Wet-dog Shake Response Research Articles

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.

Contribution of serotonin receptor subtypes to hallucinogenic activity of 25I-NBOMe and to its effect on neurotransmission

Background4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin (5-HT) receptor agonist with hallucinogenic properties. The aim of our research was to examine the role of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes in 25I-NBOMe hallucinogenic activity and its effect on dopamine (DA), 5-HT and glutamate release in the rat frontal cortex.MethodsHallucinogenic activity was investigated using the wet dog shake (WDS) test. The release of DA, 5-HT and glutamate in the rat frontal cortex was studied using a microdialysis in freely moving rats. Neurotransmitter levels were analyzed by HPLC with electrochemical detection. The selective antagonists of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes: M100907, SB242084 and WAY100635, respectively were applied through a microdialysis probe.ResultsThe WDS response to 25I-NBOMe (1 and 3 mg/kg) was significantly reduced by local administration of M100907 and SB242084 (100 nM). The 25I-NBOMe-induced increase in glutamate, DA and 5-HT release was inhibited by M100907 and SB242084. WAY100635 had no effect on 25I-NBOMe-induced WDS and glutamate release, while it decreased DA and 5-HT release from cortical neuronal terminals.ConclusionThe obtained results suggest that 5-HT2A and 5-HT2C receptors play a role in 25I-NBOMe-induced hallucinogenic activity and in glutamate, DA and 5-HT release in the rat frontal cortex as their respective antagonists attenuated the effect of this hallucinogen. The disinhibition of GABA cells by the 5-HT1A receptor antagonist seems to underlie the mechanism of decreased DA and 5-HT release from neuronal terminals in the frontal cortex.

Role of prefrontal cortical 5-HT2A receptors and serotonin transporter in the behavioral deficits in post-pubertal rats following neonatal lesion of the ventral hippocampus

Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT2A-receptor and SERT binding sites in cortical and subcortical areas in post-pubertal NVHL and sham-lesioned rats, using quantitative receptor autoradiography. We compared a 5-HT-dependent behavior in NVHL and sham animals, the wet-dog shake response (WDSr) to a 5-HT2A receptor agonist DOI. In addition, we studied prepulse inhibition (PPI) of startle responses in NVHL and Sham-lesioned animals treated with antipsychotic drugs haloperidol, risperidone and clozapine and 5-HT2A antagonists ketanserin or MDL100907. The WDSr elicited by DOI was enhanced in post-pubertal NVHL rats compared to sham-lesioned controls. Moreover, post-pubertal NVHL rats exhibited PPI deficits which was reversed by atypical antipsychotics, ketanserin and MDL100907. A significant increase in 5-HT2A-like receptor binding was observed in the medial prefrontal cortex (mPFC) in post-pubertal NVHL rats without any significant change in the striatum and ventral pallidum. A significant increase in SERT-like binding was also observed in the mPFC and striatum of NVHL rats at pre-pubertal period; however, at post-pubertal age, the binding remained elevated in mPFC only. These data suggest that increased prefrontal cortical 5-HT transmission may play a role in the behavioral deficits observed in this neurodevelopmental model of schizophrenia.

Effect of Aripiprazole on 5-HT2Receptor–mediated Wet-Dog Shake Responses and Disruption of Prepulse Inhibition in Rats

Aripiprazole, an atypical antipsychotic drug, is a D2dopamine–receptor partial agonist, but also has affinity to several serotonin receptors (5-HT1A,2A,2C,7). However, little is known about the contribution of serotonin receptors in the action of aripiprazole. The present study investigated the effects of aripiprazole on 5-HT2Areceptor–mediated behaviors and compared them with the effects on dopamine receptor–mediated behavior in rats. Aripiprazole (10, 30 mg/kg, p.o.) inhibited the stereotyped behavior induced by apomorphine (1 mg/kg, s.c.), a dopamine-receptor agonist, and the wet-dog shake responses induced by DOI (2,5-dimethoxy-4-iodoamphetamine, 2 mg/kg, s.c.), a 5-HT2A–receptor agonist. Moreover, aripiprazole improved the disruption of prepulse inhibition induced by both apomorphine and DOI significantly. These data suggest that not only the dopaminergic system, but also the serotonergic system are involved in the antipsychotic effect of aripiprazole.

