Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT and testosterone.

Background: Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated.

Serotonin 5-HT receptors mediate the antidepressant- and anxiolytic-like effects of ventromedial prefrontal cortex deep brain stimulation in a mouse model of social defeat.

Background: Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) induces antidepressant- and anxiolytic-like responses in various animal models. Electrophysiology and neurochemical studies suggest that these effects may be dependent, at least in part, on the serotonergic system. In rodents, vmPFC DBS reduces raphe cell firing and increases serotonin (5-HT) release and the expression of serotonergic receptors in different brain regions.

Sex differences in long-term fear and anxiety-like responses in a preclinical model of PTSD.

With a high prevalence of posttraumatic stress disorder (PTSD) in females, studying sex differences in preclinical models is of substantial importance. We have previously employed behavioural criteria to identify and characterize a subpopulation of rats that presented impaired fear extinction and long-term fear and anxiety responses following fear conditioning. We now exposed male and female rats to fear conditioning and extinction and segregated the animals into weak- (WE) and strong-extinction (SE) groups based on behavioural scores during extinction.

Investigating the role of CB1 endocannabinoid transmission in the anti-fear and anxiolytic-like effects of ventromedial prefrontal cortex deep brain stimulation.

Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) of rats induces anti-fear and anxiolytic-like behaviours, while reducing principal cell firing in the basolateral amygdala (BLA). In parallel, the endocannabinoid system, particularly in the vmPFC and BLA, has emerged as a target for the amelioration of fear and stress-related behaviours. We tested whether DBS-related improvements in fear and anxiety-type behaviour are mediated by endocannabinoid signalling.

Comprehensive Investigation of Metabolic Changes Occurring in the Rat Brain Hippocampus after Fluoxetine Administration Using Two Complementary In Vivo Techniques: Solid Phase Microextraction and Microdialysis.

Fluoxetine is among the most prescribed antidepressant drugs worldwide. Nevertheless, limited information is known about its definitive mechanism. Although in vivo examinations performed directly in related brain structures can provide more realistic, and therefore more insightful, knowledge regarding the mechanisms and efficacy of this drug, only a few techniques are applicable for in vivo monitoring of metabolic alterations in the brain following an inducement.

Investigation of Early Death-Induced Changes in Rat Brain by Solid Phase Microextraction via Untargeted High Resolution Mass Spectrometry: versus Postmortem Comparative Study.

Analysis of brain samples obtained postmortem remains a standard approach in neuroscience, despite often being suboptimal for inferring roles of small molecules in the pathophysiology of brain diseases. Sample collection and preservation further hinders conclusive interpretation of biomarker analysis in autopsy samples. We investigate purely death-induced changes affecting rat hippocampus in the first hour of postmortem interval (PMI) by means of untargeted liquid chromatography-mass spectrometry-based metabolomics.

Endocannabinoid modulating drugs improve anxiety but not the expression of conditioned fear in a rodent model of post-traumatic stress disorder.

The endocannabinoid (eCB) system is a potential target for the treatment of symptoms of post-traumatic stress disorder (PTSD). Similar to clinical PTSD, approximately 25-30% of rats that undergo cued fear conditioning exhibit impaired extinction learning. In addition to extinction-resistant fear, these "weak extinction" (WE) rats show persistent anxiety-like behaviors.

A Key Role for Prefrontocortical Small Conductance Calcium-Activated Potassium Channels in Stress Adaptation and Rapid Antidepressant Response.

The muscarinic acetylcholine receptor antagonist scopolamine elicits rapid antidepressant activity, but its underlying mechanism is not fully understood. In a chronic stress model, a single low-dose administration of scopolamine reversed depressive-like reactivity. This antidepressant-like effect was mediated via a muscarinic M1 receptor-SKC pathway because it was mimicked by intra-medial prefrontal cortex (intra-mPFC) infusions of scopolamine, of the M1 antagonist pirenzepine or of the SKC antagonist apamin, but not by the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine.

Ethanol-induced changes in synaptic amino acid neurotransmitter levels in the nucleus accumbens of differentially sensitized mice.

Rationale: Ethanol-induced behavioural sensitization (EBS) does not occur uniformly in mice exposed to the sensitization paradigm. This suggests innate differential responses to ethanol (EtOH) in the reward circuitry of individual animals.

Objectives: To better characterize the adaptive differences between low-sensitized (LS) and high-sensitized (HS) mice, we examined excitatory amino acid (EAA) and inhibitory amino acid (IAA) neurotransmitter levels in the nucleus accumbens (NAc) during EBS expression.

