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Background Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking GABAergic interneurons, in the prefrontal cortex (PFC) and hippocampus (HIP). However, there are discrepancies in the literature. PV reductions lead to a functional loss of PV interneurons, which is proposed to underly SCZ symptoms. Given its complex etiology, different categories of animal models have been developed to study SCZ, which may distinctly impact PV levels in rodent brain areas. Study Design We performed a quantitative meta-analysis on PV-positive cell number/density and expression levels in the PFC and HIP of animal models for SCZ based on pharmacological, neurodevelopmental, and genetic manipulations. Results Our results confirmed that PV levels are significantly reduced in the PFC and HIP regardless of the animal model. By categorizing into subgroups, we found that all pharmacological models based on NMDA receptor antagonism decreased PV-positive cell number/density or PV expression levels in both brain areas examined. In neurodevelopmental models, abnormal PV levels were confirmed in both brain areas in maternal immune activation models and HIP of the methylazoxymethanol acetate model. In genetic models, negative effects were found in neuregulin 1 and ERBB4 mutant mice in both brain regions and the PFC of dysbindin mutant mice. Regarding sex differences, male rodents exhibited PV reductions in both brain regions only in pharmacological models, while few studies have been conducted in females. Conclusion Overall, our findings support deficits in prefrontal and hippocampal PV interneurons in animal models for SCZ. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex neuropsychiatric disorder that has undergone significant advancements in its treatment. However, there are still many aspects of symptom management and prevention that could benefit from new developments in psychopharmacology. One potential avenue is the use of cannabidiol (CBD), a major phytocannabinoid found in the cannabis plant. Preliminary evidence suggests that CBD could effectively treat certain symptoms of the disorder with fewer side effects than conventional antipsychotics. This article provides the reader with an in-depth discussion of the current scientific evidence concerning the use of CBD in the treatment of schizophrenia. [Psychiatr Ann. 2023;53(6):252–255.] [ABSTRACT FROM AUTHOR]

Background and Hypothesis Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. Study Design Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31–40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. Study Results Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. Conclusions These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence. [ABSTRACT FROM AUTHOR]

Animal models of psychiatric disorders have been highly effective in advancing the field, identifying circuits related to pathophysiology, and identifying novel therapeutic targets. In this review, we show how animal models, particularly those based on development, have provided essential information regarding circuits involved in disorders, disease progression, and novel targets for intervention and potentially prevention. Nonetheless, in recent years there has been a pushback, largely driven by the US National Institute of Mental Health (NIMH), to shift away from animal models and instead focus on circuits in normal subjects. This has been driven primarily from a lack of discovery of new effective therapeutic targets, and the failure of targets based on preclinical research to show efficacy. We discuss why animal models of complex disorders, when strongly cross-validated by clinical research, are essential to understand disease etiology as well as pathophysiology, and direct new drug discovery. Issues related to shortcomings in clinical trial design that confound translation from animal models as well as the failure to take patient pharmacological history into account are proposed to be a source of the failure of what are likely effective compounds from showing promise in clinical trials. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex disorder that involves several neurotransmitters such as dopamine, glutamate, and GABA. More recently, the endocannabinoid system has also been associated with this disorder. Although initially described as present mostly in the periphery, cannabinoid type-2 (CB2) receptors are now proposed to play a role in several brain processes related to schizophrenia, such as modulation of dopaminergic neurotransmission, microglial activation, and neuroplastic changes induced by stress. Here, we reviewed studies describing the involvement of the CB2 receptor in these processes and their association with the pathophysiology of schizophrenia. Taken together, these pieces of evidence indicate that CB2 receptor may emerge as a new target for the development of antipsychotic drugs. [ABSTRACT FROM AUTHOR]

