The effect of imidazoline receptors and alpha2-adrenoceptors on the anesthetic requirement (MAC) for halothane in rats

BACKGROUND: Recent evidences have documented that several pharmacologic actions of alpha2-adrenoceptor agonists are mediated via activation of not only alpha2-adrenoceptors, but also by imidazoline receptors, which are nonadrenergic receptors in the central nervous system. However, the effect of imidazoline receptors on the anesthesia is not well known, and it is important to clarify the effects of both receptors on anesthesia. METHODS: Seventy-two rats were anesthetized with halothane, and the anesthetic requirement for halothane was evaluated as minimum alveolar concentration (MAC). The MAC for halothane was determined in the presence of dexmedetomidine (0, 10, 20, and 30 microg/kg, intraperitoneally [IP]), a selective alpha2-adrenoceptor agonist with weak affinity for imidazoline receptors. Then, the authors evaluated the inhibitory effect of rauwolscine (20 mg/kg, IP), an alpha2-adrenoceptor antagonist with little affinity for imidazoline receptors, on the MAC-reducing action of dexmedetomidine (30 microg/kg). Further, the effect of rilmenidine (20, 50, 100, 1000 microg/kg, IP), a selective imidazoline receptor agonist, on the MAC for halothane was also investigated. RESULTS: Dexmedetomidine decreased the MAC for halothane dose-dependently, and this MAC-reducing action of dexmedetomidine was completely blocked by rauwolscine. Rilmenidine alone did not change the MAC for halothane. CONCLUSIONS: The present data indicate that the anesthetic sparing action of dexmedetomidine is most likely mediated through alpha2- adrenoceptors, and the stimulation of imidazoline receptors exerts little effect on the anesthetic requirement for halothane.     

Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers

BACKGROUND: Specific and selective alpha2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an alpha2-antagonist, in healthy persons. METHODS: The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 microg/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 microg/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h. RESULTS: The mean +/- SD atipamezole dose needed in part 1 was 104+/-44 microg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 microg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 microg/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. CONCLUSIONS: The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusion rate (75 microg x kg(-1) x min(-1)) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.     

Experimental reproduction of bovine fetal Neospora infection and death with a bovine Neospora isolate

It is well established that alpha 2-adrenoceptor agonists have sedative and antinociceptive properties. In the current behavioral study we tried to find out if the alpha 2-adrenergic sedative and antinociceptive effects can be dissociated. We tested the hypothesis that alpha 2-adrenergic sedation is mediated by the locus coeruleus (LC) and antinociception by spinal alpha 2-adrenoceptors. Also, we addressed the possibility that intracerebral injection of an alpha 2-agonist might produce its antinociceptive effect by an action directly at the spinal cord. Medetomidine, an alpha 2-adrenergic agonist, or atipamezole, an alpha 2-adrenergic antagonist, were microinjected bilaterally into the LC through chronic cannulae in unanesthetized Han-Wistar rats. The effect on locomotor activity (/vigilance), tail-flick and hot-plate response, and on formalin-induced pain behavior was determined. Medetomidine microinjected into the LC (1-10 micrograms/cannula) produced dose-dependently hypolocomotion (/sedation), increase of response latencies in the hot-plate and the tail-flick tests, and a decrease in the formalin-induced pain behavior. Hypolocomotion (/sedation) was obtained at a lower medetomidine dose (1 microgram/cannula) than antinociception (3-10 micrograms/cannula). The lowest medetomidine dose used (1 microgram/cannula), which induced significant hypolocomotion (/sedation), produced either no antinociception (hot-plate and tail-flick tests) or even a slight hyperalgesia (formalin test). The hypolocomotion (/sedation) but not antinociception (tail-flick test) induced by systemic administration of medetomidine (100 micrograms/kg s.c.) could be reversed by atipamezole (10 micrograms/cannula) microinjected into the LC. Only a high systemic dose of atipamezole (1 mg/kg s.c.) reversed the antinociceptive effects of medetomidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dexmedetomidine failed to block the acute hyperdynamic response to electroconvulsive therapy