The Influence of hyperactivity of the hypothalamic-pituitary-adrenal axis and hyperglycemia on the 5-HT2A receptor-mediated wet-dog shake responses in rats.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induces hyperglycemia and serotonin (5-HT)2A receptor supersensitivity. In the present study, to investigate the effect of hyperglycemia on the function of 5-HT2A receptors, we compared the 5-HT2A receptor-mediated wet-dog shake responses in rats treated with adrenocorticotropic hormone (ACTH), dexamethasone and streptozotocin. ACTH (100 ug/rat per day, s.c.), dexamethasone (1 mg/kg per day, s.c.) and streptozotocin (60 mg/kg, i.p.) produced significant hyperglycemia at 14 days after the start of these treatments, and the hyperglycemia was most pronounced in the streptozotocin-treated rats. The wet-dog shake responses induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, were significantly enhanced at 14 days after repeated treatment with ACTH and dexamethasone. However, streptozotocin-induced diabetes had no effect on the wet-dog shake responses. The results of the present study suggest that hyperglycemia is not strongly associated with the enhanced susceptibility of 5-HT2A receptors under the condition of hyperactivity of the HPA axis.

Effects of physical and psychological stress on 5-HT2A receptor-mediated wet-dog shake responses in streptozotocin-induced diabetic rats.

Several epidemiological and clinical studies have indicated that the prevalence of psychiatric disorders is higher in diabetic patients than in the general population. In the present studies, we examined the behavioral changes in streptozotocin-induced diabetic rats, and investigated the effects of physical and psychological stress on the hippocampal BDNF levels and on the serotonin 2A (5-HT(2A)) receptor-mediated wet-dog shake responses. The streptozotocin (60 mg/kg, i.p.)-induced diabetes had no significant effects on the immobility time in the forced swim test or on locomotor activity in the open-field test. Moreover, there was no significant difference in the wet-dog shake responses induced by DOI, a 5-HT(2A) receptor agonist, between nondiabetic and diabetic rats. Five-day exposure to physical (electric footshock) and psychological (non-footshock) stress had no significant effect on the hippocampal BDNF level in diabetic or nondiabetic rats. The 2 types of stress had no significant effect on the DOI-induced wet-dog shake responses in nondiabetic rats. In diabetic rats, the repeated exposure to physical stress markedly increased the DOI-induced wet-dog shake responses, but the repeated exposure to psychological stress had no effect. These results suggest that exposure to physical stress augmented the susceptibility to the wet-dog shake responses to 5-HT(2A) receptor stimulation in streptozotocin-induced diabetic rats.

The 5-HT1A Receptor Full Agonist, 8-OH-DPAT Inhibits ACTH-Induced 5-HT2A Receptor Hyperfunction in Rats: Involvement of 5-HT1A Receptors in the DOI-Induced Wet-Dog Shakes in ACTH-Treated Rats

We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats.

Functional role of the endocannabinoid system and AMPA/kainate receptors in 5-HT 2A receptor-mediated wet dog shakes

These experiments sought to determine the influence of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and the endocannabinoid system in the functional expression of the serotonin (5-HT) type 2A receptor-mediated wet dog shake response. Male Long–Evans rats were pretreated with either 1 mg/kg i.p. of the 5-HT 2A/2C receptor antagonist ketanserin; 1, 10 or 30 mg/kg i.p. of the AMPA/kainate antagonist 6,7-dinitroquinnoxaline-2,3-dione (DNQX); 1, 5 or 10 mg/kg i.p. of the endocannabinoid uptake inhibitor AM404; or 1, 5 or 10 mg/kg i.p. of the cannabinoid CB 1 receptor antagonist AM 251 prior to injection of the 5-HT 2A/2C receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 1 mg/kg i.p.). Results demonstrated that 10 mg/kg of AM404 significantly reduced the expression of DOI-induced wet dog shakes, but lower doses were ineffective. Administration of AM251 did not induce wet dog shakes behavior when administered alone, but significantly potentiated DOI-induced wet dog shaking behavior at a dose of 10 mg/kg. Pretreatment with DNQX significantly reduced the expression of DOI-induced wet dog shakes at all doses tested. These data suggest that AMPA/kainate receptors play a role in the mediation of 5-HT 2A receptor activity, whereas the endocannabinoid system may act as a regulatory buffer system during periods of elevated activity, but not under basal conditions.

