Wet Dog Shakes Research Articles

Immunohistochemical observation of the postnatal development of the orexin neuron in the rat brain

Orexin (hypocretin) neuropeptides play a pivotal role in expression of opioid withdrawal signs. Hypothalamic orexinergic neurons provide dense afferents for the nucleus locus coeruleus (LC). Somatic signs of opioid withdrawal are associated with the enhanced activity of LC neurons. In addition, intra-LC administration of orexin-A leads to the hyperactivity of LC neurons. The present study was an attempt to investigate whether intra-LC microinjection of orexin-A induces morphine withdrawal-like signs in both morphine dependent and control rats. To end this, adult male Wistar rats weighing 250–300 g were used. For induction of morphine dependence, animals received morphine sulfate subcutaneously (10 mg/kg, s.c.) at an interval of 12 h for 9 days. On day 10, intra-LC orexin injection (100 μM, 200 nl) was carried out two hours after last morphine administration. Morphine withdrawal-like signs were assessed in a transparent Plexiglas test chamber (30 cm diameter, 50 cm height) for 25 min. Orexin-A microinjection induced some morphine withdrawal-like signs in both morphine dependent (chewing, scratching, rearing, teeth chattering, wet-dog shake and paw tremor) and control (chewing, scratching, rearing, sniffing, wet-dog shake and head tremor) rats. Furthermore, microinjection of SB-334867, a selective orexin type-1 receptor antagonist before orexin-A significantly suppressed orexin-induced morphine withdrawal-like signs. It seems that orexin-A, via increasing the activity of LC neurons, mediates the induction of some morphine withdrawal-like signs independent of morphine dependence.

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.

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

Icilin, a cooling compound, produces vigorous wet-dog shakes in rats. We have reported previously that icilin-induced wet-dog shakes are blocked by the kappa opioid receptor agonists, nalfurafine and U50,488H, and that icilin evokes a dose- and time-dependent increase in glutamate within the dorsal striatum. Since activation of kappa opioid receptors inhibits glutamate release intrastriatally, we targeted glutamate release within the dorsal striatum using nalfurafine and examined the role of the dorsal striatum in icilin-induced wet-dog shakes, more specifically, the effect that icilin-evoked intrastriatal glutamate release has on the overt stimulant behavior. We report that nalfurafine (0.04 mg/kg) inhibits icilin (0.50 mg/kg)-induced wet-dog shakes and that this inhibition is reversed by intrastriatal perfusion of the kappa opioid receptor antagonist, norbinaltorphimine (100 nM). Furthermore,we antagonized icilin-evoked glutamate release with nalfurafine (0.04 mg/kg), and reversed inhibition of glutamate release with intrastriatal norbinaltorphimine (100 nM). These findings support a central component in the behavioral response to icilin and suggest that activation of kappa opioid receptors antagonizes icilin-induced wet-dog shakes in rats by inhibiting glutamate release within the dorsal striatum.

Effects of some antiepileptics on septal-kindled seizures in rats

Purpose The present study was performed to understand the characteristics of septal kindling in rats, especially the efficacies of antiepileptic drugs in comparison with amygdala kindling. Methods Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus, and electrodes were implanted into the right frontal cortex, the hippocampus, the lateral septal and the amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. Bipolar stimulation was applied to the lateral septal or the amygdala every day until a generalized seizure was obtained. Carbamazepine (CBZ), zonisamide (ZNS) and clobazam (CLB) were orally administered to fully kindled rats. Result A considerable number of stimulations was required to establish septal-kindled seizures. In addition, wet dog shakes were observed during the septal kindling procedure, different from amygdala kindling. The oral administration of CBZ, ZNS and CLB caused a dose-dependent inhibition both of seizure stage and after-discharge (AD) duration of septal-kindled seizures. CBZ and ZNS caused a more potent inhibition of septal-kindled seizures than amygdala kindled seizures, whereas CLB inhibited both septal and amygdala kindled seizures to almost the same extent. Conclusion Septal kindling was confirmed to possess some characteristics, which were evidently different from that of amygdala kindling. In addition, it was demonstrated that septal kindling was also available as a model for the evaluation of antiepileptic drugs.

