Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group (p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine (p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 (p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST (p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group (p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group (p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD.

Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to analyze the changes in blood pressure (BP) and heart rate (HR) during 14 days of treatment with two different acetylcholinesterase inhibitors - pyridostigmine (PYR) having only peripheral effects or donepezil (DON) with both peripheral and central effects. In addition, we studied their effects on the cardiovascular response to restraint stress and on sympathovagal control of HR in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). SHR were characterized by elevated BP and increased low-frequency component of systolic BP variability (LF-SBPV), but their cardiac vagal tone and HR variability (HRV) were reduced compared with WKY. Chronic treatment with either acetylcholinesterase inhibitor decreased HR and increased HRV in both strains. PYR treatment slightly decreased BP and LF-SBPV in the dark phase of the day. Neither drug significantly altered BP response to stress, but PYR attenuated HR increase during restraint stress. Regarding sympathovagal balance, acute methylatropine administration caused a greater increase of HR in WKY than in SHR. Chronic PYR or DON treatment enhanced HRV and HR response to methylatropine (vagal tone) in WKY, whereas PYR but not DON treatment potentiated HRV and vagal tone in SHR. In conclusion, vagal tone was lower in SHR compared with WKY, but was enhanced by chronic PYR treatment in both strains. Thus, chronic peripheral, but not central, acetylcholinesterase inhibition has major effects on HR and its variability in both normotensive and hypertensive rats.

Premenstrual Dysphoric Disorder (PMDD) is related to an abrupt drop in progesterone and impairments in the HPA axis that cause anxiety. Suffering persons report higher daily-life stress and anxiety proneness that may contribute to developing PMDD, considered a chronic stress-related disorder. Here, we explored the effect of chronic unpredictable stress (CUS) in rats subjected to progesterone withdrawal (PW) and evaluated gene expression of HPA axis activation in the stress-vulnerable Wistar-Kyoto (WKY) rat strain that is prone to anxiety. Ovariectomized WKY rats were randomly assigned to CUS or Standard-housed conditions (SHC) for 30 days. To induce PW, animals received 2 mg/kg of progesterone on day 25th for 5 days; 24 h later, they were tested using the anxiety-like burying behavior test (BBT). After behavioral completion, rats were euthanized, and brains were extracted to measure Crh (PVN) and Nr3c1 (hippocampus) mRNA. Blood corticosterone and vasopressin levels were determined. Results showed that PW exacerbated anxiety-like behaviors through passive coping in CUS-WKY. PW decreased Crh-PVN mRNA and the Nr3c1-hippocampal mRNA expression in SHC. CUS decreased Crh-PVN mRNA compared to SHC, and no further changes were observed by PW or BBT exposure. CUS reduced Nr3c1-hippocampal gene expression compared to SHC animals, and lower Nr3c1 mRNA was detected due to BBT. The PW increased corticosterone in SHC and CUS rats; however, CUS blunted corticosterone when combined with PW+BBT and similarly occurred in vasopressin concentrations. Chronic stress blunts the response of components of the HPA axis regulation when PW and BBT (systemic and psychogenic stressors, respectively) are presented. This response may facilitate less adaptive behaviors through passive coping in stress-vulnerable subjects in a preclinical model of premenstrual anxiety.

Wistar-Kyoto rats (WKY), compared to Wistar rats, are a well-validated animal model for drug-resistant depression. Thanks to this, they can provide information on the potential mechanisms of treatment-resistant depression. Since deep brain stimulation in the prefrontal cortex has been shown to produce rapid antidepressant effects in WKY rats, we focused our study on the prefrontal cortex. Using quantitative autoradiography, we observed a decrease in the binding of [3H] methylspiperone to the dopamine D2 receptor, specifically in that brain region-but not in the striatum, nor the nucleus accumbens-in WKY rats. Further, we focused our studies on the expression level of several components associated with canonical (G proteins), as well as non-canonical, D2-receptor-associated intracellular pathways (e.g., βarrestin2, glycogen synthase kinase 3 beta-Gsk-3β, and β-catenin). As a result, we observed an increase in the expression of mRNA encoding the regulator of G protein signaling 2-RGS2 protein, which is responsible, among other things, for internalizing the D2 dopamine receptor. The increase in RGS2 expression may therefore account for the decreased binding of the radioligand to the D2 receptor. In addition, WKY rats are characterized by the altered signaling of genes associated with the dopamine D2 receptor and the βarrestin2/AKT/Gsk-3β/β-catenin pathway, which may account for certain behavioral traits of this strain and for the treatment-resistant phenotype.

BACKGROUND: Structural MRI has demonstrated brain alterations in depression pathology and antidepressants treatment. While synaptic plasticity has been previously proposed as the potential underlying mechanism of MRI findings at a cellular and molecular scale, there is still insufficient evidence to link the MRI findings and synaptic plasticity mechanisms in depression pathology.
METHODS: In this study, a Wistar-Kyoto (WKY) depression rat model was treated with antidepressants (citalopram or Jie-Yu Pills) and tested in a series of behavioral tests and a 7.0 MRI scanner. We then measured dendritic spine density within altered brain regions. We also examined expression of synaptic marker proteins (PSD-95 and SYP).
RESULTS: WKY rats exhibited depression-like behaviors in the sucrose preference test (SPT) and forced swim test (FST), and anxiety-like behaviors in the open field test (OFT). Both antidepressants reversed behavioral changes in SPT and OFT but not in FST. We found a correlation between SPT performance and brain volumes as detected by MRI. All structural changes were consistent with alterations of the corpus callosum (white matter), dendritic spine density, as well as PSD95 and SYP expression at different levels. Two antidepressants similarly reversed these macro- and micro-changes.
CONCLUSIONS: The single dose of antidepressants was the major limitation of this study. Further studies should focus on the white matter microstructure changes and myelin-related protein alterations, in addition to comparing the effects of ketamine.
CONCLUSIONS: Translational evidence links structural MRI changes and synaptic plasticity alterations, which promote our understanding of SPT mechanisms and antidepressant response in WKY rats.

