Wet Dog Shakes Research Articles

C-LTMRs evoke wet dog shakes via the spinoparabrachial pathway.

Many hairy mammals perform rapid oscillations of their body, called wet dog shakes, to remove water and irritants from their back hairy skin. The somatosensory mechanisms that underlie this behavior are unclear. We report that Piezo2-dependent mechanosensation mediates wet dog shakes evoked by water or oil droplets applied to back hairy skin of mice. Unmyelinated C-fiber low-threshold mechanoreceptors (C-LTMRs) were activated by oil droplets, and their optogenetic activation elicited wet dog shakes. Ablation of C-LTMRs attenuated this behavior. Moreover, C-LTMRs synaptically couple to spinoparabrachial neurons, and optogenetically inhibiting spinoparabrachial neuron synapses and excitatory neurons in the parabrachial nucleus impaired both oil droplet- and C-LTMR-evoked wet dog shakes. Thus, a C-LTMR-spinoparabrachial pathway promotes wet dog shakes for removal of water and mechanical irritants from back hairy skin.

The cell-permeant antioxidant D-thiol ester D-cysteine ethyl ester overcomes physical dependence to morphine in male Sprague Dawley rats.

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150mg/kg, SC) for 36h and continuous intravenous infusion of vehicle (20μL/h, IV). The NLX-precipitated withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8μmol/kg/h, IV) for the full 36h. NLX elicited pronounced withdrawal signs in rats treated for 48h with morphine (150mg/kg, SC), plus continuous infusion of vehicle (20μL/h, IV) that began at the 36h timepoint of morphine treatment. The NLX-precipitated withdrawal signs were reduced in rats that received a 12h infusion of D-CYSee, but not D-cysteine, (both at 20.8μmol/kg/h, IV) that began at the 36h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders.

C-LTMRs mediate wet dog shakes via the spinoparabrachial pathway.

Mammals perform rapid oscillations of their body- "wet dog shakes" -to remove water and irritants from their back hairy skin. The somatosensory mechanisms underlying this stereotypical behavior are unknown. We report that Piezo2-dependent mechanosensation mediates wet dog shakes evoked by water or oil droplets applied to hairy skin of mice. Unmyelinated low-threshold mechanoreceptors (C-LTMRs) were strongly activated by oil droplets and their optogenetic activation elicited wet dog shakes. Ablation of C-LTMRs attenuated this behavior. Moreover, C-LTMRs synaptically couple to spinoparabrachial (SPB) neurons, and optogenetically inhibiting SPB neuron synapses and excitatory neurons in the parabrachial nucleus impaired both oil droplet- and C-LTMR-evoked wet dog shakes. Thus, a C-LTMR- spinoparabrachial pathway mediates wet dog shakes for rapid and effective removal of foreign particles from back hairy skin.

Molecular and Medical Aspects of Psychedelics.

Psychedelics belong to the oldest psychoactive drugs. They arouse recent interest due to their therapeutic applications in the treatment of major depressive disorder, substance use disorder, end-of-life anxiety,= and anxiety symptoms, and obsessive-compulsive disorder. In this review, the current state of preclinical research on the mechanism of action, neurotoxicity, and behavioral impact of psychedelics is summarized. The effect of selective 5-HT2A receptor agonists, 25I- and 25B-NBOMe, after acute and repeated administration is characterized and compared with the effects of a less selective drug, psilocybin. The data show a significant effect of NBOMes on glutamatergic, dopaminergic, serotonergic, and cholinergic neurotransmission in the frontal cortex, striatum, and nucleus accumbens. The increases in extracellular levels of neurotransmitters were not dose-dependent, which most likely resulted from the stimulation of the 5-HT2A receptor and subsequent activation of the 5-HT2C receptors. This effect was also observed in the wet dog shake test and locomotor activity. Chronic administration of NBOMes elicited rapid development of tolerance, genotoxicity, and activation of microglia. Acute treatment with psilocybin affected monoaminergic and aminoacidic neurotransmitters in the frontal cortex, nucleus accumbens, and hippocampus but not in the amygdala. Psilocybin exhibited anxiolytic properties resulting from intensification of GABAergic neurotransmission. The data indicate that NBOMes as selective 5-HT2A agonists exert a significant effect on neurotransmission and behavior of rats while also inducing oxidative DNA damage. In contrast to NBOMes, the effects induced by psilocybin suggest a broader therapeutic index of this drug.

