Wet Dog Shakes Research Articles

Estradiol facilitates kainic acid-induced, but not flurothyl-induced, behavioral seizure activity in adult female rats.

This study was designed to determine whether previously demonstrated increases in hippocampal axospinous synapse density and NMDA receptor function induced by estradiol are paralleled by increased susceptibility to limbic (kainic acid induced) or generalized (flurothyl induced) behavioral seizures. Kainic acid was injected systemically to ovariectomized adult female rats treated with either estradiol or oil vehicle. The latencies to each of five stages of seizure-related behaviors (staring, wet-dog shakes, head waving and chewing, forelimb clonus, rearing, and falling) were recorded for each animal. Flurothyl was administered by inhalation to ovariectomized adult female rats treated with estradiol alone, estradiol followed by short-term progesterone, or oil vehicle. The latencies to each of three stages of seizure-related behaviors (first myoclonic jerk, forelimb clonus, wild running and bouncing) were recorded for each animal. Estradiol treatment decreased the latency to seizure-related behaviors induced by kainic acid, but neither estradiol alone nor estradiol followed by progesterone had any effect on flurothyl-induced seizure-related behaviors. The same estradiol treatment paradigm known to induce structural and functional changes in the excitatory circuitry of the hippocampus facilitates the progression of kainic acid-induced seizures, which are known to involve the hippocampus, but has no effect on flurothyl-induced seizures. The lack of an effect of estradiol alone or estradiol followed by progesterone on flurothyl-induced seizures indicates that estradiol's effects on seizure susceptibility do not result from increased neuronal excitability throughout the brain, but rather involve action within the limbic system. The data suggest that structural and functional changes in hippocampal circuitry induced by estradiol may contribute to increased susceptibility to limbic seizure activity.

Precipitated and spontaneous withdrawal in rats tolerant to anandamide

There is evidence that cannabinoids cause tolerance and physical dependence in humans and animals. The aim of this work was to study whether the endogenous ligand for the cannabinoid receptor, arachidonylethanolamide (anandamide), induced behavioral tolerance and physical dependence in rats. Rats were injected with anandamide (20 mg/kg i.p.) daily for 2 weeks. To assess tolerance, on days 1, 8 and 15 of treatment rats were observed and behavior was tested. Two common methods were employed to assess physical dependence: interruption of anandamide dosing and vehicle substitution or administration of the cannabinoid CB1 receptor antagonist SR141716A (3 mg/kg i.p.). Full or partial tolerance developed to the classical behavioral effects elicited by the cannabinoids: hypothermia, catalepsy, hypomotility, decrease in stereotypic activity (rearing and grooming) and hindlimb splaying. No tolerance to anandamide was observed for reduced defecation. An abstinence syndrome appeared after abrupt cessation of cannabinoid intake and after withdrawal precipitated by SR141716A; the withdrawal signs were scratching, licking and biting, eating of feces, ptosis, arched back, wet dog shakes, head shakes, myoclonic spasms, writhing, forepaw fluttering, teeth chattering and piloerection. These findings indicate that the endogenous cannabinoid ligand, administered exogenously, induces both tolerance and physical dependence in rats.

Activational role of cannabinoids on movement

Cannabinoid's major effect on movement is hypoactivity. Nevertheless, a biphasic excitatory/inhibitory effect of cannabinoids on movement has been repeatedly acknowledged. However, the literature is lacking a detailed description of such an effect. In this study, we performed a dose–response study of the effects of Δ 9-tetrahydrocannabinol on movement. Immediately after the administration of vehicle or a dose of Δ 9-tetrahydrocannabinol (0.2, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 mg/kg), the animal was placed in an activity monitor and observed for 1 h. Several parameters were recorded. The horizontal and vertical activities were measured as the number of photobeams broken between the photocells on the walls of an activity monitor. The number of wet dog shakes, scratches with hindpaw, mouth movements, forepaw flutters were also recorded, as was the amount of time in minutes that each subject spent grooming. The number of fecal boluses was recorded as an index of autonomic activity. Each animal was subsequently tested for catalepsy in the bar test. A triphasic effect was observed: low doses of the cannabinoid receptor agonist Δ 9-tetrahydrocannabinol (0.2 mg/kg) decreased locomotor activity while higher doses (1–2 mg/kg) dose-dependently stimulated movement until catalepsy emerged (2.5 mg/kg) accompanied by decreases in activity.