Effects of imipramine and lithium on wet-dog shakes mediated by the 5-HT 2A receptor in ACTH-treated rats

We examined the influence of imipramine and lithium on wet-dog shakes induced by the (±)-DOI, 5-HT 2A receptor agonist in adrenocorticotropic hormone (ACTH)-treated rats. The administration of imipramine for 14 days decreased the (±)-DOI-induced wet-dog shakes response; chronic administration of lithium for 14 days, however, had no effect. Chronic ACTH (100 μg/rat sc) treatment increased the wet-dog shake response induced by (±)-DOI. This effect of ACTH for 14 days, increasing the (±)-DOI-induced wet-dog shakes, was not inhibited by a 14-day administration of imipramine. Chronic coadministration of imipramine and lithium, lasting 14 days, decreased the wet-dog shakes response induced by (±)-DOI in rats treated with ACTH for 14 days. These findings indicate that lithium inhibits the hyperfunction of the 5-HT 2A receptor in rats treated with ACTH when coadministered with imipramine.

Interaction of 5-HT and HPA axis in depression and treatment-resistant depression

Psychoendocrinology studies of depressed patients focus on the disregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Abnormalities in the HPA axis have been noted in depressed patients. Numerous data have demonstrated the existence of reciprocal interactions between the central serotonin (5-HT) system and HPA axis. These interactions are of particular relevance when considering pathological conditions, such as depression, in which modifications of both the 5-HT system and HPA axis have been evidenced. In our laboratory, we examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test and on the wet-dog shakes induced by the DOI, 5-HT2 receptor agonist with the administration of imipramine and lithium. The reduction of immobility, induced by the chronic administration of imipramine for 15 days, was blocked by treatment with ACTH for 14 days. And, chronic ACTH treatment for 14 days increased the wet-dog shake response. This effect of ACTH was not inhibited by a 14-day administration of imipramine. Accordingly, the chronic treatment of rats with ACTH may prove to be an effective model for antidepressant-treatment-resistant depression. We believe that behavioral pharmacological and molecular biological research into the interaction between the 5-HT and HPA axis will elucidate the pathogenesis of depression or antidepressant-treatment-resistant depression and the mechanism of antidepressants action.

Cessation of chronic nicotine administration enhances wet-dog shake responses to 5-HT2 receptor stimulation in rats.

The involvement of central serotonergic systems has been hypothesized clinically to contribute to nicotine withdrawal symptoms. However, involvement of the serotonin2 (5-HT(2)) receptor system in nicotine withdrawal is not clear. The changes in wet-dog shake responses induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT(2) receptor agonist, following nicotine cessation was investigated in rats. DOI (1 mg/kg SC) was administered 24 h after the final treatment of saline or nicotine (0.5 mg/kg per day SC) for 7 or 21 days. Cessation of nicotine administration for 7 or 21 days increased DOI-induced wet-dog shake responses. A single administration of nicotine (0.5 mg/kg SC) had no effect on DOI-induced wet-dog shakes. The enhancement by the cessation of nicotine treatment for 7 days was abolished by coadministration of nicotine. Mecamylamine (3 mg/kg IP), a nicotinic receptor antagonist, precipitated DOI-induced wet-dog shake responses in rats chronically treated with nicotine but not with saline. These findings suggest that cessation of chronic nicotine produced increased sensitivity to 5-HT(2) receptor systems, and that the 5-HT(2) receptor systems may be involved in the nicotine withdrawal symptoms.

Transgenerational effects of maternal exposure to chemicals on the functional development of the brain in the offspring.