L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats.

The molecular mechanisms underlying the acquisition of addiction/dependence on morphine may result from the ability of the opioid to diminish the transport of L-cysteine into neurons via inhibition of excitatory amino acid transporter 3 (EAA3). The objective of this study was to determine whether the co-administration of the cell-penetrant L-thiol ester, L-cysteine ethyl ester (L-CYSee), would reduce physical dependence on morphine in male Sprague Dawley rats. Injection of the opioid-receptor antagonist, naloxone HCl (NLX; 1.5mg/kg, IP), elicited pronounced withdrawal phenomena in rats which received a subcutaneous depot of morphine (150mg/kg) for 36h and were receiving a continuous infusion of saline (20μL/h, IV) via osmotic minipumps for the same 36h period. The withdrawal phenomena included wet-dog shakes, jumping, rearing, fore-paw licking, 360° circling, writhing, apneas, cardiovascular (pressor and tachycardia) responses, hypothermia, and body weight loss. NLX elicited substantially reduced withdrawal syndrome in rats that received an infusion of L-CYSee (20.8μmol/kg/h, IV) for 36h. NLX precipitated a marked withdrawal syndrome in rats that had received subcutaneous depots of morphine (150mg/kg) for 48h) and a co-infusion of vehicle. However, the NLX-precipitated withdrawal signs were markedly reduced in morphine (150mg/kg for 48h)-treated rats that began receiving an infusion of L-CYSee (20.8μmol/kg/h, IV) at 36h. In similar studies to those described previously, neither L-cysteine nor L-serine ethyl ester (both at 20.8μmol/kg/h, IV) mimicked the effects of L-CYSee. This study demonstrates that 1) L-CYSee attenuates the development of physical dependence on morphine in male rats and 2) prior administration of L-CYSee reverses morphine dependence, most likely by intracellular actions within the brain. The lack of the effect of L-serine ethyl ester (oxygen atom instead of sulfur atom) strongly implicates thiol biochemistry in the efficacy of L-CYSee. Accordingly, L-CYSee and analogs may be a novel class of therapeutics that ameliorate the development of physical dependence on opioids in humans.

N-Formyl-Methionyl-Leucyl-Phenylalanine Plays a Neuroprotective and Anticonvulsant Role in Status Epilepticus Model.

Status epilepticus (SE) is described as continuous and self-sustaining seizures, which triggers hippocampal neurodegeneration, inflammation, and gliosis. N-formyl peptide receptor (FPR) has been associated with inflammatory process. N-formyl-methionyl-leucyl-phenylalanine (fMLP) peptide plays an anti-inflammatory role, mediated by the activation of G-protein-coupled FPR. Here, we evaluated the influence of fMLP peptides on the behavior of limbic seizures, memory consolidation, and hippocampal neurodegeneration process. Male Wistar rats (Rattus norvegicus) received microinjections of pilocarpine in hippocampus (H-PILO, 1.2mg/μL, 1μL) followed by fMLP (1mg/mL, 1μL) or vehicle (VEH, saline 0.9%, 1μL). During the 90min of SE, epileptic seizures were analyzed according to the Racine's Scale. After 24h of SE, memory impairment was assessed by the inhibitory avoidance test and the neurodegeneration process was evaluated in hippocampal areas. There was no change in latency and number of wet dog shake (WDS) after administration of fMLP. However, our results showed that the intrahippocampal infusion of fMLP reduced the severity of seizures, as well as the number of limbic seizures. In addition, fMLP infusion protected memory dysfunction followed by SE. Finally, the intrahippocampal administration of fMLP attenuated the process of neurodegeneration in both hippocampi. Taken together, our data suggest a new insight into the functional role of fMLP peptides, with important implications for their potential use as a therapeutic agent for the treatment of brain disorders, such as epilepsy. Schematic drawing on the neuroprotective and anticonvulsant role of fMLP during status epilepticus. Initially, a cannula was implanted in hippocampus and pilocarpine/saline was administered into the hippocampus followed by fMLP/saline (A-C). fMLP reduced seizure severity and neuronal death in the hippocampus, as well as protecting against memory deficit (D).