Suppression of paraquat-induced wet dog shakes by nitric oxide synthase inhibitors in rats

We have found that paraquat (PQ), a widely used herbicide, causes wet dog shakes (WDS), which involve the central opioid system, in rats. A non-selective nitric oxide (NO) synthase (NOS) inhibitor, N ω-nitro-L-arginine (L-NA), but not its less active enantiomer, N ω-nitro-D-arginine, decreased the PQ-induced WDS in a dose-related manner. A selective neuronal NOS inhibitor in vivo, 7-nitroindazole, also decreased the PQ-induced WDS. Although an opioid receptor antagonist, naloxone, reversed the suppressive effect of these NOS inhibitors on the PQ-induced WDS, L-arginine, an NO precursor, had no effect on it. These findings suggest that the suppression of the PQ-induced WDS by NOS inhibition is associated with the central opioid system and is insusceptible to exogenous L-arginine.

Melatonin enhances sexual behavior in the male rat

Anecdotal reports suggest that melatonin enhances libido in men. However, controlled trials remain to be published for any species. Accordingly, adult male rats were chronically treated for 12 weeks with melatonin via the drinking water. On the 13th week, all males were tested in the presence of sexually receptive females on measures of sexual behavior. Moreover, because of the established inverse relationship between male sexual behavior and serotonergic type 2A (5-HT 2A) receptor activity, “wet-dog shakes” (WDS), a 5-HT 2A receptor mediated behavior, were measured concurrently. All aspects of sexual activity were significantly facilitated in males treated with melatonin. In addition, there was a consistent, progressive reduction in the frequency of WDS, suggestive of a temporal decrement in serotonergic receptor activity and supportive of previous indications that melatonin possesses 5-HT 2A antagonistic properties. These results provide the first empirical evidence for a facilitatory role of melatonin in sexual behavior, and suggest that its mechanism of action may involve the 5-HT 2A receptor.

Chronic electroconvulsive shock decreases (±) 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) -induced wet-dog shake behaviors of dexamethasone-treated rats

Electroconvulsive shock (ECS) therapy is considered to be an effective treatment for depression, but its mechanism of action is still unknown. We investigated the effect of chronic ECS in rats treated for 14 days with dexamemasone (Dex), a glucocorticoid receptor agonist. Chronic injection of sesame oil decreased body weight change and increased serotonin (5-HT)-2A receptor number and DOI (5-HT-2A, 2C receptor agonist)-induced wet-dog shake (WDS) behaviors. Dex treatment for 14 days decreased body weight of rats, but repeated ECS did not reverse this decrease. Dex also abolished plasma corticosterone levels, and ECS failed to restore these levels. These results indicate that chronic ECS does not antagonize the effect of Dex. The treatment with Dex increased 5-HT-2A receptor binding density of rat frontal cortex and the number of DOI-induced WDS behaviors. Chronic ECS reduced the enhanced WDS behaviors by Dex but had little effect on receptor density. These results suggest that chronic ECS might suppress 5-HT-2A receptor function at the postreceptor signaling level rather than at the receptor itself, without changing HPA axis function in Dex-treated rats.

Dihydroetorphine: physical dependence and stereotypy after continuous infusion in the rat

In a previous study in this laboratory, exposure of rhesus monkeys to intermittent, high doses of dihydroetorphine for 42 days did not evoke behavioral signs of physical dependence on this opioid either after it was abruptly withdrawn or after challenge with a high dose of naloxone. To investigate further the physical dependence capacity of this opioid, it was given by infusion to rats thereby exposing receptors chronically and continuously to this opioid. Abstinence expressed as body weight loss, irritability, and wet-dog shakes was observed after abrupt withdrawal of the low-dose regimen (5,10, 40 and 40 μg/kg per day for 4 days, respectively). The high-dose regimen (10, 20 and 80 μg/kg per day for 3 days, respectively) produced stereotypy and physical dependence. Although many reported molecular events and dependence studies suggest otherwise, dihydroetorphine's propensity to produce physical dependence, an important determinant of opioid abuse, is real.

