence, we investigated therapeutic effects of reelin supplementation on CORT-induced behavioral abnormalities in mice. Microinjections of recombinant reelin protein into the hippocampus did not rescue behavioral deficits in mice with chronic CORT treatment. These results suggest that C57BL/6N male mice chronically treated with CORT are a suitable animal depression model, in which depressive behaviors may occur independently of the alternation of hippocampal Reelin expression.

Major depressive disorder presents a substantial global health burden, and at least 30-40% of patients exhibit treatment resistance to antidepressants. Ketamine, an NMDA receptor antagonist, is used as an anesthetic agent. In 2019, the U.S. Food and Drug Administration (FDA) approved esketamine (the S-enantiomer of ketamine) as a therapeutic agent for treatment-resistant depression; however, this drug has reportedly been associated with serious side effects such as dissociative symptoms, thus limiting its clinical use as an antidepressant. Recently, various clinical studies have reported that psilocybin, the psychoactive substance found in magic mushrooms, has a fast-acting and long-lasting antidepressant effect in patients with major depressive disorder, including those resistant to conventional treatment. Furthermore, psilocybin is a psychoactive drug that is relatively harmless compared to ketamine and other similar substances. Accordingly, the FDA has designated psilocybin as a "breakthrough therapy approach" for the treatment of major depressive disorder. Additionally, serotonergic psychedelics such as psilocybin and lysergic acid diethylamide show some potential in the treatment of depression, anxiety, and addiction. The increased attention the use of psychedelics has attracted as a psychiatric disorder treatment approach is referred to as the "psychedelic renaissance". Pharmacologically, psychedelics cause hallucinations by stimulating cortical serotonin 5-HT2A receptors (5-HT2A), although whether 5-HT2A is responsible for the manifestation of their therapeutic effects remains unclear. Furthermore, it is unclear whether the hallucinations and "mystical experience" that the patients go through because of 5-HT2A activation by psychedelics is essential for the therapeutic effect of these substances. Future research should elucidate the molecular and neural mechanisms underlying the therapeutic effects of psychedelics. This review summarizes the therapeutic effects of psychedelics on psychiatric disorders such as major depressive disorder in clinical and pre-clinical studies, and discusses the possibility of 5-HT2A as a novel therapeutic target.

Long-term exposure to physical and/or psychosocial stress during early life and/or adolescence increases the risk of psychiatric disorders such as major depressive disorder and anxiety disorders. However, the molecular mechanisms underlying early stress-induced brain dysfunction are poorly understood. In the present study, mice at 4 weeks old were subjected to chronic mild unpredictable stress (CMUS) for 4 weeks, and subsequently to assays of emotion-related behaviors. Thereafter, they were sacrificed and their brains were collected for real-time quantitative polymerase chain reaction (RT-qPCR). Mice with CMUS during adolescence showed despair behavior, anxiety-like behavior, social behavior deficits, and anhedonia in forced-swim, marble-burying, social interaction, and sucrose preference tests, respectively. Additionally, RT-qPCR revealed that the expression levels of sirtuin1 (SIRT1), a NAD+-dependent deacetylase that mediates stress responses, were down-regulated in the prefrontal cortex and hippocampus of mice with CMUS compared with control mice. Next, to investigate the pathophysiological role of decreased Sirt1 expression levels in stress-induced behavioral deficits, we assessed the effects of resveratrol, a pharmacological activator of SIRT1, in mice exposed to CMUS. Chronic treatment with resveratrol prevented CMUS-induced social behavior deficits and depression-like behaviors. These results suggest that CMUS during adolescence decreases Sirt1 expression in the brain, leading to deficits in emotional behavior. Accordingly, SIRT1 activators, such as resveratrol, may be preventive agents against abnormalities in emotional behavior following stress during an immature period.

The serotonergic and glutamatergic neurotransmitter systems have been implicated in the pathophysiology of schizophrenia, and increasing evidence shows that they interact functionally. Of note, the Gq/11-coupled serotonin 5-HT2A (5-HT2A) and the Gi/o-coupled metabotropic glutamate type 2 (mGlu2) receptors have been demonstrated to assemble into a functional heteromeric complex that modulates the function of each individual receptor. For conformation of the heteromeric complex, corresponding transmembrane-4 segment of 5-HT2A and mGlu2 are required. The 5-HT2A/mGlu2 heteromeric complex is necessary for the activation of Gq/11 proteins and for the subsequent increase in the levels of the intracellular messenger Ca2+. Furthermore, signaling via the heteromeric complex is dysregulated in the post-mortem brains of patients with schizophrenia, and could be linked to altered cortical function. From a behavioral perspective, this complex contributes to the hallucinatory and antipsychotic behaviors associated with 5-HT2A and mGlu2/3 agonists, respectively. Synaptic and epigenetic mechanisms have also been found to be significantly associated with the mGlu2/5-HT2A heteromeric complex. This review summarizes the role of crosstalk between mGlu2 and 5-HT2A in the mechanism of antipsychotic effects and introduces recent key advancements on this topic.

