Blockade of α2-adrenergic or metabotropic glutamate receptors induces glutamate release in the locus coeruleus to activate descending inhibition in rats with chronic neuropathic hypersensitivity.

Locus coeruleus (LC)-spinal noradrenergic projections are important to endogenous analgesic mechanisms and can be activated by local glutamate signaling in the LC. The current study examined the local glutamatergic, GABAergic, and noradrenergic influences on glutamate release in the LC and noradrenergic descending inhibition in rats 6 weeks after spinal nerve ligation (SNL). Intra-LC injection of the α2 adrenoceptor antagonist idazoxan or the group 2 metabotropic glutamate receptor (mGluR) antagonist (RS)-α-Methyl-4-tetrazolylphenylglycine (MTPG) increased withdrawal thresholds in SNL animals and this was reversed by the blockade of α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors in the LC or α2-adrenoceptors in the spinal cord, but not in normal animals. Neither blockade of GABA-A nor GABA-B receptors in the LC affected withdrawal thresholds in normal and SNL animals. Intra-LC perfusion of idazoxan increased extracellular glutamate in the LC in SNL animals but not in normal animals. Intra-LC perfusion of MTPG increased extracellular glutamate in the LC in both normal and SNL animals. These results suggest that local noradrenaline and glutamate tonically inhibit glutamate release in the LC after peripheral nerve injury and this may contribute to reduced descending inhibition in response to noxious input during chronic neuropathic pain.

Combining isoflurane anesthesia with midazolam and butorphanol in rats.

Representative inhalant anesthetic agent, isoflurane is commonly used during surgery in rats. However, isoflurane mediates relatively strong respiratory depression. In human and veterinary medicine, sedatives and analgesics are co-administered to complement the anesthetic action of inhalant anesthesia. The present study aimed to establish the novel balanced anesthesia that combines midazolam and butorphanol with isoflurane (MBI) in rats. Male Sprague Dawley rats were divided into 2 groups, and administered either isoflurane monoanesthesia or isoflurane with midazolam (2.5 mg/kg, ip) and butorphanol (2.0 mg/kg, ip). The minimum alveolar concentration (MAC) in each group was evaluated. Induction and recovery times were measured in each group. Adverse reactions during induction were also recorded. In each group, vital signs were assessed for 1 h under 1.5×MAC of isoflurane. Instability of vital signs was assessed under each anesthesia by calculating coefficient of variance. Compared with isoflurane monoanesthesia, MBI anesthesia caused 32% MAC reduction (isoflurane monoanesthesia: 1.30 ± 0.09%, MBI 0.87 ± 0.08%, P<0.05). MB premedication mediated smooth sedating action with low incidence of adverse reactions such as urination and defecation. Isoflurane monoanesthsesia remarkably decreased respiratory rate and saturation O2 (SPO2). In contrast, MBI anesthesia resulted in a relatively stable respiratory rate without decreases in SPO2 during the anesthetic period. In summary, MB premedication is effective for attenuating respiratory depression induced by isoflurane, and achieving smooth induction. This anesthetic protocol serves as a novel option for appropriate anesthesia in rats.

Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures.

Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.

IMMOBILIZING THE VULNERABLE APENNINE CHAMOIS (RUPICAPRA PYRENAICA ORNATA) WITH A LOW-DOSE XYLAZINE-KETAMINE COMBINATION, REVERSED WITH IDAZOXAN OR ATIPAMEZOLE.

Little information is available on chemical capture of the vulnerable subspecies within the genus Rupicapra. Low-dosage combinations of xylazine and ketamine were tested for immobilization of captive and free-ranging Apennine chamois, Rupicapra pyrenaica ornata (85 and 66 immobilizations, respectively) in a retrospective analysis. Of the six dosage groups, all of them providing an acceptable level of immobilization, the optimal trade-off between safety and efficacy was found following administration of a mean dosage of 0.24±0.03 mg/kg xylazine and 1.07±0.15 mg/kg ketamine, resulting in 7.50±3.31 min induction time, deep sedation with no or limited reaction to handling in 96% of the chamois, minimal deviation of physiologic parameters from previously reported physiologic values for anesthetized or physically restrained chamois, and no mortality. Intravenous injection of idazoxan (0.05±0.01 mg/kg) or atipamezole (0.38±0.37 mg/kg) resulted in faster reversal than intravenous injection of tolazoline (1.05±0.15 mg/kg) in 1.3 vs. 4.1 min. When free-ranging chamois were darted with similar xylazine and ketamine dosages, induction time was 8.49±5.48 min, 88% of the animals were deeply sedated, and a single animal died from respiratory arrest (1.5% mortality). Intramuscular atipamezole provided smoother reversal than intravenous idazoxan. The results of this study suggest that xylazine/ketamine combinations, at remarkably lower dosage than previously published in Caprinae, may be safely and effectively used in chemical capture protocols of Apennine chamois, to facilitate conservation-oriented relocation and research.