Hallucinogenic activity, neurotransmitters release, anxiolytic and neurotoxic effects in Rat's brain following repeated administration of novel psychoactive compound 25B-NBOMe

2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)etanoamine (25B-NBOMe) is a highly selective 5-HT2A receptor agonist, exhibiting a potent hallucinogenic activity. In the present study, we investigated the effect of a 7-day treatment with 25B-NBOMe in a dose of 0.3 mg/kg on the following: the neurotransmitter release in vivo using microdialysis in freely moving animals, hallucinogenic activity measured in the Wet Dog Shake (WDS) test, anxiety level as measured in the light/dark box (LDB) and locomotor activity in the open field (OF) test, DNA damage with the comet assay, and on a number of neuronal and glial cells with immunohistochemistry. Repeated administration of 25B-NBOMe decreased the response to a challenge dose (0.3 mg/kg) on DA, 5-HT and glutamatergic neurons in the rats’ frontal cortex, striatum, and nucleus accumbens. The WDS response dropped drastically after the second day of treatment, suggesting a rapid development of tolerance. LDB and OF tests showed that the effect of 25B-NBOMe on anxiety depends on the treatment and environmental settings. Results obtained with the comet assay indicate a genotoxic properties in the frontal cortex and hippocampus. An increase in immunopositive glial but not neuronal cells was observed in the cortical regions but not in the hippocampus. In conclusion, our study showed that a chronic administration of 25B-NBOMe produces the development of tolerance observed in the neurotransmitters release and hallucinogenic activity. The oxidative damage of cortical and hippocampal DNA implies the generation of free radicals by the drug, resulting in genotoxicity but rather not in neurotoxic tissue damage. Behavioral tests show that 25B-NBOMe exerts anxiogenic effect after single and repeated treatment.

Understanding sedative effects within the context of acute neuroinflammation in the developing brain: Potential induction of delirium-like behaviors

Neurologic morbidity is highly prevalent in pediatric critical illness, and the use of benzodiazepines and/or opioids is a risk factor for delirium and post-discharge sequelae. However, little is known about how multidrug sedation with these medications interacts with inflammation in the developing brain, a frequent condition during childhood critical illness that has not been extensively studied. In weanling rats, mild-moderate inflammation was induced with lipopolysaccharide (LPS) on postnatal day (P)18 and combined with 3 days repeated opioid and benzodiazepine sedation using morphine and midazolam (MorMdz) between P19–21. Delirium-like behaviors including abnormal response to whisker stimulation, wet dog shakes, and delay in finding buried food were induced in male and female rat pups treated with LPS, MorMdz, or LPS/MorMdz (n ≥ 17/group) and were compared using a z-score composite. Composite behavior scores were significantly increased in LPS, MorMdz, and LPS/MorMdz groups compared to saline control (F3,78 = 38.1, p < 0.0001). Additionally, expression of glial-associated neuroinflammatory markers ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) in western blots of P22 brain homogenate were significantly higher after LPS than after LPS/MorMdz (Iba1, p < 0.0001; GFAP, p < 0.001). Likewise, proinflammatory cytokines were increased in brains of LPS-treated pups versus Saline (p = 0.002), but not LPS/MorMdz-treated pups (p = 0.16). These results are of potential interest during pediatric critical illness, as inflammation is ubiquitous and the effects of multidrug sedation on homeostatic neuroimmune responses need to be considered along with neurodevelopmental effects.