In order to prevent health risk from environmental chemicals, particularly for progeny, we have been performing a risk assessment for various chemicals including therapeutic agents. This paper reports the functional effects of maternal exposure to psychoactive drugs, anticancer drugs, or herbicides on the offspring of rats. Maternal exposure to imipramine in a dose equivalent to the therapeutic dose per unit body weight induced hyperthermic response to chlorpromazine in the male offspring, while normal control rats showed a marked hypothermia. Exposure to ethosuximide resulted in an increase in play fighting behavior in young offspring that was fostered by lactating normal mothers. Single exposures to nimustine or cisplatin, anticancer drugs, at a different gestational stage resulted in an acceleration of growth when exposed at the earlier stage of gestation. Moreover, cisplatin-exposed rats were emotionally unstable, showing a short latent time to the first line-crossing in an open-field during infantile period. The rats exposed to glufosinate ammonium, an herbicide, during the time of neurogenesis in the hippocampus showed a decrease in the wet-dog shakes response to kainic acid at six weeks of age. These results suggest that maternal exposure to chemicals during pregnancy induces a variety of functional abnormalities in the brain of the offspring dependent on the pharmacologic action of chemicals and the stage of gestation even with a single exposure.

Circadian rhythm in the responsiveness of central 5-HT2A receptor to DOI in rats.

The present study investigated the circadian variation in the behavioral response to the selective 5-HT2A/2C receptor agonist (+/-)-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI). Rats were subcutaneously injected with DOI at 0000, 0400, 0800, 1200, 1600, or 2000 hours. The wet-dog shake (WDS) response was counted following administration of DOI. A circadian rhythm that peaked during the late light period (0400 hours) and reached the lowest point during the late dark period (1600 hours), was observed in the DOI-induced WDS response. In a separate experiment, DOI was administered intra-cerebroventricularly at either 0400 or 1600 hours. The WDS response to the drug at 0400 hours was significantly higher than the response at 1600 hours. These results suggest that the function of the central 5-HT2A receptor exhibits a circadian rhythm.

Alterations in the Response to Kainic Acid in Rats Exposed to Glufosinate Ammonium, a Herbicide, during Infantile Period.

Toxic effects of glufosinate ammonium (GLA), a non-selective herbicide, on the brain of infantile rats was studied. Because of the structural analogy between GLA and glutamate, GLA-exposed rats were examined for the wet-dog shakes response to kainic acid. Seven-day-old female rats were injected subcutaneously with a dose 1, 2 or 5mg/kg GLA daily for 7 days. They were weaned at 3 weeks of age and tested for the response to 9mg/kg kainic acid at 5 or 6 weeks of age. The frequency of wet-dog shakes induced by kainic acid showed a significant decrease in all GLA-exposed rats, though there was no significant difference among three dose groups. A significant decrease in the body weight gain was found in the 5mg/kg GLA group. The results suggest that exposure to GLA, even in low doses, during infantile period in the rat induces alterations in the kainic acid receptor in the brain.

Effect of ACTH, adrenalectomy and the combination treatment on the density of 5-HT2 receptor binding sites in neocortex of rat forebrain and 5-HT2 receptor-mediated wet-dog shake behaviors.

The effect of ACTH and/or adrenalectomy on serotonin (5-HT)2 receptor binding sites was evaluated in the neocortex of rat forebrain. One day after the adrenalectomy or sham operation, ACTH (50 micrograms/day) was injected subcutaneously into adult male SD rats for 10 consecutive days. Saturation analysis showed that subchronic ACTH treatment significantly increased the Bmax values for 3H-ketanserin binding without any change in the Kd values. Moreover, this ACTH-induced increase in the Bmax values was prevented by adrenalectomy. The concentrations of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) measured by HPLC-ECD were not altered by these manipulations. Ten-day administration of corticosterone (20 and 50 mg/kg) also increased 5-HT2 receptor density in the neocortex of rat forebrain. 5-HT2 (and 5-HT1C) receptor agonist, (+/-)DOI-induced wet-dog shakes in ACTH and/or adrenalectomy-treated rats were also examined. Ten-day administration of ACTH enhanced (+/-)DOI-induced wet-dog shakes and this increase was prevented by adrenalectomy. These results indicate that subchronic adrenocorticotropin-adrenal axis activation of rats increases both the number of 5-HT2 receptors in neocortex of forebrain and the wet-dog shake responses induced by (+/-)DOI.