Both α1- and α2-adrenoceptors in the insular cortex are involved in the cardiovascular responses to acute restraint stress in rats.

The insular cortex (IC) is a limbic structure involved in cardiovascular responses observed during aversive threats. However, the specific neurotransmitter mediating IC control of cardiovascular adjustments to stress is yet unknown. Therefore, in the present study we investigated the role of local IC adrenoceptors in the cardiovascular responses elicited by acute restraint stress in rats. Bilateral microinjection of different doses (0.3, 5, 10 and 15 nmol/100 nl) of the selective α1-adrenoceptor antagonist WB4101 into the IC reduced both the arterial pressure and heart rate increases elicited by restraint stress. However, local IC treatment with different doses (0.3, 5, 10 and 15 nmol/100 nl) of the selective α2-adrenoceptor antagonist RX821002 reduced restraint-evoked tachycardia without affecting the pressor response. The present findings are the first direct evidence showing the involvement of IC adrenoceptors in cardiovascular adjustments observed during aversive threats. Our findings indicate that IC noradrenergic neurotransmission acting through activation of both α1- and α2-adrenoceptors has a facilitatory influence on pressor response to acute restraint stress. Moreover, IC α1-adrenoceptors also play a facilitatory role on restraint-evoked tachycardiac response.

The effect of piribedil on L-DOPA-induced dyskinesias in a rat model of Parkinson's disease: differential role of α(2) adrenergic mechanisms.

Piribedil is a non-ergoline, dopamine D(2)/D(3) receptor agonist with α(2) adrenoceptor antagonist properties that has been used in the treatment of Parkinson's disease (PD). Noradrenergic neurotransmission may be involved in the pathogenesis of dyskinesias induced by chronic treatment with L-DOPA (3,4-dihydroxyphenylalanine, levodopa), but its role in the in vivo action of piribedil or on different subclasses of abnormal involuntary movements (AIMs) remains unclear. The aims of this study were therefore (1) to investigate the anti-dyskinetic effects of piribedil on L-DOPA-induced contralateral turning behaviour, locomotive dyskinesias (LD), axial dystonia (AD), orolingual dyskinesia (OD) and forelimb dyskinesia (FD) and (2) to compare these effects to the α(2) adrenoceptor antagonist, idazoxan, or the α(2) adrenoceptor agonist, clonidine. Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and injected intraperitoneally twice daily with L-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg). After 3 weeks, the effects of piribedil (5, 15, 40 mg/kg), clonidine (0.15 mg/kg), idazoxan (10 mg/kg) and combinations of these drugs were scored during 2 h. Pre-treatment with 5 and 40 mg/kg, but not 15 mg/kg, of piribedil reduced turning behaviour and AD, OD and FD, but piribedil increased LD at the 40 mg/kg doses compared to the L-DOPA group. Idazoxan induced similar effects as piribedil (40 mg/kg), except that it had no effect on LD. Idazoxan blocked the effect of piribedil on AD and FD. Clonidine reduced all AIMs except OD, possibly because of its sedative effect. Clonidine blocked the effect of piribedil on AD, OD and FD. These data suggest a differential involvement of α(2) adrenergic receptors in the action of piribedil on different subclasses of L-DOPA-induced dyskinesias.

Intestinal fatty acid infusion modulates food preference as well as calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways in rats.