Calmodulin-Stimulated Adenylyl Cyclase Gene Deletion Affects Morphine Responses

To define the roles of the calmodulin-stimulated adenylyl cyclases (AC1 and AC8) in morphine-induced analgesia, tolerance, physical dependence, and conditioned place preference, we used mice having targeted disruptions of either the AC1 or AC8 genes or both genes [double knockout mice (DKO)]. Mice lacking either AC1 or AC8 genes or DKO did not differ from wild-type mice in short-term antinociceptive responses to morphine measured in the tail-flick analgesia assay. Morphine tolerance that developed immediately within 3 h of morphine administration (10 mg/kg s.c.) was significantly attenuated in DKO mice and AC8 single knockout mice. Tolerance induced continually by daily injections of morphine (10 mg/kg s.c.) was also reduced in DKO mice. In DKO mice continually treated with morphine, there was a significant reduction in withdrawal behaviors, including reduced wet-dog shakes and forepaw tremor after naloxone injection (10 mg/kg i.p.). Morphine produced hyperlocomotion and conditioned place preference in wild-type mice, whereas DKO mice displayed significantly less hyperlocomotion and conditioned place preference. Furthermore, the significant increase in phosphorylated cAMP-response element binding protein (CREB) staining in ventral tegmental area induced by long-term morphine treatment was not evident in DKO mice, suggesting that CREB activation by morphine requires cAMP generated by AC1 and AC8. These results support the hypothesis that calmodulin-stimulated adenylyl cyclases are important mediators of the neuronal responses to morphine.

Hippocampal partial kindling decreased hippocampal GABA B receptor efficacy and wet dog shakes in rats

To test the hypothesis that GABA B receptor efficacy in the behaving rat decreases after partial hippocampal kindling, we measured GABA B receptor efficacy by the number of wet dog shakes (WDSs) induced by baclofen (5 mM in 0.2 μL of saline) infusion into the dorsal hippocampus; these WDSs were blocked by prior infusion of GABA B receptor antagonist CGP55845A. Rats were given 15 afterdischarges (ADs) evoked in CA1 over 3 days or control stimulations. The partially kindled rats (after 15 ADs) showed a significant decrease in baclofen-induced WDSs as compared to control rats, on days 1, 4 and 21 after kindling. In contrast, kindled and control rats did not show a significant difference in WDSs induced by hippocampal infusion of GABA A receptor antagonist bicuculline. Also, the number of WDSs induced after subcutaneous injection of serotonin-2A/2C agonist ± 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane was not different between kindled and control rats on 4 and 21 days after kindling. We further tested the hypothesis that the decrease in hippocampal AD-induced WDSs during kindling is caused by a decrease in GABA B receptor efficacy. However, we found no convincing evidence to support the latter hypothesis since the AD-induced WDSs were not suppressed by hippocampal infusion of CGP55845A, with the exception that CGP55845A infusion into ventral hippocampus suppressed both hippocampal ADs and WDSs. Together with results derived from previous electrophysiological studies in vitro, it is suggested that a decrease of GABA B receptor, possibly GABA B autoreceptor, efficacy may explain the decrease of baclofen-induced WDSs after hippocampal kindling.

Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats

Icilin is a cooling agent that precipitates vigorous wet-dog shakes in rats after acute i.p. administration. Recent research has emphasized the peripheral agonist properties (e.g. activation of transient receptor potential channels, TRPM8 and TRPA1) of icilin rather than its unusual and pronounced behavioral effects, often classified as quasi-morphine withdrawal. We tested selective opioid receptor agonists against icilin-induced wet-dog shakes in rats. Shaking was antagonized following s.c. pretreatment with the mu agonists, morphine (1, 2, 3 mg/kg) and buprenorphine (0.10 mg/kg) or the kappa agonists, nalfurafine (0.02, 0.04 mg/kg) and U50,488H (5 mg/kg). Pretreatment with ICI 204,448 (1, 5, 10 mg/kg), the peripherally directed kappa agonist, or the delta agonist, SNC 80 (0.30, 1, 3, 10 mg/kg), had no marked effect on the incidence of shaking. We conclude that (a) icilin can trigger shaking via interactions within the central nervous system and (b) mu and kappa opioid receptors are involved in suppressing this stimulant behavior.

