Effect of dexmedetomidine on cardiorespiratory regulation in spontaneously breathing adult rats

Purpose We examined the cardiorespiratory effect of dexmedetomidine, an α2- adrenoceptor/imidazoline 1 (I1) receptor agonist, in spontaneously breathing adult rats. Methods Male rats (226−301 g, n = 49) under isoflurane anesthesia had their tail vein cannulated for drug administration and their tail artery cannulated for analysis of mean arterial pressure (MAP), pulse rate (PR), and arterial blood gases (PaO2, PaCO2, pH). After recovery, one set of rats received normal saline for control recording and was then divided into three experimental groups, two receiving dexmedetomidine (5 or 50 μg·kg−1) and one receiving normal saline (n = 7 per group). Another set of rats was divided into four groups receiving dexmedetomidine (50 μg·kg−1) followed 5 min later by 0.5 or 1 mg∙kg−1 atipamezole (selective α2-adrenoceptor antagonist) or efaroxan (α2-adrenoceptor/I1 receptor antagonist) (n = 6 or 8 per group). Recordings were performed 15 min after normal saline or dexmedetomidine administration. Results Compared with normal saline, dexmedetomidine (5 and 50 μg·kg−1) decreased respiratory frequency (fR, p = 0.04 and < 0.01, respectively), PR (both p < 0.01), and PaO2 (p = 0.04 and < 0.01), and increased tidal volume (both p = 0.049). Dexmedetomidine at 5 μg·kg−1 did not significantly change minute ventilation (V′E) (p = 0.87) or MAP (p = 0.24), whereas dexmedetomidine at 50 μg·kg−1 significantly decreased V′E (p = 0.03) and increased MAP (p < 0.01). Only dexmedetomidine at 50 μg·kg−1 increased PaCO2 (p < 0.01). Dexmedetomidine (5 and 50 μg·kg−1) significantly increased blood glucose (p < 0.01), and dexmedetomidine at 50 μg·kg−1 increased hemoglobin (p = 0.04). Supplemental atipamezole or efaroxan administration similarly prevented the 50 μg·kg−1 dexmedetomidine-related cardiorespiratory changes. Principal conclusion These results suggest that dexmedetomidine-related hypoventilation and hypertension are observed simultaneously and occur predominantly through activation of α2-adrenoceptors, but not I1 receptors, in spontaneously breathing adult rats.

Response Calls Evoked by Playback of Natural 50-kHz Ultrasonic Vocalizations in Rats

Rats are highly social animals known to communicate with ultrasonic vocalizations (USV) of different frequencies. Calls around 50 kHz are thought to represent a positive affective state, whereas calls around 22 kHz are believed to serve as alarm or distress calls. During playback of natural 50-kHz USV, rats show a reliable and strong social approach response toward the sound source. While this response has been studied in great detail in numerous publications, little is known about the emission of USV in response to natural 50-kHz USV playback. To close this gap, we capitalized on three data sets previously obtained and analyzed USV evoked by natural 50-kHz USV playback in male juvenile rats. We compared different rat stocks, namely Wistar (WI) and Sprague-Dawley (SD) and investigated the pharmacological treatment with the dopaminergic D2 receptor antagonist haloperidol. These response calls were found to vary broadly inter-individually in numbers, mean peak frequencies, durations and frequency modulations. Despite the large variability, the results showed no major differences between experimental conditions regarding call likelihood or call parameters, representing a robust phenomenon. However, most response calls had clearly lower frequencies and were longer than typical 50-kHz calls, i.e., around 30 kHz and lasting generally around 0.3 s. These calls resemble aversive 22-kHz USV of adult rats but were of higher frequencies and shorter durations. Moreover, blockade of dopamine D2 receptors did not substantially affect the emission of response calls suggesting that they are not dependent on the D2 receptor function. Taken together, this study provides a detailed analysis of response calls toward playback of 50-kHz USV in juvenile WI and SD rats. This includes calls representing 50-kHz USV, but mostly calls with lower frequencies that are not clearly categorizable within the so far known two main groups of USV in adult rats. We discuss the possible functions of these response calls addressing their communicative functions like contact or appeasing calls, and whether they may reflect a state of frustration. In future studies, response calls might also serve as a new read-out in rat models for neuropsychiatric disorders, where acoustic communication is impaired, such as autism spectrum disorder.