The intestine plays important roles in the regulation of feeding behavior by sensing macronutrients. Intestinal fatty acids strongly suppress food intake, but little is known about whether intestinal fatty acids affect food preference. We investigated the effects of jejunal fatty acids infusion on food preference by conducting two-diet choice experiments in rats fed a high-fat diet (HFD) and a high-carbohydrate diet (HCD). Jejunal linoleic acid (18:2) infusion reduced HFD intake dose-dependently, while HCD intake increased with the middle dose of the infusion we examined (100 µL/h) and reduced to the control level with the higher doses (150 and 200 µL/h). α-Linolenic acid (18:3), but not caprylic acid (8:0), altered the food preference and total calorie intake in the same manner as linoleic acid. Linoleic acid infusion dose-dependently increased plasma glucagon-like peptide-1, peptide YY and cholecystokinin levels, but not ghrelin levels. Subdiaphragmatic vagotomy or midbrain transection prevented the change in food preference and total calorie intake by linoleic acid infusion. Jejunal linoleic acid infusion increased norepinephrine turnover in the paraventricular hypothalamic nucleus, while intracerebroventricular injection of idazoxan, an α2-adrenergic receptor (AR) antagonist, suppressed the increased HCD intake, but did not affect the decreased HFD intake. These findings indicated that intestinal long-chain fatty acids modulated food preference as well as total calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways. The effects of the α2-AR antagonist in the brain suggested that the brain distinctly controlled HCD and HFD intake in response to jejunal linoleic acid infusion.

The alpha2 adrenergic receptor antagonist idazoxan, but not the serotonin-2A receptor antagonist M100907, partially attenuated reward deficits associated with nicotine, but not amphetamine, withdrawal in rats.

Based on phenomenological similarities between anhedonia (reward deficits) associated with drug withdrawal and the negative symptoms of schizophrenia, we showed previously that the atypical antipsychotic clozapine attenuated reward deficits associated with psychostimulant withdrawal. Antagonism of alpha(2) adrenergic and 5-HT(2A) receptors may contribute to these effects of clozapine. We investigated here whether blockade of alpha(2) or 5-HT(2A) receptors by idazoxan and M100907, respectively, would reverse anhedonic aspects of psychostimulant withdrawal. Idazoxan treatment facilitated recovery from spontaneous nicotine, but not amphetamine, withdrawal by attenuating reward deficits and increase the number of somatic signs. Thus, alpha(2) adrenoceptor blockade may have beneficial effects against nicotine withdrawal and may be involved in the effects of clozapine previously observed. M100907 worsened the anhedonia associated with nicotine and amphetamine withdrawal, suggesting that monotherapy with M100907 may exacerbate the expression of the negative symptoms of schizophrenia or nicotine withdrawal symptoms in people, including schizophrenia patients, attempting to quit smoking.

Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: implications for neurodegeneration.

Evidence indicates that the monoamine neurotransmitter noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and consequently may play a neuroprotective role where inflammatory events contribute to CNS pathology. Here we examined the ability of pharmacologically enhancing central noradrenergic tone to induce expression of anti-inflammatory cytokines in rat brain. Administration of the noradrenaline reuptake inhibitor reboxetine (15mg/kg; ip) combined with the alpha(2)-adrenoceptor antagonist idazoxan (1mg/kg; ip) induced interleukin-10 (IL-10) expression in rat cortex and hippocampus. In addition, these drug treatments induced IL-10 signaling as indicated by increased STAT3 phosphorylation and suppressor of cytokine signaling-3 (SOCS-3) mRNA expression. In contrast to the profound increase in IL-10 induced by the reboxetine/idazoxan combination, the other two broad spectrum anti-inflammatory cytokines IL-4 and TGF-beta were not induced by this treatment. The ability of combined treatment with reboxetine and idazoxan to induce IL-10 and SOCS3 expression was mediated by beta-adrenoceptor activation, as their induction was blocked by pre-treatment with the beta-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant beta(2)-adrenoceptor agonist clenbuterol induced a time- and dose-dependent increase in central IL-10 and SOCS3 expression, and the ability of clenbuterol to induce IL-10 and SOCS-3 expression was blocked by the centrally acting beta-adrenoceptor antagonist, propranolol, and was mimicked by the highly selective beta(2)-adrenoceptor agonist formoterol. In all, these data indicate that increasing central noradrenergic tone induces IL-10 production and signaling in the CNS, which may protect against neurodegeneration.