Ethological analysis of scopolamine treatment or pretreatment in morphine dependent rats

Although scopolamine is currently used to treat morphine addiction in humans, its extensive actions on behaviors have not been systematically analyzed yet, and the underlying mechanisms of its effects still remain ambiguous. The present study was carried out to clarify the possible mechanisms by evaluating the effects of scopolamine pretreatment and treatment on naloxone-precipitated withdrawal signs and some of other general behaviors in morphine dependent rats. Our results showed that scopolamine pretreatment and treatment attenuated naloxone-precipitated withdrawal signs including jumping, writhing posture, weight loss, genital grooming, teeth-chattering, ptosis, diarrhea and irritability, except for wet dog shakes, while general behaviors such as water intake, urine volume and morphine excretion in urine were increased. Our findings suggest that scopolamine has significant actions in the treatment of opiate addiction, which might result from increasing morphine excretion from urine.

Effects of escitalopram on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of escitalopram, a selective serotonin reuptake inhibitor, on ethanol withdrawal syndrome in rats. Adult male Wistar rats (266–278 g) were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed with an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Escitalopram (2.5, 5 and 10 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the second and sixth hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes, tremors and audiogenic seizures were recorded or rated. A second series of injections was given 30 min before sixth hour of withdrawal test. Effects of escitalopram on the locomotor activities of the naïve (no ethanol-dependent) rats were also evaluated. Escitalopram (5 mg/kg) reduced the increased stereotyped behaviors at the sixth hour of ethanol withdrawal. It inhibited tremors at the second hour of ethanol withdrawal at doses of 5 and 10 mg/kg. Escitalopram (2.5 and 5 mg/kg) also produced some significant attenuations in the incidence of wet dog shakes at the second and sixth hours of the observation period. It was found ineffective on locomotor hyperactivity, agitation and audiogenic seizures. Escitalopram (2.5 and 5 mg/kg) did not cause any significant effect on locomotor activities of the naïve rats. Our results suggest that acute escitalopram treatment has some limited beneficial effects on ethanol withdrawal syndrome in rats.

Icilin evokes a dose- and time-dependent increase in glutamate within the dorsal striatum of rats

Icilin, the peripheral cold channel agonist, activates TRPM8 and TRPA1, localized on dorsal root ganglia and trigeminal neurons in rats. Icilin precipitates immediate wet-dog shakes in this species, which are antagonized by centrally acting mu and kappa opioid agonists, implicating the central nervous system in the behavioral response. We studied the effect icilin has on glutamate levels in the dorsal striatum, a brain region involved in movement. Icilin (0.25, 0.5 and 0.75 mg/kg, i.p.) elicited a dose- and time-dependent increase in glutamate within the striatum, indicative of icilin's neurochemical effect in rats.

Veratridine‐Induced Wet Dog Shake Behaviour and Apoptosis in Rat Hippocampus

We have previously evaluated veratridine as an in vitro model of seizure using conventional electrophysiological recordings in rat hippocampal CA1 pyramidal neurones. The aim of this investigation is to further characterize this convulsant as an in vivo model of seizure. Veratridine was administered intraperitoneally to male Fisher rats in a dose range of 100-400 mug/kg. Within 5 min. after the injections, the animals entered a quiescent period which was followed 10-15 min. later by facial automatism (washing), grooming, masticatory jaw movement and profuse salivation. This phenomenon was followed by the development of wet dog shake and forelimb clonus. The time (mean+/-S.E.M.) for the onset of induction of these shakes for all tested doses was 31.65+/-2.85 min. and the number of shakes (mean+/-S.E.M.) 30 min. after the onset was 17.2+/-2.85. The onset and number of wet dog shakes induced by veratridine was dose-dependent. No rat death was recorded until 2 weeks after the experiments. Histopathological studies of animals 2 weeks after veratridine administration showed evidence of apoptosis in the hippocampus. Our results indicate that veratridine produced a behavioural pattern of a limbic seizure which mimics temporal lobe epilepsy in man. Based on our previous findings in vitro and of this investigation in vivo, veratridine can be used as an experimental tool to evaluate potential antiepileptic drugs effective against this type of limbic behaviour.