In the pathophysiology of Alzheimer’s disease, the deposition of amyloid β peptide (Aβ) is associated with oxidative stress, leading to cognitive impairment and neurodegeneration. We have already reported that betaine (glycine betaine), an osmolyte and methyl donor in cells, prevents the development of cognitive impairment in mice with intracerebroventricular injection of Aβ25–35, an active fragment of Aβ, associated with oxidative stress in the hippocampus, but molecular mechanisms of betaine remain to be determined. Here, to investigate a key molecule underlying the preventive effect of betaine against cognitive impairments in Aβ25–35-injected mice, cognitive tests and qPCR assays were performed in Aβ25–35-injected mice with continuous betaine intake, in which intake was started a day before Aβ25–35 injection, and then continued for 8 days. The Aβ25–35 injection impaired short-term and object recognition memories in the Y-maze and object recognition tests, respectively. PCR assays revealed the down-regulation of Sirtuin1 (SIRT1), a NAD+-dependent deacetylase that mediates metabolic responses, in the hippocampus of Aβ25–35-injected mice, whereas betaine intake prevented memory deficits as well as the decrease of hippocampal SIRT1 expression in Aβ25–35-injected mice. Further, sirtinol, an inhibitor of the Sirtuin family, blocked the preventive effect of betaine against memory deficits. On the other hand, resveratrol, the potent compound that activates SIRT1, also prevented memory impairments in Aβ25–35-injected mice, suggesting that SIRT1 plays a causative role in the preventive effect of betaine against memory deficits caused by Aβ exposure.

Background: The deposition of amyloid-β (Aβ) and hyperphosphorylation of tau are well-known as the pathophysiological features of Alzheimer’s disease (AD), leading to oxidative stress and synaptic deficits followed by cognitive symptoms. We already demonstrated that betaine (glycine betaine) prevented cognitive impairment and hippocampal oxidative stress in mice intracerebroventricularly injected with an active fragment of Aβ, whereas the effect of betaine in chronic models of AD remains unknown. Objective: Our objective was to investigate the effects of chronic betaine intake on cognitive impairment and aberrant expression of genes involved in synapse and antioxidant activity in the hippocampus of a genetic AD model. Methods: We performed cognitive tests and RT-PCR in the hippocampus in 3xTg mice, a genetic AD model. Results: Cognitive impairment in the Y-maze and novel object recognition tests became evident in 3xTg mice at 9 months old, and not earlier, indicating that cognitive impairment in 3xTg mice developed age-dependently. To examine the preventive effect of betaine on such cognitive impairment, 3xTg mice were fed betaine-containing water for 3 months from 6 to 9 months old, and subsequently subjected to behavioral tests, in which betaine intake prevented the development of cognitive impairment in 3xTg mice. Additionally, the expression levels of genes involved in synapse and antioxidant activity were downregulated in hippocampus of 3xTg mice at 9 months old compared with age-matched wild-type mice, which were suppressed by betaine intake. Conclusion: Betaine may be applicable as an agent preventing the progression of AD by improving the synaptic structure/function and/or antioxidant activity.

Previous studies demonstrate an association between activation of the maternal immune system during pregnancy and increased risk of neurodevelopmental psychiatric conditions, such as schizophrenia and autism, in the offspring. Relatively recent findings also suggest that the gut microbiota plays an important role in shaping brain development and behavior. Here we show that maternal immune activation (MIA) accomplished by infection with a mouse-adapted influenza virus during pregnancy induced up-regulation of frontal cortex serotonin 5-HT2A receptor (5-HT2AR) density in the adult offspring, a phenotype previously observed in postmortem frontal cortex of schizophrenic subjects. 5-HT2AR agonist-induced head-twitch behavior was also augmented in this preclinical mouse model. Using the novel object recognition (NOR) test to evaluate cognitive performance, we demonstrate that MIA induced NOR deficits in adult offspring. Oral antibiotic treatment of prepubertal mice prevented this cognitive impairment, but not increased frontal cortex 5-HT2AR density or psychedelic-induced head-twitch behavior in adult MIA offspring. Additionally, gut microbiota transplantation from MIA mice produced behavioral deficits in antibiotic-treated mock mice. Adult MIA offspring displayed altered gut microbiota, and relative abundance of specific components of the gut microbiota, including Ruminococcaceae, correlated with frontal cortex 5-HT2AR density. Together, these findings provide a better understanding of basic mechanisms by which prenatal insults impact offspring brain function, and suggest gut-brain axis manipulation as a potential therapeutic approach for neurodevelopmental psychiatric conditions.