Adjunctive alpha2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission.

Compared to both first- and second-generation antipsychotic drugs (APDs), clozapine shows superior efficacy in treatment-resistant schizophrenia. In contrast to most APDs clozapine possesses high affinity for alpha2-adrenoceptors, and clinical and preclinical studies provide evidence that the alpha2-adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D2 receptor antagonists as well as olanzapine. Risperidone has lower affinity for alpha2-adrenoceptors than clozapine but higher than most other APDs. Here we examined, in rats, the effects of adding idazoxan to risperidone on antipsychotic effect using the conditioned avoidance response (CAR) test, extrapyramidal side-effect (EPS) liability using the catalepsy test, brain dopamine efflux using in-vivo microdialysis in freely moving animals, cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission using intracellular electrophysiological recording in vitro, and ex-vivo autoradiography to assess the in-vivo alpha2A- and alpha2C-adrenoceptor occupancies by risperidone. The dose of risperidone needed for antipsychotic effect in the CAR test was approximately 0.4 mg/kg, which produced 11% and 17% in-vivo receptor occupancy at alpha2A- and alpha2C-adrenoceptors, respectively. Addition of idazoxan (1.5 mg/kg) to a low dose of risperidone (0.25 mg/kg) enhanced the suppression of CAR, but did not enhance catalepsy. Both cortical dopamine release and NMDA receptor-mediated responses were enhanced. These data propose that the therapeutic effect of risperidone in schizophrenia can be enhanced and its EPS liability reduced by adjunctive treatment with an alpha2-adrenoceptor antagonist, and generally support the notion that the potent alpha2-adrenoceptor antagonistic action of clozapine may be highly important for its unique efficacy in schizophrenia.

Low doses of alpha 2-adrenoceptor antagonists augment spinal morphine analgesia and inhibit development of acute and chronic tolerance.

BACKGROUND AND PURPOSE: Ultra-low doses of opioid receptor antagonists augment spinal morphine antinociception and block the induction of tolerance. Considering the evidence demonstrating functional and physical interactions between the opioid and alpha(2)-adrenoceptors, this study investigated whether ultra-low doses of alpha(2)-adrenoceptor antagonists also influence spinal morphine analgesia and tolerance. EXPERIMENTAL APPROACH: Effects of low doses of the competitive alpha(2)-adrenoceptor antagonists-atipamezole (0.08, 0.8 ng), yohimbine (0.02, 2 ng), mirtazapine (0.02 ng) and idazoxan (0.08 ng) were investigated on intrathecal morphine analgesia, as well as acute and chronic morphine antinociceptive tolerance using the rat tail flick and paw pressure tests. KEY RESULTS: At doses markedly lower than those producing alpha(2)-adrenoceptor blockade, atipamezole, yohimbine, mirtazapine and idazoxan, prolonged the antinociceptive effects of morphine. When co-administered with repeated acute spinal injections of morphine, all four agents blocked the induction of acute tolerance. Co-injection of atipamezole with morphine for 5 days inhibited the development of tolerance in a chronic treatment paradigm. Spinal administration of atipamezole also reversed established antinociceptive tolerance to morphine as indicated by the restoration of morphine antinociceptive potency. The effects of atipamezole on spinal morphine tolerance were not influenced by treatment with 6-hydroxydopamine. CONCLUSIONS AND IMPLICATIONS: Low doses of competitive alpha(2)-adrenoceptor antagonists can augment acute morphine analgesia and block or reverse tolerance to spinal administration of morphine. These actions are interpreted in terms of their interaction with an opioid-alpha(2)-adrenoceptor complex, whose activity may have a function in the genesis of analgesic tolerance.

Alpha(2)-noradrenergic antagonist administration into the central nucleus of the amygdala blocks stress-induced hypoalgesia in awake behaving rats.