BACKGROUND: Orally administered clonidine (0.2-0.3 mg) has been reported to decrease the acute hypertensive response to electroconvulsive therapy (ECT) without prolonging early recovery. This preliminary study was designed to evaluate the acute hemodynamic effects of the investigational alpha2-adrenergic agonist, dexmedetomidine, in patients undergoing a series of ECT treatments. METHODS: Six patients undergoing a series of three to six consecutive ECT treatments were studied according to a randomized, double-blind, placebo-controlled protocol All patients received either saline or dexmedetomidine, 0.5 or 1.0 microg/kg intravenously, 10-30 min before induction of anesthesia for ECT using a standardized anesthesia protocol. In addition to assessing the cardiovascular variables, the duration of seizure activity, degree of sedation, and time to discharge from the Phase I recovery unit were assessed. RESULTS: Although dexmedetomidine produced dose-related increases in the level of sedation before the ECT procedure, it failed to decrease the peak blood pressure and heart rate responses after the ECT treatment. The 0.5 and 1.0 microg/kg doses of dexmedetomidine prolonged the times to orientation and to discharge from the Phase I unit. CONCLUSIONS: The results of this pilot study suggest that dexmedetomidine (0.5-1.0 microg/kg given intravenously) is not beneficial in controlling the acute hyperdynamic response after ECT.     

Central NO is involved in the antinociceptive action of intracisternal antidepressants in freely moving rats

The present study was performed to examine the central effects of antidepressants on nociceptive jaw opening reflex after intracisternal injection. we also investigated the mechanisms of central antinociceptive action of intracisternal antidepressants. We recorded the jaw opening reflex in freely moving rats and chose to administer antidepressants intracisternally in order to eliminate the effects of anesthetic agents on the pain assessment and evaluate the importance of the spinal site of action of antidepressants. After intracisternal injection of 15 microg imipramine, digastric electromyogram (dEMG) was decreased to 76+/-6% of the control. Intracisternal administration of 30 microg desipramine, nortriptyline or imipramine suppressed dEMG remarkably to 48+/-2, 27+/-8, or 25+/-5% of the control, respectively. The suppression of dEMG was maintained for 50 min. L-NG-Nitroarginine methyl ester (NAME) blocked the suppression of dEMG from 32+/-2 to 81+/-5% of the control. These results indicate that antidepressants produce antinociception through central mechanisms in the orofacial area. The central NO pathway seems to be involved in the antinociception of intracisternal antidepressants at supraspinal sites.     

The analgesic potency of dexmedetomidine is enhanced after nerve injury: a possible role for peripheral alpha2-adrenoceptors

This study investigated the analgesic potency and site of action of systemic dexmedetomidine, a selective alpha2-adrenoceptor (alpha2AR) agonist, in normal and neuropathic rats. Ligation of the L5-6 spinal nerves produced a chronic mechanical and thermal neuropathic hyperalgesia in rats. von Frey fibers and a thermoelectric Peltier device were used to measure mechanical and heat withdrawal thresholds over the hindpaw. Systemic dexmedetomidine dose-dependently increased the mechanical and thermal thresholds in the control animals (50% effective dose [ED50] 144 and 180 microg/kg intraperitoneally [i.p.], respectively). Neuropathic animals responded to much smaller doses of dexmedetomidine with mechanical and thermal ED50 values of 52 and 29 microg/kg i.p., respectively. There was no difference between the control and neuropathic animals with respect to dexmedetomidine-evoked sedation, as determined by decreased grid crossings in an open-field activity chamber (ED50 12 and 9 microg/kg i.p., respectively). Atipamezole, a selective alpha2AR antagonist, blocked the analgesic and sedative actions of dexmedetomidine inboth the neuropathic and control animals. However, L-659,066, a peripherally restricted alpha2AR antagonist, could only block the analgesic actions of dexmedetomidine in the neuropathic rats, with no effect in control animals. In conclusion, nerve injury enhanced the analgesic but not the sedative potency of systemic dexmedetomidine and may have shifted the site of alpha2 analgesic action to outside the blood-brain barrier. IMPLICATIONS: We tested the analgesic efficacy of the alpha2 agonist dexmedetomidine in normal and nerve-injured rats. The analgesic potency of dexmedetomidine was enhanced after nerve injury with a site of action outside the central nervous system. Peripherally restricted alpha2 agonists may be useful in the management of neuropathic pain.     