Effect of Lithium Carbonate on the Enhancement of Serotonin 2A Receptor Elicited by Dexamethasone

The purpose of this study was to investigate whether chronic dexamethasone (Dex) administration induces serotonin (5-HT) 2A receptor supersensitivity and if chronic lithium carbonate (Li) administration contributes to the normalization of 5-HT2A receptor supersensitivity induced by Dex in rat brain. We investigated the effects of a 14-day administration of Dex and/or Li on changes in body weight (BW), on plasma corticosterone levels, on plasma lithium levels, on 5-HT2A receptor binding sites, and on (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI)-induced wet dog shake (WDS), which is mediated by 5-HT2A receptor in rats. Dex significantly reduced the BW of rats. Li did not have any effect on BW gain and did not prevent the BW loss induced by Dex. The plasma corticosterone levels of rats treated with Dex were too low to be detected. Li did not have any effect on corticosterone levels and did not prevent the decrease in the corticosterone levels induced by Dex. Six hours after the last treatment, the plasma lithium levels of rats treated with Li were significantly higher than those of rats treated with Dex/Li. Chronic Dex administration resulted in a significant increase in the density (B_max) of the 5-HT2A receptor without a significant change in the affinity (K_d). The increase in the B_max induced by Dex was not prevented by chronic combined treatment with Dex and Li. Chronic Dex administration potentiated the WDS, and this increase was prevented by chronic combined treatment with Dex and Li. Chronic Li administration did not have any effect on WDS. These results indicate that chronic Li administration may improve the supersensitivity of the 5-HT2A receptor elicited by chronic Dex administration without decreasing the density of the 5-HT2A receptor, and the effect of Li was also independent of hypothalamo-pituitary-adrenal axis function.

Convulsive effects of some isolated venom fractions of the Tityus serrulatus scorpion: behavioral, electroencephalographic, and neuropathological aspects

It has been previously shown that the crude venom of Tityus serrulatus can cause convulsions. This study was designed to investigate the neurotoxic effects of B, C, G, and K fractions isolated from this venom. Intravenous injection of these fractions in mice (0.6 - 6.0 mg/kg body weight) showed that the C fraction is a potent convulsant and G fraction decreased the threshold for tonic hand limb extension elicited by transauricular electroshock. Unilateral injection of B, C, and K fractions, but not G fraction, into the hippocampus of rats (0.6 - 6.0 µg) caused electroencephalographic alterations consisting of spikes and epileptic discharges that began in the hippocampus and evolved to the cortex. The following motor signs were observed: movements of facial muscles, wet dog shake, immobility, myoclonus, wild-running with clonus, and in some cases, loss of postural control. Intrahippocampal injection of B, C, and K fraction, but not G fraction, caused neuronal loss at the injection site as well as in other hippocampal areas. The effect of these fractions on epileptiform activity and on neuronal loss was dose-dependent. The severity of the epileptiform activity in the ipsilateral hippocampus correlated with the severity of the neuronal loss. The electrographic, behavioral, and histological changes induced by B, C, and K fractions were similar to those obtained with other drugs that are commonly used to induce convulsion. The convulsant effects of the crude venom may be caused by the fractions studied in this work.

Orphanin FQ/nociceptin inhibits morphine withdrawal

The influence of orphanin FQ/nociceptin (OFQ/N) on the morphine-withdrawal symptom was investigated. Withdrawal syndrome was induced in the morphine-dependent rats by an intraperitoneal (ip) injection of 2 mg/kg naloxone hydrochloride — an opioid receptors antagonist. Wet-dog shakes were used as a measure of the abstinence syndrome. Intraventricular injections of OFQ/N (5–20 μg/animal) caused significant inhibition of the withdrawal signs at doses between 15–20 μg, in the morphine-dependent rats. OFQ/N alone did not change behavior of the morphine-dependent animals. The obtained results indicate that OFQ/N can inhibit the morphine withdrawal symptoms induced by naloxone.