Gender- and morphine dose-linked expression of spontaneous somatic opiate withdrawal in mice

The opiate withdrawal syndrome powerfully motivates opiate seeking and abuse. Development of effective medications for opiate withdrawal symptoms is thus a primary research goal and heavily relies on improved experimental models. This study was carried out to establish a clinically relevant paradigm to assess somatic opiate withdrawal in mice. Female and male C57BL/6J mice were treated with saline or increasing morphine doses (10–50 mg/kg or 20–100 mg/kg) during 6 consecutive days and tested for the spontaneous expression of somatic opiate withdrawal signs 8, 32, 56 and 80 h after last drug administration. Contrary to opioid receptor antagonist-precipitated procedures, the spontaneous opiate withdrawal paradigm used here revealed interesting gender- and morphine dose-linked differences. In particular, 56 h after last morphine administration elevated global opiate withdrawal scores were still evident in female but not in male mice treated with 20–100 mg/kg. The severity of somatic opiate withdrawal directly correlated with the prior cumulative morphine exposure. Timing of expression of somatic opiate withdrawal signs also varied as a function of both gender and morphine dose. For example, expression of paw tremors and wet dog shakes was earlier in opiate-withdrawn male than in female mice. Overall, these findings highlight the possibility to detect gender- and opiate dose-linked differences in the expression and duration of somatic opiate withdrawal using a clinically relevant research model. The behavioral paradigm described here may represent a more appropriate tool to investigate the neurobiological bases of opiate withdrawal as opposed to opioid receptor antagonist-precipitated opiate withdrawal procedures.

Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats

Effects of acute and chronic tianeptine treatments on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Acute or chronic (twice daily) tianeptine (5, 10 and 20 mg/kg) and saline were administered to rats intraperitoneally. Acute and last chronic tianeptine injections and saline were done 30 min before ethanol withdrawal testing. After 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, tremor, wet dog shakes, stereotyped behavior and audiogenic seizures were recorded or rated. Locomotor activity in naive (no ethanol-dependent rats) was also tested after acute tianeptine treatments. Acute but not chronic tianeptine treatment attenuated locomotor hyperactivity and agitation in ethanol-dependent rats. Both acute and chronic tianeptine treatment produced some significant inhibitory effects on tremor, wet dog shakes, stereotyped behaviors and audiogenic seizures during the ethanol withdrawal. Our results suggest that acute or chronic tianeptine treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

P.6.d.008 Calcium channel antagonists attenuate amphetamine-and nicotine-induced anxiety-related responses in mice

The possibility that central adenosine A1 and A2a receptors mediate opiate dependence was examined in morphine-treated mice using radioligand binding methods. Mice treated with morphine for 72 h demonstrated significant increases in naloxone-precipitated abstinence behaviors of jumping, wet-dog shakes, teeth chattering, forepaw treads, forepaw tremors and diarrhea compared to vehicle-treated mice. Increased concentrations of cortical adenosine A1 receptor sites, but not striatal adenosine A2a sites, were found in saturation binding studies from morphine-dependent mice. Decreases in cortical A1 agonist binding affinity values aling with increases in agonist binding sites were demonstrated in competition binding studies. These results suggest that adaptive changes of upregulation and sensitization of adenosine A1 receptors play a role in mediating the opiate abstinence syndrome.

