Dorsal and ventral hippocampus modulate autonomic responses but not behavioral consequences associated to acute restraint stress in rats.

Recent evidence has suggested that the dorsal (DH) and the ventral (VH) poles of the hippocampus are structurally, molecularly and functionally different regions. While the DH is preferentially involved in the modulation of spatial learning and memory, the VH modulates defensive behaviors related to anxiety. Acute restraint is an unavoidable stress situation that evokes marked and sustained autonomic changes, which are characterized by elevated blood pressure (BP), intense heart rate (HR) increases, skeletal muscle vasodilatation and cutaneous vasoconstriction, which are accompanied by a rapid skin temperature drop followed by body temperature increases. In addition to those autonomic responses, animals submitted to restraint also present behavioral changes, such as reduced exploration of the open arms of an elevated plus-maze (EPM), an anxiogenic-like effect. In the present work, we report a comparison between the effects of pharmacological inhibition of DH and VH neurotransmission on autonomic and behavioral responses evoked by acute restraint stress in rats. Bilateral microinjection of the unspecific synaptic blocker cobalt chloride (CoCl2, 1mM) into the DH or VH attenuated BP and HR responses, as well as the decrease in the skin temperature, elicited by restraint stress exposure. Moreover, DH or VH inhibition before restraint did not change the delayed increased anxiety behavior observed 24 h later in the EPM. The present results demonstrate for the first time that both DH and VH mediate stress-induced autonomic responses to restraint but they are not involved in the modulation of the delayed emotional consequences elicited by such stress

Effects of bilateral microinjection of 200 nL of vehicle (n=6/ DH and VH) or 1 mM of CoCl₂ (n=6/ DH and VH) administered into DH or VH immediately before a 1-h restraint period on behavior observed 24 h later in the elevated plus-maze (EPM).

<p>A non-stressed group was used as control. Columns represent the means and the bars the SEM. *P<0.05, Bonferroni’s post-hoc test.</p

Time-course of bilateral microinjection of 200 nL of vehicle (n=6/ DH and VH) or 1 mM of CoCl₂ (Cobalt, n=6/ DH and VH) administered into DH or VH on changes in mean arterial pressure (∆MAP), heart rate (∆HR) and cutaneous temperature (∆Temp) of animals submitted to 60 min of restraint stress.

<p>Symbols represent the means and bars the SEM. *P<0.05, Bonferroni’s post-hoc test.</p

Infrared digital images of representative rats which received either CoCl2 (indicated by A) or vehicle (indicated by B) into DH, in its home cage and during the first minute, thirty and sixty minutes of restraint.

<p>Note the drop in cutaneous tail temperature during the restraint in vehicle treated animal and the absence of this drop in CoCl2 treated animal. The same effects were observed in VH treated animals. All images use the same color-coding for temperature.</p

A diagrammatic representation based on the rat brain atlas of Paxinos and Watson (1997) indicating injections sites of vehicle or CoCl₂ (closed circle) into the Dorsal Hippocampus (DH) and Ventral Hippocampus (VH).

<p>cc- corpus callosum; IA- Inter aural.</p

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders

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

<b>Repeated cannabidiol treatment affects neuroplasticity and endocannabinoid signaling in the prefrontal cortex of a rat model of depression</b>

Delayed therapeutic responses and limited efficacy are the main challenges of existing antidepressant drugs, thereby incentivizing the search for new potential treatments. Cannabidiol (CBD), a non-psychostimulant component of cannabis, has shown promising antidepressant effects in different rodent models, but its mechanism of action remains unclear. Herein, we investigated the antidepressant-like effects of repeated CBD treatment on behavior, neuroplasticity markers and lipidomic (endocannabinoid) profile in the prefrontal cortex (PFC) of Flinders Sensitive Line (FSL), an animal model of depression, along with their control counterparts, the Flinders Resistant Line (FRL) rats. Male FSL animals were treated with CBD (10 mg/kg; i.p.) or vehicle (7 days) followed by Open Field Test (OFT) and the Forced Swimming Test (FST). The PFC was analyzed by a) western blotting to assess markers of synaptic plasticity and cannabinoid signaling in synaptosome and cytosolic fractions (CB1, CB2, CaMKII, Akt, eEF2, GSK-3β, ERK1, ERK2, mGluR5, PSD95, Synaptophysin, BDNF, TrkB); b) mass spectrometry-based lipidomics to investigate endocannabinoid levels (eCB). CBD attenuated the increased immobility observed in FSL, compared to FRL in FST, without changing the locomotor behavior in the OFT. In synaptosomes, CBD increased ERK1, mGluR5, and Synaptophysin, but failed to reverse the reduced CB1 and CB2 levels in FSL rats. In the cytosolic fraction, CBD increased ERK2 and decreased mGluR5 expression in FSL rats. Surprisingly, there were no significant changes in eCB levels in response to CBD treatment. These findings suggest that CBD effects in FSL animals are associated with changes in synaptic plasticity markers involving mGluR5, ERK1, ERK2, and synaptophysin signaling in the PFC, without increasing the levels of endocannabinoids in this brain region.</p