Prenatal Morphine Exposure Alters N-Methyl- d-Aspartate- and Kainate-Induced Seizures in Adult Male Rats

ŠLAMBEROVÁ, R., L. VELÍŠEK AND I. VATHY. Prenatal morphine exposure alters N- methyl- d -aspartate- and kainate-induced seizures in adult male rats. PHARMACOL BIOCHEM BEHAV 65(1) 39–42, 2000 .—The purpose of the present study was to investigate whether prenatal exposure to morphine has effects on excitatory amino acid-induced seizures. Adult male rats, exposed on embryonic days 11–18 to saline or morphine, were injected with N-methyl- d -aspartate (NMDA) (150, 175, 200, 225, and 250 mg/kg) or kainic acid (KA) (15 or 20 mg/kg) in adulthood to assess the occurrence and latency to onset of stereotypy and seizures. The latency to onset of stereotypy was significantly increased after 175 mg/kg, and decreased after 200 mg/kg of NMDA in morphine-exposed animals. The lowest dose of NMDA (150 mg/kg) induced seizures in prenatally saline-treated control male rats but not in the morphine-exposed male rats. In the KA-injected group, prenatally morphine-exposed males had shorter latency to onset of wet-dog shakes, but there were no effects on the latency to onset of clonic seizures. The data suggest that prenatal morphine exposure has long-term effects on seizure susceptibility and the onset of stereotypy in the excitatory amino acid-induced seizure models.

The effect of the NK 1 receptor antagonist CP-99,994 on emesis and c-fos protein induction by loperamide in the ferret

The site of the anti-emetic action of the neurokinin 1 receptor antagonist CP-99,994 was studied in the ferret using the centrally acting opiate receptor agonist loperamide at a dose (0.5 mg/kg s.c.) which induced emesis in all animals tested. CP-99,994 (1 mg/kg, s.c.×2) abolished the emetic response (retching and vomiting) and the behaviours (licking, wet dog shakes, mouth scratching and gagging) induced by loperamide over a 2-h observation period. The enantiomer of this compound CP-100,263 (1 mg/kg, s.c.×2) did not have any significant effect on emesis or related behaviours. Loperamide (0.5 mg/kg s.c.) administration (but not its vehicle) resulted in dense fos-like immunoreactivity (FLI) mainly throughout the rostro-caudal extent of the nucleus tractus solitarius but not the area postrema. Although CP-99,994 (1 mg/kg×2) abolished the loperamide-induced emesis, it did not have any statistically significant effect on FLI in the brainstem. In loperamide and CP-100,263 (1 mg/kg, s.c.×2) treated animals FLI was comparable to that in animals treated with loperamide and CP-99,994. The results from this study taken together with those from previous studies indicate that loperamide exerts its emetic effect via nucleus tractus solitarius dendrites projecting into the area postrema. The lack of significant effect of CP-99,994 on the FLI induced by loperamide in this nucleus suggests that it is acting at a site “deep” in the nucleus tractus solitarius or elsewhere. The marked reduction in behaviours associated with loperamide administration by CP-99,994 provides a preliminary indication that NK 1 receptor antagonist (as represented by CP-99,994) may in the clinic have effects on behaviours induced by emetic agents in addition to their previously described effects on retching and vomiting.

Context-specific morphine withdrawal: Evidence that rearing reflects withdrawal, not exploration

Several studies have demonstrated that contextual cues previously paired with morphine elicit conditioned withdrawal in the absence of the drug. Conditioned withdrawal signs have included circling, jumping, rearing, and wet dog shakes. One of these signs, rearing, may in fact reflect exploration rather than withdrawal. In those studies, rats had morphine paired or unpaired with distinctive contextual cues for several sessions and then were tested in that environment. During conditioning, the rats that received the drug in that context may have explored it less because they were sedated by the morphine. In the withdrawal test, this environment would have been more novel for these rats, as compared with the rats for which the contextual cues had been paired with saline. In the present study, rats were given eight injections of morphine, spaced 48 h apart, either paired or unpaired with distinctive contextual cues. During these sessions, the rats were physically restrained. Although both groups were equated for exploration of this context, the paired group, which received morphine in this context, displayed more rearing during the test session. These results suggest that rearing is an index of conditioned withdrawal.

