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Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativacomponent. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01–3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15–60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects.

The nucleus reuniens of the thalamus (RE) is a pivotal area responsible for the connectivity of the prefrontal-hippocampus pathway that regulates cognitive, executive, and fear learning processes. Recently, it was proposed that the RE participates in the pathophysiological states related to affective dysregulation. We investigated the role of RE in motivational behavioral and electrophysiological dysregulation induced by stress. Adult Sprague-Dawley rats were exposed to a combination of stressors (restraint stress+footshock) for 10 days and tested one to two weeks later in the forced swim test (FST), ventral tegmental area (VTA)dopamine (DA) neuron electrophysiological activity, and hippocampal-nucleus accumbens plasticity. The RE was inactivated by injecting TTX prior to the procedures. The stress exposure increased the immobility in the FST and decreased VTA DA neuron population activity. Whereas an early long-term potentiation (e-LTP) in the ventral hippocampus-nucleus accumbens pathway was found after fimbria high-frequency stimulation in naïve animals, stressed animals showed an early long-term depression (e-LTD). Inactivation of the RE reversed the stress-induced changes in the FST and restored dopaminergic activity. RE inactivation partially recovered the stress-induced abnormal hippocampal-accumbens plasticity observed in controls. Our findings support the role of the RE in regulating affective dysregulation and blunted VTA DA system function induced by stress. Also, it points to the hippocampal-accumbens pathway as a potential neural circuit through which RE could modulate activity. Therefore, RE may represent a key brain region involved in the neurobiology of amotivational states and may provide insights into circuit dysfunction and markers of the maladaptive stress response.

Stress is a socio-environmental risk factor for the development of psychiatric disorders, with the age of exposure potentially determining the outcome. Several brain regions mediate stress responsivity, with a prominent role of the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) and their reciprocal inhibitory connectivity. Here we investigated the impact of stress exposure during adolescence and adulthood on the activity of putative pyramidal neurons in the BLA and corticoamygdalar plasticity using in vivo electrophysiology. 155 male Sprague-Dawley rats were subjected to a combination of footshock/restraint stress in either adolescence (postnatal day 31–40) or adulthood (postnatal day 65–74). Both adolescent and adult stress increased the number of spontaneously active putative BLA pyramidal neurons 1–2 weeks, but not 5–6 weeks post stress. High-frequency stimulation (HFS) of BLA and mPFC depressed evoked spike probability in the mPFC and BLA, respectively, in adult but not adolescent rats. In contrast, an adult-like BLA HFS-induced decrease in spike probability of mPFC neurons was found 1–2 weeks post-adolescent stress. Changes in mPFC and BLA neuron discharge were found 1–2 weeks post-adult stress after BLA and mPFC HFS, respectively. All these changes were transient since they were not found 5–6 weeks post adolescent or adult stress. Our findings indicate that stress during adolescence may accelerate the development of BLA–PFC plasticity, probably due to BLA hyperactivity, which can also disrupt the reciprocal communication of BLA–mPFC after adult stress. Therefore, precocious BLA–mPFC connectivity alterations may represent an early adaptive stress response that ultimately may contribute to vulnerability to adult psychiatric disorders.

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAAand NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5GABAAreceptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.

Unregulated stress during critical periods of development is proposed to drive deficits consistent with schizophrenia in adults. If accurate, reopening the critical period could make the adult susceptible to pathology. We evaluated the impact of early adolescent and adult stress exposure (combination of daily footshock for 10 days and 3 restraint sessions) on (1) midbrain dopamine (DA) neuron activity, (2) ventral hippocampal (vHipp) pyramidal neuron activity, and (3) the number of parvalbumin (PV) interneurons in the vHipp and their associated perineuronal nets (PNNs). Ventral tegmental area (VTA) DA neuron population activity and vHipp activity was increased 1–2 and 5–6 weeks post-adolescent stress, along with a decrease in the number of PV+, PNN+, PV?+?/PNN?+?cells in the vHipp, which are consistent with the MAM model of schizophrenia. In contrast, adult stress decreased VTA DA neuron population activity only at 1–2 weeks post stress, which is consistent with what has been observed in animal models of depression, without impacting vHipp activity and PV/PNN expression. Administration of valproate (VPA), which can re-instate the critical period of plasticity via histone deacetylase (HDAC) inhibition, caused adult stress to produce changes similar to those induced by adolescent stress, presumably by increasing stress vulnerability to early adolescent levels. Our findings indicate that timing of stress is a critical determinant of the pathology produced in the adult: adolescent stress led to circuit deficits that recapitulates schizophrenia, whereas adult stress induced a depression-like hypodopaminergic state. Reopening the critical period in the adult restores vulnerability to stress-induced pathology resembling schizophrenia.

Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socio-environmental factors and coinciding with the incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with a dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area (VTA) dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, recreates an adolescent-like phenotype of stress susceptibility.

A correction to this paper has been published and can be accessed via a link at the top of the paper.