In the majority of schizophrenia patients, chronic atypical antipsychotic administration produces a significant reduction in or even complete remission of psychotic symptoms such as hallucinations and delusions. However, these drugs are not effective in improving cognitive and emotional deficits in patients with schizophrenia. Atypical antipsychotic drugs have a high affinity for the dopamine D2 receptor, and a modest affinity for the serotonin 5-HT2A receptor. The cognitive and emotional deficits in schizophrenia are thought to involve neural networks beyond the classical dopaminergic mesolimbic pathway, however, including serotonergic systems. For example, mutations in the RELN gene, which encodes Reelin, an extracellular matrix protein involved in neural development and synaptic plasticity, are associated with neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. Furthermore, hippocampal Reelin levels are down-regulated in the brains of both schizophrenic patients and in rodent models of schizophrenia. In the present study, we investigated the effect of Reelin microinjection into the mouse hippocampus on behavioral phenotypes to evaluate the role of Reelin in neurodevelopmental disorders and to test a therapeutic approach that extends beyond classical monoamine targets. To model the cognitive and emotional deficits, as well as histological decreases in Reelin-positive cell numbers and hippocampal synaptoporin distribution, a synaptic vesicle protein, offspring that were prenatally exposed to maternal immune activation were used. Microinjections of recombinant Reelin protein into the hippocampus rescued impairments in object memory and anxiety-like behavior and recruited synaptoporin in the hippocampus in offspring exposed to antenatal inflammation. These results suggest that Reelin supplementation has the potential to treat cognitive and emotional impairments, as well as synaptic disturbances, in patients with neurodevelopmental disorders such as schizophrenia.

Sodium valproate (VPA) is the most widely used antiepileptic drug and is increasingly also being used for several non-epileptic indications including migraines and bipolar disorder. It is known that maternal VPA exposure during pregnancy increases the risk of autism spectrum disorder (ASD) in children. Animal model studies have shown that maternal treatment with VPA in rodents conveys an increased risk for ASD-like phenotypes at the molecular, cellular, and behavioral levels. In contrast, the effect of paternal VPA exposure on behaviors in offspring is unknown. This study seeks to investigate whether paternal VPA exposure in rodents triggers behavioral and epigenetic alterations in offspring. The results show that paternal VPA exposure impairs object cognitive memory, suppresses the hyperactivity evoked by an NMDA receptor antagonist in male and female offspring, and disturbs sensorimotor gating in only females. In addition, since VPA is well known as an inhibitor of histone deacetylases, we examined the levels of acetylated histone H3 in the frontal cortex and hippocampus in the offspring of VPA-exposed sires. Interestingly, paternal VPA exposure down-regulates the levels of acetylated histone H3 in the brain in offspring even though VPA exposure increased acetylated histone H3 levels in the testes of sires. Collectively, these findings suggest that paternal VPA exposure may disturb the histone acetylation balance in the brain of offspring through changes in the germline epigenome, leading to behavioral alterations in offspring.

It is suggested that the smoking during pregnancy might impair the neurodevelopment of offspring, emotional and cognitive function. Previously, we clarified that prenatal nicotine exposure affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring. Recently, there is a hypothesis that inflammation during pregnancy may induce the brain dysfunction of offspring. In this study, we examined whether prenatal nicotine exposure might affect the expression of chemokines in mice.

The cigarette smoking during pregnancy is thought to induce the dysfunction of emotional and cognitive function of offspring. In our previous studies, we have reported that prenatal nicotine exposure affects the proliferation and maturation of progenitor cells to glutamatergic and dopaminergic neurons during neurodevelopment in the medial PFC, which may be associated with behavioral impairments in the offspring. Recently, there is a hypothesis that inflammation during pregnancy might impair brain function of offspring. Here, we investigated whether prenatal nicotine exposure might affect the expression of chemokines in mice.