Effects of agmatine on ethanol withdrawal syndrome in rats

Effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of l-arginine, have been investigated on the ethanol withdrawal syndrome in rats. Adult male Wistar rats were used in the study. Ethanol (7.2% v/v) was given to the rats by a liquid diet for 21 days. Agmatine (20, 40, 80 and 160 mg/kg) and saline were injected to rats intraperitoneally 30 min before ethanol withdrawal testing. After 30th min, 2nd and 6th h of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes and tremor were recorded or rated. A second series of injections was given at 6 h after the first one, and subjects were then tested for audiogenic seizures. Agmatine caused dose-dependent and significant inhibitory effects on stereotyped behaviors, wet dog shakes and tremors during the observation period. It did not cause any significant change in motor coordination of naive (not ethanol-dependent) rats. Our results suggest that agmatine attenuates withdrawal syndrome in ethanol-dependent rats; thus, this drug may be beneficial in the treatment of ethanol dependence.

Anticonvulsive and free radical scavenging actions of two herbs, Uncaria rhynchophylla (Miq) jack and Gastrodia elata Bl., in kainic acid-treated rats

Uncaria rhynchophylla (Miq.) Jack (UR) and Gastrodia elata BI. (GE) are traditional Chinese herbs that are usually used in combination to treat convulsive disorders, such as epilepsy, in China. The aim of this study was to compare the anticonvulsive and free radical scavenging activities of UR alone and UR in combination with GE in rats. For the in vitro studies, brain tissues from 6 male Sprague-Dawley (SD) rats were treated with 120 μg ml kainic acid (KA), with or without varied concentrations of UR or UR plus GE. For the in vivo studies, male SD rats (6 per group) received intraperitoneal (i.p.) injection of KA 12 mg kg to induce epileptic seizures and generation of free radicals, with or without oral administration of UR 1 g kg alone or UR 1 g kg plus GE 1 g kg . Epileptic seizures were verified by behavioral observations, and electroencephalography (EEG) and electromyography (EMG) recordings. These results showed that UR alone decreased KA-induced lipid peroxide levels in vitro, whereas UR plus GE did not produce a greater effect than UR alone. UR significantly reduced counts of wet dog shakes (WDS), paw tremor (PT) and facial myoclonia (FM) in KA-treated rats and significantly delayed the onset time of WDS, from 27 min in the control group to 40 min in the UR group. UR plus GE did not inhibit seizures more effectively than UR alone, but did further prolong the onset time of WDS to 63 min (P < 0.05 vs. UR alone). UR alone reduced the levels of free radicals in vivo, as measured by lipid peroxidation in the brain and luminol-chemiluminescence (CL) counts and lucigenin-CL counts in the peripheral whole blood, but the combination of GE and UR did not reduce free radical levels more markedly than UR alone. In conclusion, our results indicate that UR has anticonvulsive and free radical scavenging activities, and UR combined with GE exhibit greater inhibition on the onset time of WDS than UR alone. These findings suggest that the anticonvulsive effects of UR and GE may be synergistic. However, the mechanism of interaction between UR and GE remains unknown.

Nefazodone attenuates the stress-induced facilitation of wet dog shaking behaviour but not the facilitation of sexual behaviour in female rats

The effects of chronic stress both alone and in combination with the antidepressant, nefazodone, which possesses antagonistic activity at the 5-HT 2A receptor, were examined on the 5-HT 2A receptor-mediated behaviour, wet dog shaking and sexual behaviour. Ovariectomized female rats received either a chronic stressor or no stress for 30 days, and half of each group received concurrent nefazodone treatment (100 mg/kg/day). Following treatment with either estrogen, or estrogen combined with progesterone, sexual behaviour and wet dog shaking were recorded. Chronic stress alone was found to facilitate sexual behaviour and increase wet dog shaking, while nefazodone administration alone was without effect. Furthermore, nefazodone completely attenuated the stress-induced facilitation of wet dog shaking, but not sexual behaviour.

Corticosterone Regulation of 5-HT 2A Receptor-Mediated Behaviors : Attenuation by Melatonin

The effects of chronic corticosterone treatment on sexual behavior and on wet-dog shakes (WDS), a serotonergic type 2A (5-HT 2A) receptor-mediated behavior, were explored in the male rat. In addition, the effects of acute melatonin treatment, both alone and in combination with corticosterone, were investigated. Chronic injections of corticosterone resulted in an overall decrease in consummatory measures of sexual behavior, and an increase in WDS. Furthermore, although an acute injection of melatonin alone had no effect on any recorded behavior, it attenuated the effects of corticosterone on sexual behavior and WDS. The data suggest that in the context of 5-HT 2A receptor-mediated behaviors, melatonin has possible implications as a 5-HT 2A antagonist.