Stress-induced hypoalgesia (SIH) is an adaptive behavioral phenomenon mediated in part by the amygdala. Acute stress increases amygdalar noradrenaline levels and focal application of alpha(2)-adrenoceptor agonists in the central nucleus of the amygdala (CeA) is antinociceptive. We hypothesized that alpha(2)-adrenoceptor antagonist administration into the CeA may block SIH. Bilateral microinjections of drug or saline via chronically implanted CeA cannulae were followed by either a period of restraint stress or rest. The nocifensive paw-withdrawal latency (PWL) to a focused beam of light was measured. PWLs were longer in restrained rats, constituting SIH. Microinjection of the alpha(2)-adrenoceptor antagonist idazoxan into the CeA prior to restraint blocked SIH. Idazoxan administration in unrestrained rats had no effect. Microinjection of the alpha(2)-adrenoceptor agonist clonidine in unrestrained rats caused dose dependent hypoalgesia, mimicking the effects of environmental stress. alpha(2)-Adrenoceptor function in the CeA is necessary for restraint-induced SIH.

Involvement of basolateral amygdala alpha2-adrenoceptors in modulating consolidation of inhibitory avoidance memory.

These experiments investigated the role of the alpha(2)-adrenoceptors of the basolateral nucleus of the amygdala (BLA) in modulating the retention of inhibitory avoidance (IA). In Experiment 1, male Sprague Dawley rats implanted with bilateral cannulae in the BLA received microinfusions of a selective alpha(2)-adrenoceptor antagonist idazoxan 20 min either before or immediately after training. Retention was tested 48 h later. Idazoxan induced a dose-dependent enhancement of retention performance and was more effective when administered post-training. In Experiment 2, animals received pre- or post-training intra-BLA infusions of a selective alpha(2)-adrenoceptor agonist UK 14,304. The agonist induced a dose-dependent impairment of retention performance and, as with the antagonist treatments, post-training infusions were more effective. These results provide additional evidence that consolidation of inhibitory avoidance memory depends critically on prolonged activation of the noradrenergic system in the BLA and indicate that this modulatory influence is mediated, in part, by pre-synaptic alpha(2)-adrenoceptors.

Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery.

BACKGROUND: Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the alpha2delta subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain. METHODS: Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin. RESULTS: Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the alpha2-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. In humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements. CONCLUSIONS: These data suggest that gabapentin activates the descending noradrenergic system and induces spinal norepinephrine release, which produces analgesia via spinal alpha2-adrenoceptor stimulation, followed by activation of G protein-coupled inwardly rectifying potassium channels. The authors' clinical data suggest that gabapentin activates the descending noradrenergic system after preoperative oral administration at the time of surgery. These data support a central mechanism of oral gabapentin to reduce postoperative pain and suggest that this effect could be magnified by treatments that augment the effect of norepinephrine release.

Differential noradrenergic influence on seizure expression in genetically Fast and Slow kindling rat strains during massed trial stimulation of the amygdala.

The involvement of alpha(2) noradrenergic receptors during amygdala 'massed' stimulation (MS) was examined in rats that were selectively bred to be seizure-prone (Fast) or seizure-resistant (Slow) to amygdala kindling. The selective alpha(2) noradrenergic agonist guanfacine, or the antagonist idazoxan, was intraperitoneally injected during the MS procedure to study subsequent changes in afterdischarge (AD) threshold, AD duration and behavioral seizure expression. These measurements were again assessed weekly for 2 weeks after the MS treatment. Daily kindling began immediately thereafter. Following 6 stage-5 once daily convulsive seizures, guanfacine or idazoxan were re-administered. With idazoxan, the Slow rats expressed greater numbers of convulsive seizures and longer AD durations compared to guanfacine or saline controls during MS treatment. This pro-convulsive property of idazoxan was absent in Fast rats. By contrast, Fast rats showed enhanced convulsive expression in the presence of guanfacine. In the fully kindled rat, idazoxan and guanfacine differentially impacted seizure duration and severity in the Slow rats, but again not in the Fast rats. These data suggest that some aspect(s) of the alpha(2) noradrenergic system in the Fast and Slow rats are dissimilar and the mechanisms by which these receptors govern seizure genesis and propagation may be genetically controlled and distinct.

Endogenous alpha2-adrenergic receptor-mediated neuroprotection after severe hypoxia in preterm fetal sheep.