Characterization of the 5‐HT receptor subtypes involved in the motor behaviours produced by intrathecal administration of 5‐HT agonists in rats

1. The motor behavioural effects of intrathecal injections of 5-hydroxytryptamine (5-HT) and a variety of 5-HT receptor agonists were examined in adult Wistar rats to establish; (a) which 5-HT receptor subtype/s elicit each behaviour and (b) whether these receptors are located within the spinal cord. 2. Intrathecal injection of 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT), (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) or 2,5-dimethoxy-alpha,4-dimethylbenzene ethamine hydrochloride (DOM) produced dose-related back muscle contractions (BMC) and wet dog shakes (WDS) which were both markedly attenuated by intraperitoneal pretreatment with either ritanserin (1 mg kg-1), ketanserin (0.16 mg kg-1) or mianserin (0.6 mg kg-1) indicating the involvement of 5-HT2 receptors in both these motor behaviours. Both fluoxetine (1-20 mg kg-1, i.p.) and high doses of 5-HT (50 micrograms) following fluoxetine (5 mg kg-1, i.p.) also elicited BMC, further confirming the involvement of 5-HT in this behaviour. 3. Intrathecal 5-carboxamidotryptamine (5-CT) evoked a marked wet-dog shake response without producing any BMC. Intrathecal pretreatment with 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) enhanced, while in contrast 2-methyl-5-HT pretreatment attenuated, 5-HT agonist-induced BMC without affecting WDS. These data suggest that the spinal 5-HT2 receptors mediating BMC are positively modulated by 5-HT1A but negatively influenced by 5-HT3 receptor activation and may be of a different subtype to the supra-spinal 5-HT2 receptors which elicit WDS. 4. A contrast, reciprocal forepaw treading, lateral head weaving, flat body posture and Straub-tail were evoked by 5-MeODMT, 8-OH-DPAT or 5-CT but not by DOI or DOM indicating that these behaviours were not produced by 5-HT2 receptor activation alone. Ritanserin (1 mg kg- 1, i.p.) or ketanserin (0.16mgkg-1, i.p.) pretreatment reduced the reciprocal forepaw treading induced by high intrathecal doses of either 5-MeODMT (25.pg) or 5-CT (50,ug) suggesting that this behaviour may be facilitated by 5-HT2 receptor activation. 5. Intrathecal injection of 5-HT (0.05-50pg, after systemic fluoxetine, 5mg kg 1, i.p.), or 1-(3-chlorophenyl) piperazine (mCPP) produced dose-related forepaw-licking and grooming, neither of which were attenuated by ketanserin (0.16 mgkg-1, i.p.) pretreatment suggesting these behaviours may be mediated by 5-HT1c receptors. In contrast, 2-methyl-5-HT (50 and 100pg) produced sideward tail-flicks, not evoked by any other 5-HT agonist and could therefore be mediated by spinal 5-HT3 receptor activation. 6. These data provide behavioural evidence for the existence of spinal 5-HT2 receptors which produce a novel motor behaviour, BMC. Ligand binding studies and dose-response studies with a range of selective 5-HT antagonists are required to establish whether BMC and WDS are mediated by different subtypes of 5-HT2 receptors.

Inhibition of DOI-induced wet dog shakes in the guinea-pig by 5-HT2 receptor antagonists

The preferential 5-HT( 2)/5-HT(1C) receptor agonist DOI (0.1-4 mg/kg s.c.) caused an increase in locomotor activity, grooming and 'wet-dog' shakes (WDS) in the adult guinea-pig. The DOI-induced WDS behaviour was potently inhibited by several antagonists that have high affinity for the 5-HT(2) binding site. The WDS response is likely to be centrally-mediated since the effects of peripherally administered DOI were poorly antagonized by the peripherally-acting 5-HT(2) receptor antagonist BW501C67. Although these studies do not exclude an effect of DOI at 5-HT(1C) receptors, the high potency of ketanserin and spiperone in attenuating the effects of DOI would suggest an effect at the 5-HT(2) receptor. The present data suggest that antagonism of the directly-acting agonist DOI may be useful for assessing the selectivity and duration of action of centrally-acting 5-HT(2) receptor antagonists in the guinea-pig.