Estradiol administration increases anxiety-like behavior following chronic escalating morphine administration in hormone-replaced ovariectomized female rats

Withdrawal from opioids can induce a state of anxiety and irritability. This negative state can facilitate continued drug taking, as the administration of opioids can alleviate unpleasant symptoms associated with acute and protracted withdrawal. It is, therefore, of interest to investigate factors that can contribute to the severity of anxiety during periods of abstinence. One such factor is the fluctuation of ovarian hormones. Evidence from a non-opioid drug indicates that estradiol increases, while progesterone decreases anxiety during withdrawal. However, no work has yet studied how ovarian hormones might influence the severity of anxiety during withdrawal from opioids. To explore this, we ovariectomized female rats and provided a four-day repeating cycle of ovarian hormone administration (Day 1: estradiol, Day 2: estradiol, Day 3: progesterone, Day 4: peanut oil). Male rats were given sham surgeries and administered peanut oil daily in lieu of hormone replacement. All rats received twice daily injections of morphine (or 0.9 % saline) for 10 days total at a dose that doubled every two days (2.5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kg). Rats underwent spontaneous withdrawal and were tested for anxiety-like behaviors 12 and 108 h after the last morphine treatment. At 12 h, morphine-withdrawn female rats treated with estradiol on the day of testing displayed significantly more anxiety-like behavior in light-dark box testing than female morphine-withdrawn and (marginally) male morphine-withdrawn rats receiving vehicle that day. Somatic withdrawal behaviors (wet dog shakes, head shakes, writhing) were also taken every 12 h through 108 h. We found no meaningful contribution of sex or hormones for these measures. This study is the first of its kind to provide evidence that ovarian hormones influence anxiety-like behavior during morphine withdrawal.

Cortical Correlates of Psychedelic-Induced Shaking Behavior Revealed by Voltage Imaging.

(1) From mouse to man, shaking behavior (head twitches and/or wet dog shakes) is a reliable readout of psychedelic drug action. Shaking behavior like psychedelia is thought to be mediated by serotonin 2A receptors on cortical pyramidal cells. The involvement of pyramidal cells in psychedelic-induced shaking behavior remains hypothetical, though, as experimental in vivo evidence is limited. (2) Here, we use cell type-specific voltage imaging in awake mice to address this issue. We intersectionally express the genetically encoded voltage indicator VSFP Butterfly 1.2 in layer 2/3 pyramidal neurons. We simultaneously capture cortical hemodynamics and cell type-specific voltage activity while mice display psychedelic shaking behavior. (3) Shaking behavior is preceded by high-frequency oscillations and overlaps with low-frequency oscillations in the motor cortex. Oscillations spectrally mirror the rhythmics of shaking behavior and reflect layer 2/3 pyramidal cell activity complemented by hemodynamics. (4) Our results reveal a clear cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior and open a promising methodological avenue relating a cross-mammalian psychedelic effect to cell-type specific brain dynamics.

Multi-view image-based behavior classification of wet-dog shake in Kainate rat model.

The wet-dog shake behavior (WDS) is a short-duration behavior relevant to the study of various animal disease models, including acute seizures, morphine abstinence, and nicotine withdrawal. However, no animal behavior detection system has included WDS. In this work, we present a multi-view animal behavior detection system based on image classification and use it to detect rats' WDS behavior. Our system uses a novel time-multi-view fusion scheme that does not rely on artificial features (feature engineering) and is flexible to adapt to other animals and behaviors. It can use one or more views for higher accuracy. We tested our framework to classify WDS behavior in rats and compared the results using different amounts of cameras. Our results show that the use of additional views increases the performance of WDS behavioral classification. With three cameras, we achieved a precision of 0.91 and a recall of 0.86. Our multi-view animal behavior detection system represents the first system capable of detecting WDS and has potential applications in various animal disease models.

Kronik Monosodyum Glutamat Tüketiminin Yavru Sıçanlarda Naloksonla Tetiklenen Morfin Yoksunluğu Üzerine Etkileri

Aim: The aim of this study was to investigate chronic oral monosodium glutamate (MSG) consumption effects on symptoms of withdrawal, locomotor activity, and anxiety in morphine withdrawal syndrome induced by naloxone in infant rats.&#x0D; Materials and Methods: Twelve 21-day-old male Wistar rats used in the study. Infant rats were given unlimited access to saline (control group) or MSG (MSG group) added to drinking water for 32 days. Withdrawal was induced by naloxone in morphine-dependent rats. Evaluation of withdrawal symptoms and anxiety were performed simultaneously with locomotor activity measurements.&#x0D; Results: Withdrawal sings, such as jumping, wet dog shake, and weight loss; stereotypic, ambulatory, and vertical locomotor activity movements; central, peripheral, and total activities used in the assessment of anxiety in infant rats with naloxone-induced withdrawal syndrome that consumed oral MSG for 32 days were not different from the control group.&#x0D; Conclusion: These findings obtained in our study indicate that chronic consumption of oral MSG in infant rats whose blood-brain barrier has not yet developed does not affect morphine dependence and naloxone-induced withdrawal. Further studies are needed to investigate the mechanism of action of orally administered MSG.