Alpha-terpineol (TPN) is one of the major components of the resin obtained from Protium heptaphyllum. This plant has been utilized as medicine by Brazilian indigenous tribes to treat cardiovascular diseases. Scientific reports have shown that the TPN possesses vasorelaxant and antihypertensive effects. This study was conducted to assess the cardioprotective action of TPN against isoproterenol (ISO)-induced cardiotoxicity. Wistar rats were randomly divided into six groups. Rats were orally administered with TPN (25, 50, and 75 mg/kg, respectively) for 15 days, and ISO was administered (85 mg/kg, subcutaneously) on the 14th and 15th days. At the end of the experiment, the hemodynamic, baroreflex test, ECG, biochemical, histological, and morphometric changes were monitored from control and experimental groups, i.e., on the 15th day. ISO-induced myocardial infarcted rats showed an increase in mortality rates, cardiac marker enzymes, tachycardia, hypertrophy, myocardium necrosis, edema, hemorrhagic areas, infiltration of inflammatory cells like lymphocytes, and increased myocardial infarct size. However, pretreatment with TPN significantly inhibited these effects of ISO. The histopathological findings obtained for the myocardium further confirmed the biochemical results. Thus, the present study provides evidence for the efficacy of TPN against ISO-induced myocardial infarction in rats.

The Wistar-Kyoto (WKY) rat was developed as a control for the spontaneous hypertensive rat but has subsequently also been used as a genetic animal model of depression due to its hyper-responsiveness to stress. We used anticipation of social reward (i.e., a play partner) to assess behavioural and vocal differences between the WKY and normal Wistar (WI) rats in the juvenile period. We found marked differences between groups; the WKY rats, were less active, vocalized less, and used significantly fewer types of 50-kHz calls in comparison to their WI counterparts. The animals were re-tested in adulthood and the same differences existed in overall activity, types of vocalizations and the behavioural vocal profiles used by the two groups of animals. These findings provide a robust baseline for an animal model of depression using a social paradigm. This paradigm may be useful to evaluate the efficacy of pharmaceutical interventions as potential treatments of depression in WKY rats.

Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity, and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar-Kyoto rats were treated chronically or acutely with caffeine, a non-selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212-2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased, whereas treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB1 receptor-mediated increase in impulsive behavior. An acute pre-treatment with caffeine blocked WIN effects. Conversely, a chronic treatment with caffeine increased the impulsive phenotype and potentiated the WIN effects. The results indicate that both cannabinoid and adenosine receptors modulate impulsive behavior in SHR: the antagonism of cannabinoid receptors might be effective in reducing impulsive symptoms present in ADHD; in addition, caffeine showed the opposite effects on impulsive behavior depending on the length of treatment. These observations are of particular importance to consider when therapeutic manipulation of CB1 receptors is applied to ADHD patients who consume coffee.

Aside from its clinical symptoms of inattention, impulsivity and hyperactivity, patients with Attention/Deficit-Hyperactivity Disorder (ADHD) display reward and motivational impairments. These impairments may reflect a deficit in action control, that is, an inability to flexibly adapt behavior to changing consequences. We previously showed that spontaneously hypertensive rats (SHR), an inbred rodent model of ADHD, show impairments in goal-directed action control, and instead are predominated by habits. In this study, we examined the effects of specific dopamine receptor sub-type (D1 and D2) agonists and antagonists on goal-directed behavior in SHR and the normotensive inbred control strain Wistar-Kyoto (WKY) rats. Rats acquired an instrumental response for different-flavored food rewards. A selective-satiety outcome devaluation procedure followed by a choice test in extinction revealed outcome-insensitive habitual behavior in SHR rats. Outcome-sensitive goal-directed behavior was restored in SHR rats following injection prior to the choice test of the dopamine D2 receptor agonist Quinpirole or dopamine D1 receptor antagonist SCH23390, whereas WKY rats showed habitual responding following exposure to these drugs. This novel finding indicates that the core behavioral deficit in ADHD might not be a consequence of dopamine hypofunction, but rather is due to a misbalance between activation of dopamine D1 and D2 receptor pathways that govern action control.

Stroke is one of the leading causes of mortality and morbidity worldwide, and few therapeutic treatments have shown beneficial effect clinically. One reason for this could be the lack of risk factors incorporated into the preclinical stroke research. We have previously demonstrated phenotypic receptor changes to be one of the injurious mechanisms occurring after stroke but mostly in healthy rats. The aim of this study was to investigate if hypertension has an effect on vasoconstrictive receptor responses to endothelin 1, sarafotoxin 6c and angiotensin II after stroke by inducing transient middle cerebral artery occlusion in spontaneously hypertensive rats and Wistar-Kyoto rats using the wire-myograph. We demonstrated an increased contractile response to endothelin 1 and extracellular potassium as well as an increased carbachol-induced dilator response in the middle cerebral arteries from hypertensive rats after stroke. This study demonstrates the importance of including risk factors in experimental stroke research.