カイニン酸間けつ投与時に見られるラットのＷｅｔ‐ｄｏｇ ｓｈａｋｅｓの減弱とけいれん発現の変化

The effect of an intermittent administration of kainic acid on the KA-induced behavior, scratching, wet-dog shakes and limbic seizures was studied in the rat. Nine mg/kg kainic acid was injected i.p. at 3, 7, 14 or 21 days after the priming with the same dose of kainic acid at 25 days of age. There was no significant effect of KA-priming on the onset time of scratching. The frequency of wet-dog shakes decreased significantly in all the KA-primed rats. Fourteen day-priming of kainic acid was most effective for reducing the wet-dog shakes response. The onset time of limbic seizures tended to be shorter in all the KA-primed groups; seven day-priming resulted in a significant decrease. Histological findings showed a delay in the formation of dendritic processes of pyramidal cells in the CA3 area of the hippocampus. The results indicated that an intermittent administration of kainic acid with an interval of 3 to 21 days induces a marked tolerance in the wet-dog shakes response to kainic acid in juvenile rats, while no change in the scratching and an acceleration of the onset of limbic seizures were shown, implying that different neuronal systems are involved in these three behaviors induced by kainic acid.

Biochemical and behavioural effects of isamoltane, a ?-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain

The biochemical and behavioural effects of isamoltane, a beta-adrenoceptor and 5-HT1B receptor antagonist that has higher affinity for 5-HT1B receptors than for 5-HT1A receptors, on 5-HT neurotransmission in the rat brain were examined. In binding experiments isamoltane was found to be about five times more potent as a ligand for the 5-HT1B receptor than for the 5-HT1A receptor (Ki values 21 and 112 nmol/l, respectively). Isamoltane increased the K(+)-evoked overflow of 3H from 3H-5-HT loaded slices of rat occipital cortex at 0.1 mumol/l, consistent with inhibition of the terminal 5-HT autoreceptor. In vivo, isamoltane significantly increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus and hippocampus indicating an increased 5-HT turnover with a maximal effect at 3 mg/kg s.c. A higher dose produced a less pronounced effect. This effect did not seem to be due to the beta-adrenoceptor blocking action of isamoltane since the beta-adrenoceptor antagonists. (-)-alprenolol, betaxolol or ICI 118.551 had no significant effects on 5-HT turnover at 5 mg/kg s.c. Isamoltane at 3 mg/kg s.c. induced the wet-dog shake response which was blocked by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. In contrast, the same response induced by the 5-HT2 receptor agonist quipazine was not blocked by pretreatment with p-chlorophenylalanine. The wet-dog shakes evoked by isamoltane and quipazine were blocked by ritanserin, which indicates that 5-HT2 receptors are involved in their expression. These observations indicate that isamoltane, by inhibiting the terminal 5-HT autoreceptors, increased the synaptic concentration of 5-HT to a level that induced a behavioural response.

Shaking behaviour induced by putrescine in naive rats: a pharmacological and histological study.

In untreated rats, the intraperitoneal injection of putrescine evoked a typical wet-dog shake response, that was maximal at a dose of 300 mg/kg and at room temperature (22 degrees) (number of shakes: 84.00 +/- 17.90/hr). In a hot environment (30 degrees) the number of shakes was markedly reduced (26.90 +/- 5.19/hr). The putrescine-induced shaking behaviour was unaffected by atropine, bicuculline, chlorpheniramine, cimetidine, methysergide, naloxone and noradrenaline, but was markedly antagonized by morphine. Naloxone pretreatment nullified the antagonistic activity of morphine. Histological studies showed marked alterations in brain vascular permeability, which was increased by putrescine. Morphine completely prevented this putrescine-induced vascular effect. These results suggest a correlation between WDS produced by putrescine and increase in brain vascular permeability. Furthermore they show that morphine can affect brain vascular permeability.