Modeling spontaneous opioid withdrawal in male and female outbred mice using traditional endpoints and hyperalgesia.

Opioid withdrawal significantly impacts drug dependence cycles as hyperalgesia associated with withdrawal is often a reason for continued drug use. Animal models of addiction are important tools for studying how drug dependence and withdrawal impact not only normal neurocircuitry but also the effectiveness of potential treatments for dependence and withdrawal. We conducted a study of the time course of spontaneous morphine withdrawal in outbred male and female mice that can be used to examine sex differences in male and female mice using both traditional somatic endpoints and mechanical hyperalgesia as an endpoint of withdrawal. Male and female national institute of health (NIH) Swiss mice were made dependent upon morphine using an escalating dosing schedule. Injections were stopped after 5 days. Withdrawal behavior was assessed at time intervals up to 106 h after the final injection. Numbers of forepaw tremors, wet-dog shakes, jumps and other behaviors were scored to create a global score. Paw pressure readings were then also taken to track changes in sensitivity to a painful stimulus over time. Male and female mice had approximately similar withdrawal severity peaking at 24 h after the final injection as measured by composite global scores. Females did exhibit an earlier and greater frequency of tremors than males. Although males and females showed similar hyperalgesia during withdrawal, females recovered faster. Spontaneous opioid withdrawal peaking at 24 h was demonstrated in male and female NIH Swiss mice. We also successfully demonstrated that hyperalgesia is an endpoint that varies over the course of withdrawal.

The Effects of Bupropion and Varenicline on Morphine Withdrawal Syndrome in Rats

Objective: Opioid dependence is a chronic and complex disorder characterized by relapse and remission. Chronic administration of morphine causes symptoms of physical and psychological dependence. The purpose of the present study was to investigate the effect of anti-addictive drugs such as bupropion and varenicline on morphine dependence and naloxone precipitated withdrawal syndrome in a rat model. Materials and Methods: To assess the physical dependence of morphine, Wistar albino rats were intraperitoneal (i.p.) administered increasing doses of morphine twice daily for 5 days, 4 hours after a single dose of morphine on day 6, and 15 minutes before subcutaneous (s.c.) naloxone (2 mg/kg, s.c.) administration to elicit withdrawal symptoms. Physical dependence was evaluated by giving intraperitoneal bupropion (5, 10 and 20 mg/kg, i.p.) and varenicline (0.5. 1 and 2 mg/kg, s.c) for 15 minutes. Results: The morphine-dependent rats had significantly more withdrawal symptoms than naive control rats. The results demonstrated administration of bupropion and varenicline during induction of morphine dependence attenuated the most of the severity of withdrawal symptoms. Co-administration of bupropion reduced withdrawal symptoms such as jumping, wet dog shaking, weight loss and total withdrawal symptoms. Co-administration of varenicline was found to be effective on withdrawal symptoms such as bupropion, but had no effect on weight loss. Conclusion: These outcomes provide preliminary data that bupropion and varenicline could be used as a candidate drugs to attenuate morphine withdrawal symptoms.

Sex differences in the impact of pain, morphine administration and morphine withdrawal on quality of life in rats