Tactile Stimulation in Adult Rats Modulates Dopaminergic Molecular Parameters in the Nucleus Accumbens Preventing Amphetamine Relapse.

Amphetamine (AMPH) is a psychostimulant drug frequently related to addiction, which is characterized by functional and molecular changes in the brain reward system, favoring relapse development and pharmacotherapies have shown low effectiveness. Considering the beneficial influences of tactile stimulation (TS) in different diseases that affect the central nervous system (CNS), here we evaluated if TS applied in adult rats could prevent or minimize the AMPH-relapse behavior also accessing molecular neuroadaptations in the Nucleus accumbens (NAc). Following AMPH conditioning in the conditioned place preference (CPP) paradigm, male rats were submitted to TS (15-min session, 3 times a day, for 8 days) during the drug abstinence period, which were re-exposed to the drug in the CPP paradigm for additional 3 days for relapse observation and molecular assessment. Our findings showed that besides AMPH relapse; TS prevented the dopamine transporter (DAT), dopamine 1 receptor (D1R), tyrosine hydroxylase (TH), mu opioid receptor (MOR) increase and AMPH-induced delta FosB (ΔFosB). Based on these outcomes, we propose TS as a useful tool to treat psychostimulant addiction, which subsequent to clinical studies; it could be included in detoxification programs together with pharmacotherapies and psychological treatments already conventionally established.

Maternal High-Fat Diet Alters the Characteristics of Astrocytes and Worsens the Outcome of Stroke in Rat Offspring, Which Improves After FGF21 Administration

Background: Maternal high-fat diet (MHFD) has been shown to increase susceptibility to neurological disease in later offspring, but the underlying mechanism is not clear. Fibroblast growth factor 21 (FGF21) has been reported to have a neuroprotective effect in stroke, but its mechanism of action remains unknown. In this study, we investigated the mechanism of the effect of MHFD on stroke in offspring in adulthood and the mechanism by which FGF21 acts on stroke and restores neurological function.Methods: We performed transcriptome sequencing analysis on D21 neonatal rats. Bodyweight and blood indicators were recorded in the adult rats after MHFD. FGF21 was administered 7 h after photochemical modeling twice a day for three consecutive days.Results: We found numerous mRNA changes between the MHFD group and a normal maternal normal diet (MND) group at D21, including genes related to astrocyte and PI3K/Akt pathways. The body weight, blood glucose, and triglycerides of the MHFD offspring were higher, ischemic lesions were larger, the number of activated astrocytes was lower, and the neurological function score was worse than that of the MND group. After FGF21 administration, WB and qPCR analyses showed that astrocytes and the PI3K/Akt pathway were upregulated, while NF-κB and inflammatory cytokines expression were inhibited in stroke and peri-stroke regions.Conclusion: Taken together, we conclude that MHFD alters the characteristics of astrocytes and other transcriptome changes in their offspring, leading to a worse prognosis of stroke, while FGF21 plays a neuroprotective role by inhibiting NF-κB and inflammatory factors and activating the PI3K/Akt pathway and activating more astrocytes in the MND group than the MHFD group.