In Vivo Brain Sampling Using a Microextraction Probe Reveals Metabolic Changes in Rodents after Deep Brain Stimulation.

Brain metabolomics is an emerging field that complements the more traditional approaches of neuroscience. However, typical brain metabolomics workflows require that animals be sacrificed and tend to involve tedious sample preparation steps. Microdialysis, the standard technique to study brain metabolites in vivo, is encumbered by significant limitations in the analysis of hydrophobic metabolites, which are prone to adsorption losses on microdialysis equipment.

Rostrocaudal subregions of the ventral tegmental area are differentially impacted by chronic stress.

Rationale: The ventral tegmental area (VTA) is implicated in the pathophysiology of depression and addictive disorders and is subject to the detrimental effects of stress. Chronic stress may differentially alter the activity pattern of its different subregions along the rostrocaudal and dorsoventral axes, which may relate to the variable behavioral sensitivity to stress mediated by these subregions.

Objectives: Here, chronic stress-exposed rats were tested for depressive-like reactivity.

High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: involvement of the prefrontal cortex and dorsal raphe?

Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping.

Deep brain stimulation and fluoxetine exert different long-term changes in the serotonergic system.

Both selective serotonin reuptake inhibitors (SSRIs) and ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) modulate serotonergic activity. We compared the acute (1 day) and long-term (12 days) effects of vmPFC stimulation and fluoxetine on serotonin (5-HT) release and receptor expression in rats. Samples to measure serotonin levels were collected from the hippocampus using microdialysis.

Deep brain stimulation induces antidepressant-like effects in serotonin transporter knockout mice.

Background: Some of the antidepressant-like effects of ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) in rodents have been attributed to the modulation of prefrontal-raphe pathways. This is largely different from selective serotonin reuptake inhibitors (SSRIs), which increase serotonin (5-HT) levels by inhibiting the serotonin transporter (SERT). SSRIs have limited efficacy when given to SERT knockout (KO) mice, or patients with mutations in the serotonin transporter promoter gene (5-HTTLPR).

Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia.

Dystonia is a hyperkinetic disabling movement disorder. In the dt(sz) hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective KV7.

Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release.

Background: Medial forebrain bundle (MFB) deep brain stimulation (DBS) is currently being investigated in patients with treatment-resistant depression. Striking features of this therapy are the large number of patients who respond to treatment and the rapid nature of the antidepressant response.

Objective: To study antidepressant-like behavioral responses, changes in regional brain activity, and monoamine release in rats receiving MFB DBS.

Towards a better preclinical model of PTSD: characterizing animals with weak extinction, maladaptive stress responses and low plasma corticosterone.

Most of the available preclinical models of PTSD have focused on isolated behavioural aspects and have not considered individual variations in response to stress. We employed behavioural criteria to identify and characterize a subpopulation of rats that present several features analogous to PTSD-like states after exposure to classical fear conditioning. Outbred Sprague-Dawley rats were segregated into weak- and strong-extinction groups on the basis of behavioural scores during extinction of conditioned fear responses.

Deep brain stimulation in rats: different targets induce similar antidepressant-like effects but influence different circuits.

Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens.

Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats.

Background: Clinical trials have shown promising results with the use of subcallosal cingulate gyrus deep brain stimulation (DBS) for treatment-resistant depression. However, strategies to manage patients who do not respond to this therapy have not been explored in detail. In rats, DBS in the ventromedial prefrontal cortex (vmPFC) induces a significant antidepressant-like response in the forced swim test (FST).

Supraorbital stimulation does not induce an antidepressant-like response in rats.

Background: Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve.

Objective: To show that supraorbital stimulation is effective in preclinical models.

Antagonizing 5-HT₂A receptors with M100907 and stimulating 5-HT₂C receptors with Ro60-0175 blocks cocaine-induced locomotion and zif268 mRNA expression in Sprague-Dawley rats.

Serotonin (5-HT) plays a role in several psychiatric disorders including drug addiction. The 5-HT system modulates the activity of midbrain dopamine (DA) systems, and the behavioural effects of psychostimulants mediated by these systems. The direction of this modulation depends upon the 5-HT receptor subtypes involved, with 5-HT(2A) and 5-HT(2C) receptors having opposing effects.

Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects.

We report that coupling between dopamine D1 and D2 receptors was markedly increased in postmortem brain of subjects suffering from major depression. Biochemical analyses revealed that D1 and D2 receptors form heterodimers via a direct protein-protein interaction. Administration of an interfering peptide that disrupts the D1-D2 receptor complex substantially reduced immobility in the forced swim test (FST) without affecting locomotor activity, and decreased escape failures in learned helplessness tests in rats.