The disruptive effects of pain on quality of life are greater in men than in women, but the disruptive effects of opioid administration and withdrawal tend to be greater in women. These sex differences in pain, acute opioid effects, and opioid withdrawal tend to be opposite to sex differences reported in laboratory rats. We hypothesized that sex differences in humans and rats would more closely align if animal research measured quality of life as opposed to traditional evoked behaviors of pain (e.g., nociceptive reflexes) and opioid withdrawal (e.g., wet dog shakes). The present study assessed quality of life in adult female and male rats by measuring voluntary wheel running in the rat's home cage. Hindpaw inflammation induced by administration of Complete Freund's Adjuvant (CFA) into the right hindpaw caused a greater depression of wheel running in male compared to female rats. Twice daily injections of high morphine doses (5–20 mg/kg) and the subsequent morphine withdrawal caused a greater depression of wheel running in female compared to male rats. These sex differences are consistent with human data that shows the impact of pain on quality of life is greater in men than women, but the negative effects of opioid administration and withdrawal are greater in women. The present data indicate that the clinical significance of animal research would be enhanced by shifting the endpoint from pain and opioid evoked behaviors to measures of quality of life such as voluntary wheel running.

Influence of Selective Dopamine Agonist Ropinirole on Conditioned Place Preference and Somatic Signs of Morphine Withdrawal in Rats.

The underlying mechanism of dependence and rewarding effects of morphine is imperative to understand. The primary aim of this study was to investigate whether ropinirole D2/3 agonist affects the rewarding and reinforcing properties of morphine-induced conditioned place preference (CPP) and withdrawal syndromes in rats. On day one, the animals were randomly divided to conduct the pre-test. The morphine (10 mg/kg, i.p.) and/or saline was administered on alternate days in an 8-day CPP session. On day 10, 15 min prior to the post-conditioning test (expression), a single dose of ropinirole (1, 2, and 5 mg/kg, i.p.) was given to rats. In extinction session, ropinirole was injected daily, and CPP was extinguished by repeated testing, with intervals of 3 days. Finally, reinstatement was assessed by administering ropinirole (1, 2, and 5 mg/kg) 15 min before the morphine injection. Morphine dependence was developed by administering increasing doses of morphine (10–50 mg/kg, i.p.). To assess withdrawal symptoms, ropinirole (1, 2, and 5 mg/kg) was injected 15 min before naloxone (2 mg/kg, s.c.) administration. The present study confirms that ropinirole attenuates expression and reinstatement of CPP, while it precipitates the extinction of morphine-induced CPP. Naloxone-precipitated morphine withdrawal symptoms, including wet dog shakes and weight loss, were attenuated although jumping was increased by a single ropinirole injection. Thus, ropinirole was influential in attenuating expression, reducing drug seeking and weakening reinstatement via the dopaminergic system. These findings show that ropinirole might affect neuro-adaptive changes related to dependence.

Fructose ingestion modifies NMDA receptors and exacerbates the seizures induced by kainic acid

Fructose ingestion elicits a diversity of brain alterations, but it is unknown how it affects N-methyl-D-Aspartate receptors (NMDAr). Here, we analyzed the expression of NMDAr subunits and protein kinases after the long-term dietary fructose intake. Since NMDAr are related to epileptogenesis, we also examined whether fructose increases the susceptibility to seizures after the microinjection of kainic acid (KA) in the rat hippocampus. Wistar rats were randomly divided into water (control) and fructose groups. For twelve weeks, groups had ad libitum access to water or fructose solution (10% w/v). After treatment, hippocampal protein expression of NMDAr subunits and protein kinases involved in NMDAr regulation were analyzed. Additionally, electroencephalographic and behavioral changes related to seizures were evaluated after the microinjection of a sub-convulsive dose of KA in the hippocampus. Fructose induced the decrease of NR1 and, conversely, the increase of NR2A subunits expression in the hippocampus. Also, the phosphorylation of protein kinase C alpha (PKCα) and c-Src increased significantly. No electroencephalographic or behavioral patterns related to convulsive motor seizures were observed in the control group. However, all the rats that ingested fructose showed stage 3 seizures (forelimb clonus) and a significant increase in the number of wet-dog shakes. Moreover, electroencephalographic recordings revealed pronounced epileptiform activity and increased total spectral power at 30 and 60 min after the microinjection of KA. This study shows for the first time that fructose intake exacerbates the seizures induced by KA. Therefore, we propose that this proconvulsant effect could be mediated by changes in NMDAr subunits expression and increased activation of kinases modulating NMDAr function.

Effect of 5-HT 1b/1d agonist on ethanol withdrawal syndrome and ethanol withdrawal induced anxiety.