Prenatal Exposure to Classical Music Improves Learning and Memory in Adult Rats

Background: Exposure to music during pregnancy enhances brain development and improves learning in neonatal rats. Methods: In these experiments, we examined the effects of exposure to silence, hard rock, classical, and rap music in utero plus 60 days postpartum on learning and memory in adult Wistar rats. Passive avoidance learning (PAL) was assessed at age 60 days, and a retention test was done 24 hours after training. Elevated plus maze (EPM) was also used as a standard behavioral task for assessing the effects of music therapy on anxiety. Furthermore, we measured serum corticosterone levels and adrenal weight at the end of experiments to show the possible effect of stress on the rats’ behavior. Results: Hard rock music impaired acquisition, increasing the number of trials to acquisition in PAL task. Hard rock music also impaired the retrieval process by decreasing step-through latency and increasing time spent in the dark compartment during the retention trial. Further, in the hard rock group, there were increases in serum corticosterone and adrenal weight of rats. Classical music, in turn, improved acquisition learning and retention memory and decreased serum corticosterone levels compared to the silence group. Rats’ exposure to rap music did not show any significant change in acquisition and retrieval processes compared to the silence group. In the EPM task, classical music exposure had anxiolytic-like effects revealed in an increase in the number of entries into open arms and time spent in the open arms. However, in this task, hard rock music induced an anxiogenic effect. Conclusions: Prenatal and postnatal exposure to music improves PAL and memory in adult rats. The effects of music therapy with classical music might be related to stress reduction by lowering corticosterone as a stress biomarker or anxiolytic effects; this deserves further examination.

Effects of omega fatty acids on the short-term postprandial satiety related peptides in rats

We aimed to assess the effects of omega fatty acids on time depending on responses of satiety hormones. Sixty adult rats were randomly divided into 4 groups; linoleic acid (LA), α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) groups. For each fatty acid, the dose of 400 mg/kg was applied by oral gavage. Blood samples were taken after the 15, 30, 60 and 120 minutes. Ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin and insulin hormones were analyzed by ELISA. We observed the significant increases (p<0.05) of the levels of CCK between n-3 (ALA, at 60th min; EPA, at 30th and 60th min and DHA, at 60 min) and n-6 (LA) supplemented rats. The highest GLP-1 levels were in ALA (0.70 ng/mL) and DHA (0.67 ng/mL) supplemented groups at 60th and 120th min indicating n-3 fatty acids efficiency on satiety compared to LA. It seems that ALA at 60th min and EPA at 120th min could provide the highest satiety effect with the highest insulin response, while the efficiency of LA supplementation on insulin-induced satiety diminished. The only significant change in AUC values among all hormones was in the CCK of the ALA group (p=0.004). The level of leptin increased in DHA and EPA supplemented rats (p=0.140). Our results showed that dietary omega fatty acids influenced the releasing of hormones in different ways possibly depending on chain length or saturation degree. Comprehensive studies need to be addressed for each fatty acid on satiety-related peptide hormones.

Early Life Stress Induces Different Behaviors in Adolescence and Adulthood May Related With Abnormal Medial Prefrontal Cortex Excitation/Inhibition Balance

Early life stress is thought to be a risk factor for emotional disorders, particularly depression and anxiety. Although the excitation/inhibition (E/I) imbalance has been implicated in neuropsychiatric disorders, whether early life stress affects the E/I balance in the medial prefrontal cortex at various developmental stages is unclear. In this study, rats exposed to maternal separation (MS) that exhibited a well-established early life stress paradigm were used to evaluate the E/I balance in adolescence (postnatal day P43–60) and adulthood (P82–100) by behavior tests, whole-cell recordings, and microdialysis coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis. First, the behavioral tests revealed that MS induced both anxiety- and depressive-like behaviors in adolescent rats but only depressive-like behavior in adult rats. Second, MS increased the action potential frequency and E/I balance of synaptic transmission onto L5 pyramidal neurons in the prelimbic (PrL) brain region of adolescent rats while decreasing the action potential frequency and E/I balance in adult rats. Finally, MS increases extracellular glutamate levels and decreased the paired-pulse ratio of evoked excitatory postsynaptic currents (EPSCs) of pyramidal neurons in the PrL of adolescent rats. In contrast, MS decreased extracellular glutamate levels and increased the paired-pulse ratio of evoked EPSCs of pyramidal neurons in the PrL of adult rats. The present results reveal a key role of E/I balance in different MS-induced disorders may related to the altered probability of presynaptic glutamate release at different developmental stages.