Ionotropic glutamatergic neurotransmission in the ventral tegmental area modulates ΔFosB expression in the nucleus accumbens and abstinence syndrome in morphine withdrawal rats

The present study sought to assess whether the blockade of ionotropic glutamate receptors in the ventral tegmental area could modulate morphine withdrawal in morphine-dependent rats and the expression of stable ΔFosB isoforms in the nucleus accumbens during morphine withdrawal. Rats were injected (i.p.) with increasing doses of morphine for 1 week to develop physical dependence, and withdrawal was then precipitated by one injection of naloxone (2 mg/kg, i.p.). Abstinence signs such as jumping, wet-dog shake, writhing posture, weight loss, and Gellert-Holtzman scale score were recorded to evaluate naloxone-induced morphine withdrawal. Two ionotropic glutamate receptor antagonists, dizocilpine (MK-801) and 6, 7-dinitroquinnoxaline-2, 3-dione (DNQX), were microinjected unilaterally into the ventral tegmental area 30 min before naloxone precipitation. A second injection of naloxone (2 mg/kg i.p.) was given 1 h after the first naloxone injection to sustain a maximal level of withdrawal so that the expression of stable ΔFosB isoforms in the nucleus accumbens could be measured. This would enable determination of the correlation between the MK-801 or DNQX-induced decrease in somatic withdrawal signs and the change in neuronal activity in the nucleus accumbens. The results showed that both MK-801 and DNQX significantly alleviated all symptoms of morphine withdrawal except for weight loss and reduced the expression of stable ΔFosB isoforms within the nucleus accumbens. These data suggest that ionotropic glutamatergic neurotransmission in the ventral tegmental area regulates the levels of stable ΔFosB isoforms in the nucleus accumbens, which play a very important role in modulating opiate withdrawal.

Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine

18-Methoxyroconaridine (18-MC), a synthetic derivative of ibogaine, reduces morphine self-administration and alleviates several signs of acute opioid withdrawal in rats. Although there is already well documented evidence of the mechanism mediating 18-MC's action to reduce the rewarding effects of morphine, nothing is known about the mechanism responsible for 18-MC's attenuation of opioid withdrawal. In vitro studies have demonstrated that 18-MC is a potent antagonist of α 3β 4 nicotinic receptors (IC 50 = 0.75 μM), which are predominantly located in the medial habenula and interpeduncular nuclei. Previous work indicating that α 3β 4 nicotinic receptors mediate 18-MC's effects on drug self-administration prompted us to assess whether brain areas having high or moderate densities of α 3β 4 receptors might be involved in 18-MC's modulation of opioid withdrawal. To test this possibility, 18-MC was locally administered into the medial habenula, interpeduncular nucleus and locus coeruleus of morphine-dependent rats; this treatment was followed by naltrexone to precipitate a withdrawal syndrome. Pretreatment with various doses of 18-MC into the locus coeruleus significantly reduced wet-dog shakes, teeth chattering, burying and diarrhea, while pretreatment into the medial habenula attenuated teeth chattering, burying, and weight loss. Some doses of 18-MC administered into the interpeduncular nucleus significantly ameliorated rearing, teeth chattering, and burying, while other doses exacerbated diarrhea and teeth chattering. The present findings suggest that 18-MC may act in all three nuclei to suppress various signs of opioid withdrawal.

Effects of JDTic, a selective κ-opioid receptor antagonist, on the development and expression of physical dependence on morphine using a rat continuous-infusion model

JDTic, (3 R)-7-hydroxy- N-{(1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide, is a potent and selective κ -opioid antagonist with a very long duration of action [Carroll, F.I., Thomas, J.B., Dykstra, L.A., Granger, A.L., Allen, R.M., Howard, J.L., Pollard, G.T., Aceto, M.D., Harris, L.S., 2004. Pharmacological properties of JDTic: A novel k-opioid receptor antagonist. Eur. J. Pharmacol. 501, 111–119.]. When given 24 h prior to a continuous 4-day infusion of morphine sulfate in rats, JDTic did not prevent the stereotypy that developed during the infusion of morphine. It had no effect on the dramatic loss of body weight associated with the abrupt withdrawal of morphine. However, it decreased the number of important withdrawal signs designated wet-dog shakes and facial rubs. These data suggest that JDTic may find some application in the treatment of opiate abuse.