Schizophrenia is a neurodevelopmental disorder with genetic predisposition, and stress has long been linked to its etiology. While stress affects all stages of the illness, increasing evidence suggests that stress during critical periods of development may be particularly detrimental, increasing individual's vulnerability to psychosis. To thoroughly understand the potential causative role of stress, our group has been focusing on the prenatal methylazoxymethanol acetate (MAM) rodent model, and discovered that MAM offspring display abnormal stress reactivity and heightened anxiety prepubertally, prior to the manifestation of a hyperdopaminergic state. Furthermore, pharmacologically treating anxiety during prepuberty prevented the emergence of the dopamine dysfunction in adulthood. Interestingly, sufficiently strong stressors applied to normal rats selectively during early development can recapitulate multiple schizophrenia-related phenotypes of MAM rats, whereas the same stress paradigm during adulthood only produced short-term depression-related deficits. Altogether, the evidence is thus converging: developmental disruption (genetic or environmental) might render animals more susceptible to the deleterious effects of stress during critical time windows, during which unregulated stress can lead to the emergence of psychosis later in life. As an important region regulating the midbrain dopamine system, the ventral hippocampus is particularly vulnerable to stress, and the distinct maturational profile of its fast-spiking parvalbumin interneurons may largely underlie such vulnerability. In this review, by discussing emerging evidence spanning clinical and basic science studies, we propose developmental stress vulnerability as a novel link between early predispositions and environmental triggering events in the pathophysiology of schizophrenia. This promising line of research can potentially provide not only insights into the etiology, but also a "roadmap" for disease prevention. [ABSTRACT FROM AUTHOR]

• Female rats are resistant to long-term behavior changes after adolescent stress. • Female rats are resistant to long-term DA changes induced by adolescent stress. • Female rats are resistant to long-term behavior changes induced by adult stress. • Female rats are resistant to long-term DA system changes induced by adult stress. • Adolescent and adult stress have short-term effects on VTA DA system activity. Stress during adolescence is a risk factor for neuropsychiatric diseases, including schizophrenia. We recently observed that peripubertal male rats exposed to a combination of daily footshock plus restraint stress exhibited schizophrenia-like changes. However, numerous studies have shown sex differences in neuropsychiatric diseases as well as on the impact of coping with stress. Thus, we decided to evaluate, in adolescent female rats, the impact of different stressors (restraint stress [RS], footshock [FS], or the combination of FS and RS [FS+RS]) on social interaction (3-chamber social approach test/SAT), anxiety responses (elevated plus-maze/EPM), cognitive function (novel object recognition test/NOR), and dopamine (DA) system responsivity by evaluating locomotor response to amphetamine and in vivo extracellular single unit recordings of DA neurons in the ventral tegmental area (VTA) in adulthood. The impact of FS+RS during early adulthood was also investigated. Adolescent stress had no impact on social behavior, anxiety, cognition and locomotor response to amphetamine. In addition, adolescent stress did not induce long-lasting changes in VTA DA system activity. However, a decrease in the firing rate of VTA DA neurons was found 1–2 weeks post-adolescent stress. Similar to adolescent stress, adult stress did not induce long-lasting behavioral deficits and changes in VTA DA system activity, but FS+RS decreased VTA DA neuron population activity 1–2 weeks post-adult stress. Our results are consistent with previous studies showing that female rodents appear to be more resilient to developmental stress-induced persistent changes than males and may contribute to the delayed onset and lesser severity of schizophrenia in females. [ABSTRACT FROM AUTHOR]

Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition. [ABSTRACT FROM AUTHOR]

Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization with film and grain analyses, CB1R messenger RNA (mRNA) levels were quantified in multiple brain regions, including the medial prefrontal cortex (mPFC), secondary motor cortex, dorsomedial and dorsolateral striatum, dorsal subregions and ventral subiculum of the hippocampus, of MAM-treated rats and normal controls at three developmental periods [juvenile - postnatal day (PD) 30; adolescence - PD45; and adulthood - PD85]. In all brain regions studied, CB1R mRNA levels were highest in juveniles and then decreased progressively toward adolescent and adult levels in control and MAM-treated rats. However, in MAM-treated rats, CB1R mRNA levels were lower in the mPFC at PD85 and higher in the dorsolateral striatum at PD45 and PD85 relative to controls. Cellular analyses confirmed the changes in CB1R mRNA expression in MAM-treated rats. These findings are in accordance with previous studies showing a decrease in the CB1R mRNA expression from juvenile period to adolescence to adulthood in cortical, striatal, and hippocampal regions. Additionally, similar to most of the schizophrenia-like signs observed in the MAM model, embryonic exposure to MAM leads to schizophrenia-related changes in CB1R mRNA expression that only emerge later in development. [ABSTRACT FROM AUTHOR]