Central alpha-adrenergic receptor activity is important for fetal adaptation to hypoxia before birth. It is unclear whether it is also important during recovery. We therefore tested the hypothesis that an infusion of the specific alpha(2)-adrenergic receptor antagonist idazoxan (1 mg/kg/h i.v.) from 15 min to 4 h after profound hypoxia induced by 25 min umbilical cord occlusion in fetal sheep at 70% of gestation (equivalent to the 28-32 weeks in humans) would increase neural injury. After 3 days' recovery, idazoxan infusion was associated with a significant increase in neuronal loss in the hippocampus (P<0.05), expression of cleaved caspase-3 (P<0.05), and numbers of activated microglia (P<0.05). There was no significant effect on other neuronal regions or on loss of O4-positive premyelinating oligodendrocytes in the subcortical white matter. Idazoxan was associated with an increase in evolving epileptiform electroencephalographic (EEG) transient activity after occlusion (difference at peak 2.5+/-1.0 vs. 11.7+/-4.7 counts/min, P<0.05) and significantly reduced average spectral edge frequency, but not EEG intensity, from 54 until 72 h after occlusion (P<0.05). Hippocampal neuronal loss was correlated with total numbers of epileptiform transients during idazoxan infusion (P<0.01; r(2)=0.7). In conclusion, endogenous inhibitory alpha(2)-adrenergic receptor activation after severe hypoxia appears to significantly limit evolving hippocampal damage in the immature brain.

A comparison of neurokinin 1 receptor knock-out (NK1-/-) and wildtype mice: exploratory behaviour and extracellular noradrenaline concentration in the cerebral cortex of anaesthetised subjects.

In behavioural screens, mice lacking functional NK1 receptors (NK1-/-) resemble wildtypes (NK1+/+) that have been given an antianxiety/antidepressant drug. Most, if not all, antidepressants increase noradrenergic transmission in the brain. Here, we have used in vivo microdialysis to compare the concentrations of extracellular noradrenaline ('efflux') in the cerebral cortex of anaesthetised NK1-/- and NK1+/+ mice. The effects of systemic administration of the antidepressant, desipramine, with and without local infusion of the alpha(2)-adrenoceptor antagonist, RX821002, were also evaluated. Finally, we compared the effects of desipramine on behaviour of NK1+/+ and NK1-/- mice in an activity chamber and in a light/dark exploration box. Basal noradrenaline efflux was increased 2 to 4-fold in NK1-/- mice compared with NK1+/+ mice but there was no difference in the effects of desipramine. RX821002 increased noradrenaline efflux in all vehicle-injected mice but, in desipramine-pretreated mice, noradrenaline efflux was increased in NK1+/+ mice, only. All behaviours in the light/dark exploration box differed in the two genotypes. Furthermore, with the exception of 'grooming', the effects of desipramine on behaviour of NK1-/- mice could be explained by the effects of this antidepressant on locomotor activity. Finally, alpha(2)-adrenoceptors are possibly desensitised in NK1-/- mice. We have yet to establish whether this is a cause or a consequence of the increased noradrenaline efflux.

Activation of alpha2-adrenergic receptors into the lateral parabrachial nucleus enhances NaCl intake in rats.