Interactions of lithium and drugs that affect signal transduction on behaviour in rats

The therapeutic mechanism of the action of lithium in the treatment of bipolar affective disorder is not known, in spite of a burgeoning number of biochemical studies linking lithium to signal transduction processes. This article reviews a decade of studies examining the behavioural manifestations of manipulating inositol, cyclic adenosine monophosphate (cAMP) and G proteins in rats. Inositol, forskolin, dibutyryl cAMP and pertussis toxin all interacted with lithium when rearing behavior was measured. Lithium potentiated the increase in locomotion induced by injections of cholera toxin into the nucleus accumbens, consistent with the hypothesis that it inactivates inhibitory G proteins. More specific interactions were found between lithium and inositol following cholinergic and serotonergic stimulation. Inositol, but not forskolin, attenuated lithium-pilocarpine seizures and the enhancement of the serotonin syndrome; however, inositol had no effect on lithium-induced attenuation of wet dog shakes following an injection of 5-hydroxytryptophan. Behavioural evidence supports biochemical findings suggesting that lithium’s interactions with the phoshphatidyl inositol and cyclic AMP signal transduction systems may be relevant to its therapeutic effects in bipolar disorder. Further research on more specific behaviours may elucidate the relevant pharmacological mechanisms underlying the therapeutic effect of lithium.

Contribution of Glutamatergic Systems in Locus Coeruleus to Nucleus Paragigantocellularis Stimulation-Evoked Behavior

The role of extracellular glutamate, within the locus coeruleus, in mediation of the behavioral signs elicited by electrical stimulation of the nucleus paragigantocellularis (PGi) was investigated in conscious, opioid-naı̈ve rats. Each rat was prepared with a chronically implanted unilateral electrode within the PGi and a microdialysis guide cannula directed at the ipsilateral locus coeruleus. Opioid withdrawal-like behaviors (rearing, teeth-chattering, wet-dog shakes, etc.) and increases in extracellular glutamate concentrations within the locus coeruleus were evoked, in a frequency-dependent (0.5–50 Hz) manner, during PGi stimulation. Reverse dialysis perfusion of the locus coeruleus with the nonspecific glutamate receptor antagonist, kynurenic acid (0.1, 1 mM), reduced the intensity of stimulation-induced behaviors by roughly 50%, but had no effect on the corresponding increases in glutamate concentrations. Perfusion of the locus coeruleus with the glutamate transporter inhibitor, l- trans-pyyrolidine dicarboxylic acid, at 1, but not at 0.1, mM significantly increased glutamate levels in dialysates. Neither concentration of the transporter inhibitor altered the behavioral score. The results indicate that the opioid withdrawal-like behaviors elicited by electrical stimulation of the brainstem at the site of the PGi are positively correlated with locus coeruleus levels of glutamate, and suggest further that the behaviors are partially mediated by release of glutamate within the locus coeruleus or its immediate vicinity.

Kainic acid (KA)-induced seizures in Sprague-Dawley rats and the effect of dietary taurine (TAU) supplementation or deficiency.

Male Sprague-Dawley rats received TAU supplementation (1.5% in drinking water) or TAU deficient diets for 4 weeks to test for a possible neuroprotective role of TAU in KA-induced (10 mg/kg s.c.) seizures. TAU supplementation significantly increased serum and hippocampal TAU levels, but not TAU content in temporal cortex or striatum. TAU deficient diets did not attenuate serum or tissue TAU levels. Dietary TAU supplementation failed to decrease the number or latency of partial or clonic-tonic seizures or wet dog shakes, whereas a TAU deficient diet decreased the number of clonictonic and partial seizures. This study does not support previous observations of an anticonvulsant effect of TAU against KA-induced seizures. KA-treatment decreased alpha 2-adrenergic receptor binding sites and TAU content in the temporal cortex across all dietary treatment groups, supporting previous evidence of severe KA-induced damage and neuronal loss in this brain region.