This Editorial highlights an article by Gulchina and colleagues in the current issue of the Journal of Neurochemistry, in which the authors describe molecular and epigenetic changes in the developing prefrontal cortex of the rats exposed to methylazoxymethanol acetate (MAM). They found an NMDAR hypofunction present in the prefrontal cortex of juvenile MAM rats which was associated with abnormal epigenetic regulation of the Grin2b gene. These changes may be related to early cognitive impairments observed in MAM rats and schizophrenia patients. [ABSTRACT FROM AUTHOR]

Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here. [ABSTRACT FROM AUTHOR]

Adolescence is a time of extensive neuroanatomical, functional and chemical reorganization of the brain, which parallels substantial maturational changes in behavior and cognition. Environmental factors that impinge on the timing of these developmental factors, including stress and drug exposure, increase the risk for psychiatric disorders. Indeed, antecedents to affective and psychotic disorders, which have clinical and pathophysiological overlap, are commonly associated with risk factors during adolescence that predispose to these disorders. In the context of schizophrenia, psychosis typically begins in late adolescence/early adulthood, which has been replicated by animal models. Rats exposed during gestational day (GD) 17 to the mitotoxin methylazoxymethanol acetate (MAM) exhibit behavioral, pharmacological, and anatomical characteristics consistent with an animal model of schizophrenia. Here we provide an overview of adolescent changes within the dopamine system and the PFC and review recent findings regarding the effects of stress and cannabis exposure during the peripubertal period as risk factors for the emergence of schizophrenia-like deficits. Finally, we discuss peripubertal interventions appearing to circumvent the emergence of adult schizophrenia-like deficits. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4'-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are one of the leading causes of disability worldwide. Although several therapeutic options are available, the exact mechanisms responsible for the genesis of these disorders remain to be fully elucidated. In the last decade, a body of evidence has supported the involvement of the immune system in the pathophysiology of these conditions. Microglial cells play a significant role in maintaining brain homeostasis and surveillance. Dysregulation of microglial functions has been associated with several psychiatric conditions. Cannabinoids regulate the brain-immune axis and inhibit microglial cell activation. Here, we summarized evidence supporting the hypothesis that microglial cells could be a target for cannabinoid influence on psychiatric disorders, such as anxiety, depression, schizophrenia, and stress-related disorders. [ABSTRACT FROM AUTHOR]

Background: Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801. Methods: Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1 mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60 mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1 mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calciumbinding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Results: MK-801 administration at the dose of 1 mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60 mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. Conclusions: These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimeticlike effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties. [ABSTRACT FROM AUTHOR]

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder. [ABSTRACT FROM AUTHOR]

[Display omitted] The intricate balance between excitation and inhibition (E/I) in the brain plays a crucial role in normative information processing. Dysfunctions in the E/I balance have been implicated in various psychiatric disorders, including schizophrenia (SCZ). In particular, abnormalities in GABAergic signaling, specifically in parvalbumin (PV)-containing interneurons, have been consistently observed in SCZ pathophysiology. PV interneuron function is vital for maintaining an ideal E/I balance, and alterations in PV interneuron-mediated inhibition contribute to circuit deficits observed in SCZ, including hippocampus hyperactivity and midbrain dopamine system overdrive. While current antipsychotic medications primarily target D2 dopamine receptors and are effective primarily in treating positive symptoms, novel therapeutic strategies aiming to restore the E/I balance could potentially mitigate not only positive symptoms but also negative symptoms and cognitive deficits. This could involve, for instance, increasing the inhibitory drive onto excitatory neurons or decreasing the putative enhanced pyramidal neuron activity due to functional loss of PV interneurons. Compounds targeting the glycine site at glutamate NMDA receptors and muscarinic acetylcholine receptors on PV interneurons that can increase PV interneuron drive, as well as drugs that increase the postsynaptic action of GABA, such as positive allosteric modulators of α5-GABA-A receptors, and decrease glutamatergic output, such as mGluR2/3 agonists, represent promising approaches. Preventive strategies aiming at E/I balance also represent a path to reduce the risk of transitioning to SCZ in high-risk individuals. Therefore, compounds with novel mechanisms targeting E/I balance provide optimism for more effective and tailored interventions in the management of SCZ. [ABSTRACT FROM AUTHOR]