Water and NaCl intake is strongly inhibited by the activation of alpha(2)-adrenergic receptors with clonidine or moxonidine (alpha(2)-adrenergic/imidazoline agonists) injected peripherally or into the forebrain and by serotonin and cholecystokinin in the lateral parabrachial nucleus (LPBN). Considering that alpha(2)-adrenergic receptors exist in the LPBN and the similar origin of serotonergic and adrenergic afferent pathways to the LPBN, in this study we investigated the effects of bilateral injections of moxonidine alone or combined with RX 821002 (alpha(2)-adrenergic antagonist) into the LPBN on 1.8% NaCl and water intake induced by the treatment with s.c. furosemide (10mg/kg)+captopril (5 mg/kg). Additionally, we investigated if moxonidine into the LPBN would modify furosemide+captopril-induced c-fos expression in the forebrain. Male Holtzman rats with cannulas implanted bilaterally in the LPBN were used. Contrary to forebrain injections, bilateral LPBN injections of moxonidine (0.1, 0.5 and 1 nmol/0.2 microl) strongly increased furosemide+captopril-induced 1.8% NaCl intake (16.6+/-2.7, 44.5+/-3.2 and 44.5+/-4.3 ml/2 h, respectively, vs. vehicle: 6.9+/-1.5 ml/2 h). Only the high dose of moxonidine increased water intake (23.3+/-3.8 ml/2 h, vs. vehicle: 12.1+/-2.6 ml/2 h). Prior injections of RX 821002 (10 and 20 nmol/0.2 microl) abolished the effect of moxonidine (0.5 nmol) on 1.8% NaCl intake. Moxonidine into the LPBN did not modify furosemide+captopril-induced c-fos expression in forebrain areas related to the control of fluid-electrolyte balance. The results show that the activation of LPBN alpha(2)-adrenergic receptors enhances furosemide+captopril-induced 1.8% NaCl and water intake. This enhancement was not related to prior alteration in the activity of forebrain areas as suggested by c-fos expression. Previous and present results indicate opposite roles for alpha(2)-adrenergic receptors in the control of sodium and water intake according to their distribution in the rat brain.

Chronic lithium administration enhances noradrenergic responses to intravenous administration of the alpha2 antagonist idazoxan in healthy volunteers.

The acute and chronic effects of lithium carbonate administration at therapeutic blood levels on peripheral noradrenergic activity and sympathetic responses to alpha2 adrenoceptor blockade were examined in 10 medically and psychiatrically healthy volunteers. Supine resting levels of plasma norepinephrine and the increases in norepinephrine following intravenous infusion of 200 microg/kg of idazoxan, a selective alpha2 adrenoceptor antagonist, were determined before lithium (Li+) administration and after 5 days and after 4 weeks of daily Li+ treatment. Chronic Li+ treatment significantly increased mean resting plasma norepinephrine levels by 53.6%. The noradrenergic responses to infusions of idazoxan were slightly enhanced after 5 days of Li+ administration and significantly increased following 4 weeks of Li+ treatment. The possibility that Li+ produces functional alpha2 subsensitivity causing enhanced peripheral noradrenergic activity in humans is supported by the findings of increased mean resting plasma norepinephrine and increased response to idazoxan following chronic Li+ administration. Alteration of regulatory mechanisms in the noradrenergic system may be relevant to understanding the clinical effects of Li+ in manic-depressive illness.

Sympathetic mechanisms in cerebral blood flow alterations induced by spinal cord stimulation.

OBJECT: Cervical spinal cord stimulation (SCS) has been found to augment cerebral blood flow (CBF) in a number of animal models, although the mechanisms underlying the cerebrovascular effects of SCS are poorly described. In this study, the authors examined the role of sympathetic tone in CBF alterations induced by SCS in rats. METHODS: Spinal cord stimulation was performed at three intervals while CBF was monitored with laser Doppler flowmetry (LDF). Either hexamethonium (5, 10, or 20 mg/kg), prazosin (0.25, 0.5, or 1 mg/kg), idazoxan (0.5, 1, or 2 mg/kg), propranolol (1, 2, or 4 mg/kg), or vehicle was administered intravenously before the second stimulation. Changes in LDF values due to SCS were recorded as the percentage of change from baseline values and were analyzed. In vehicle-treated animals, SCS increased LDF values by 60.5 +/- 1.8% over baseline, whereas both high-dose hexamethonium and prazosin completely abolished the SCS-induced increases in LDF values. On the other hand, LDF values increased by 50.9 +/- 4% and 61.4 +/- 4% after SCS in the presence of idazoxan or propranolol, respectively. Administration of sympathetic nervous system blockers resulted in a variable degree of systemic hypotension as well. Nevertheless, induced hypotension without sympathetic blockade had only a minimal effect on SCS-induced augmentation of LDF values (48 +/- 1.4% over baseline). CONCLUSIONS: Sympathetic tone plays a major role in SCS-induced increases in CBF. This effect seems to be mediated primarily by alpha1-adrenergic receptors. Systemic hypotension alone cannot explain the effects of sympathetic blockade on the SCS response. Clinical use of SCS in the treatment of cerebral ischemia should take alpha1-adrenergic receptor sympathetic tone into account.