Ethanol dependence and abuse is an important problem of public health worldwide and its withdrawal shows some severe behavioural complication. Management of ethanol withdrawal syndrome (EWS) is still a challenge, thus the presented report postulates the possible mechanism involved in the development of EWS. EWS was induced by administration of ethanol for 21 days and 5-hydroxytryptamine (5-HT) 1b/1d agonist treated group receives Zolmitriptan (ZMT) at 30 mg/kg i.p. 30 min prior to ethanol withdrawal. The effect of 5-HT 1b/1d receptor agonist on EWS was determined by estimating the change in the behaviour of withdrawal signs that included locomotor hyperactivity, agitation, tremor, tail stiffness, stereotyped behaviour, and wet dog shakes at 1, 2, 4, 6 and 12 h of ethanol withdrawal. Ethanol withdrawal induced anxiety was determined by using the elevated plus maze and levels of neurochemicals such as g-aminobutyric acid (GABA), glutamate and dopamine were determined in the brain of each group of rats. Data of the given report reveal that Zolmitriptan reverses ( p < 0.01) the behavioural changes induced due to EWS and also reduces the anxiety level in EWS rats. Moreover, Zolmitriptan was found to stimulate ( p < 0.01) the level of GABA and ameliorate the level of other neurochemicals in the brain of EWS rats. In conclusion, data of investigation reveal that 5-HT 1b/1d receptor involved in the EWS and treatment with its agonist prevents the behavioural changes in EWS by regulating the level of different neurochemicals.

Morphine restores and naloxone-precipitated withdrawal depresses wheel running in rats with hindpaw inflammation

Opioids such as morphine are the most effective treatment for pain, but termination of opioid use can produce severe withdrawal symptoms. The present study models this process by using home cage wheel running to assess well-being as a result of pain, morphine analgesia, and opioid withdrawal. Injection of CFA into the right hindpaw caused a dramatic decrease in wheel running and body weight. Implantation of two morphine pellets (75 mg each) resulted in an increase in body weight on Day 1 of administration and a more gradual restoration of wheel running that was only evident during the dark phase of the circadian cycle on Days 3 and 4 of morphine administration. Continuous morphine administration decreased wheel running during the relatively inactive light phase. These findings are consistent with the clinical goal of pain therapeutics to restore normal activity during the day and facilitate sleep at night. Administration of naloxone (1 mg/kg) on Day 5 of morphine administration depressed wheel running for approximately 4 h and caused an increase in wet dog shakes. Naloxone-precipitated changes were no longer evident 6 h after administration. These findings demonstrate that the use of morphine to treat pain does not protect against opioid withdrawal. Moreover, this study provides additional support for the use of home cage wheel running as a method to assess changes in well-being as a result of pain, analgesia, and opioid withdrawal.

Comparative benefits of social housing and buprenorphine on wheel running depressed by morphine withdrawal in rats.

Social support and opioid replacement therapy are commonly used to treat opioid withdrawal. The present study tested the hypothesis that social housing and buprenorphine administration can restore wheel running depressed by morphine withdrawal in rats. Experiment 1 assessed disruptive side effects of buprenorphine and found that administration of low doses (3.2, 10, & 32µg/kg, s.c.) had no impact on voluntary wheel running. Experiment 2 assessed the impact of social housing and acute buprenorphine administration (10µg/kg) on morphine withdrawal. Two 75mg morphine pellets were implanted for 3days to induce dependence. Removal of the morphine pellets caused a decrease in body weight, increase in wet dog shakes, and depression of wheel running during the normally active dark phase of the circadian cycle. Social housing restored wheel running and reduced the number of wet dog shakes but did not affect body weight. Administration of buprenorphine restored wheel running depressed by morphine withdrawal for 2days in individually housed rats and produced time-dependent changes in socially housed rats: Depression of wheel running in the 3h following administration and restoration of running subsequently compared to saline-treated controls. The impact of buprenorphine and social housing to reduce the effect of morphine withdrawal in rats is consistent with the use of opioid substitution therapy and psychotherapy/social support to treat opioid withdrawal in humans. These data provide further validation for the clinical relevance for the use of wheel running to assess spontaneous opioid withdrawal.