Long-term kindling of the basolateral amygdala impairs copulatory behavior in male rats

This experiment examined the consequences of long-term kindling of the basolateral amygdala on male sexual behavior and the frequency of both spontaneous wet dog shakes (WDS) and those induced by the 5-HT 2A receptor agonist DOI. Results demonstrated that following 60 stimulations of the left basolateral amygdala over a 4-week period, male Long–Evans rats exhibited decrements in every aspect of sexual behavior. Specifically, latencies to mount, intromit and ejaculate were all prolonged following long-term kindling, and ejaculation frequencies were significantly reduced. Furthermore, spontaneous peri-copulatory WDS were increased in kindled rats, suggesting a possible role of the 5-HT 2A receptor. However, countering this suggestion, there were no differences between sham and kindled rats on WDS induced by the 5-HT 2A receptor agonist DOI. These results suggest that kindled rats may exhibit elevated levels of endogenous serotonin during exposure to a female rat, which would attenuate copulatory behavior, while concurrently increasing WDS expression.

Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats

Nefiracetam is a novel pyrrolidone-type nootropic agent, and it has been reported to possess a potential for antiepileptic therapy as well as cognition-enhancing effects. We investigated the anticonvulsant and neuroprotective effects of nefiracetam in kainic acid-induced seizures of rats, compared with levetiracetam and standard antiepileptic drugs. Subcutaneous injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Nefiracetam (25, 50 and 100 mg/kg po) had no effect on the behavioral seizures and dose-dependently inhibited the hippocampal damage. In contrast, levetiracetam, a pyrrolidone-type antiepileptic drug, inhibited neither. Valproic acid and ethosuximide prevented the hippocampal damage without attenuating the behavioral seizures as nefiracetam. Zonisamide and phenytoin did not inhibit the behavioral seizures, while zonisamide enhanced the hippocampal damage and phenytoin increased the lethality rate. Carbamazepine inhibited the behavioral seizures at 50 mg/kg and enhanced that at 100 mg/kg, and it completely inhibited the hippocampal damage at both doses. We have previously reported that anticonvulsant spectrum of nefiracetam paralleled that of zonisamide, phenytoin or carbamazepine in standard screening models. However, the pharmacological profile of nefiracetam was closer to valproic acid or ethosuximide than that of zonisamide, phenytoin or carbamazepine in this study. These results suggest that anticonvulsant spectrum and mechanism of nefiracetam are distinct from those of standard antiepileptic drugs, and nefiracetam possesses a neuroprotective effect that is unrelated to seizure inhibition.

The ventral tegmental area as a putative target for tachykinins in cardiovascular regulation

Tachykinin receptor agonists and antagonists were microinjected into the ventral tegmental area (VTA) to study the relative participation of the three tachykinin receptors in cardiovascular regulation in freely behaving rat. Selective agonists (1-100 pmol) for NK1 ([Sar9, Met (O2)11]SP), NK2 ([beta-Ala8]NKA (4-10)) and NK3 (senktide) receptors evoked increases in blood pressure, heart rate (HR) along with behavioural manifestations (face washing, sniffing, head scratching, rearing, wet dog shake). At 1 pmol, NK1 and NK3 agonists did not affect behaviour and blood pressure but only HR. Tachykinin agonists-induced cardiovascular responses were selectively and reversibly blocked by the prior injection of antagonists for NK1 receptors (LY 303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane), 5 nmol), NK2 receptors (SR 48968 ([(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl)butyl]benzamide]), 250 pmol) and NK3 receptors (SB 235375 ((-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide), 25 nmol). With the exception of the NK2 agonist, most behavioural effects were also blocked by antagonists. Tachykinin agonists-induced cardiovascular responses were inhibited by intravenous (i.v.) treatments with antagonists for D1 dopamine receptor (SCH23390, 0.2 mg kg(-1)) and beta1-adrenoceptor (atenolol, 5 mg kg(-1)) but not for D2 dopamine receptor (raclopride, 0.16 mg kg(-1)). Behavioural responses were blocked by SCH23390 only. The present study provides the first pharmacological evidence that the three tachykinin receptors in the rat VTA can affect the autonomic control of blood pressure and HR by increasing midbrain dopaminergic transmission. This mechanism may be involved in the coordination of behavioural and cardiovascular responses to stress and noxious stimulation.