Background: Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing, or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia. Methods: This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2mg/kg) was extended over 25 days throughout puberty (postnatal days 40–65) in control and MAM rats. The rats received 20 injections, which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons. Results: MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration, and an increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats (Sal). Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states. Conclusions: Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted. [ABSTRACT FROM AUTHOR]

Despite attenuating the positive symptoms, drugs currently used to treat schizophrenia frequently do not improve the negative symptoms and cognitive impairments. In addition, they show low tolerability, which has been associated with high rates of treatment discontinuation. Recent evidence suggests that the endocannabinoid system may be a target for schizophrenia treatment. The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients. Here, we aimed to evaluate whether HU-910, a selective CB2 receptor agonist, would reverse schizophrenia-related behavioral changes observed after the acute injections of amphetamine or the N -methyl- d -aspartate receptor (NMDAR) antagonist MK-801. We also investigated the effects of HU-910 in the memory impairment caused by repeated MK-801 administration. Finally, we tested whether HU-910 would produce the cannabinoid tetrad (catalepsy, hypolocomotion, hypothermia, and antinociception). In male C57BL/6 mice, the acute treatment with HU-910 (30 mg/kg) prevented the hyperlocomotion induced by acute MK-801. This effect was blocked by the CB2 receptor antagonist AM630 (1 mg/kg). On the contrary, HU-910 did not prevent the increased locomotor activity caused by acute amphetamine. The acute treatment with HU-910 (3, 10, and 30 mg/kg) also attenuated the impairments in the prepulse inhibition test induced by acute MK-801 and amphetamine. The repeated treatment with HU-910 attenuated the cognitive impairment caused by chronic administration of MK-801 in the novel object recognition test. Furthermore, HU-910 did not produce the cannabinoid tetrad. These results indicate that HU-910 produced antipsychotic-like effects and support further research on the potential therapeutic properties of this compound to treat schizophrenia. • HU-910 decreased acute MK-801-induced hyperlocomotion and attenuated PPI disruption induced by amphetamine and MK-801. • HU-910 attenuated impairments in the novel object recognition test induced by repeated MK-801. • AM630, a CB2 receptor antagonist, prevented HU-910 effects in MK-801-induced hyperlocomotion • HU-910 did not produce the cannabinoid tetrad [ABSTRACT FROM AUTHOR]

Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABA A receptors (α5-GABA A R), which are expressed mainly by pyramidal neurons in the hippocampus, have been proposed as a potential target to treat these psychiatric disorders. Here, we evaluated the effects produced by GL-II-73 and SH-053–2′F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of α5-GABA A R in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties in male and female C57BL/6 mice. In both males and females, GL-II-73 produced an anxiolytic-like effect in the elevated plus-maze (EPM) and novelty-suppressed feeding and a rapid and sustained antidepressant-like effect in the forced swim test. GL-II-73 also induced antipsychotic-like effects in males indicated by attenuating MK-801-induced hyperlocomotion and prepulse inhibition (PPI) disruption. However, GL-II-73 per se increased locomotor activity and impaired fear memory extinction in males and females and PPI in males. On the other hand, SH-053–2′F-R-CH3 induced anxiolytic-like effects in the EPM and facilitated fear memory extinction in males. Contrary to GL-II-73, SH-053–2′F-R-CH3 attenuated MK-801-induced hyperlocomotion and PPI disruption in females but not in males. Neither of these drugs induced rewarding effects or impaired motor coordination. These findings suggest that GL-II-73 and SH-053–2′F-R-CH3 cause distinct sex-dependent behavioral responses and support continued preclinical research on the potential of positive allosteric modulators of α5-GABA A R for the treatment of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Abstract: The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14–18, 2012 and this year had as its emphasis, “The Globalization of Research”. Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research. [Copyright &y& Elsevier]