Reduction of the minimum alveolar concentration of isoflurane by dexmedetomidine

BACKGROUND: alpha 2-Adrenergic agonists have been shown to reduce anesthetic requirements of other anesthetics, and they may even act as complete anesthetics by themselves at high doses in animal models. The present study was designed to define the interaction of intravenous infusion of dexmedetomidine, an alpha 2-adrenergic agonist, and isoflurane in patients having surgery by using the minimum alveolar concentration (MAC) of isoflurane as the measure of anesthetic potency. METHODS: Forty-nine women scheduled for abdominal hysterectomy were randomly allocated to receive either a placebo infusion (n = 16) or a two-stage infusion of dexmedetomidine with target plasma concentration of 0.3 ng/ml (n = 17) or 0.6 ng/ml (n = 16). The study drug infusion was commenced 15 min before induction of anesthesia with thiopental and alfentanil and was continued until skin incision. The end-tidal concentration of isoflurane for each patient was predetermined according to the "up-down" method of Dixon, and it was maintained for at least 15 min before the patient's response to skin incision was assessed. RESULTS: The MAC of isoflurane was 0.85% end-tidal in the control group, 0.55% end-tidal with the low dose of dexmedetomidine, and 0.45% end-tidal with the high dose of dexmedetomidine. CONCLUSIONS: The MAC of isoflurane in the control group was lower than that reported previously in similar patients having surgery, probably due to anesthesia induction with thiopental and alfentanil. Nevertheless, with the high dose of dexmedetomidine, the MAC of isoflurane was still 47% less than that without dexmedetomidine.     

Assessment of the role of alpha2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

1. The role of alpha2-adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the alpha2AR selective agonist dexmedetomidine (Dex) in mice devoid of individual alpha2AR subtypes through either a point (alpha2A) or null (alpha2B/alpha2C) mutation ('knock-out'). 2. In a rodent model of acute thermal nociception, the mouse tail immersion test, Dex, in wild type (WT) control animals, produced a dose-dependent increase in the threshold for tail withdrawal from a 52 degrees C water bath with mean ED50 values of 99.9+/-14.5 (alpha2A), 94.6+/-17.8 (alpha2B) and 116.0/-17.1 (alpha2C) microg kg(-1), i.p. 3. In comparison to the WT controls, Dex (100-1000 microg kg(-1), i.p.), was completely ineffective as an antinociceptive agent in the tail immersion test in the alpha2A AR D79N mutant animals. Conversely, in the alpha2B AR and alpha2C AR knock-outs, Dex produced a dose-dependent antinociceptive effect that was not significantly different from that observed in WT controls, with ED50 values of 85.9+/-15.0 (P>0.05 vs WT control) and 226.0+/-62.7 (P>0.05 vs WT control) microg kg(-1) i.p., respectively. 4. Dex (10-300 microg kg(-1), i.p.) produced a dose-dependent reduction in spontaneous locomotor activity in the alpha2A, alpha2B and alpha2C AR WT control animals with ED50 values of 30.1+/-9.0, 23.5+/-7.1 and 32.3+/-4.6 microg kg(-1), i.p., respectively. Again, Dex (100-1000 microg kg(-1), i.p.) was ineffective at modulating motor behaviour in the alpha2A AR D79N mutants. In the alpha2B AR and alpha2C AR knock-out mice, Dex produced a dose-dependent reduction in spontaneous locomotor activity with ED50 values of 29.1+/-6.4 (P>0.05 vs WT control) and 57.5+/-11.3 (P>0.05 vs WT control) microg kg(-1), respectively. 5. Dex was also found to produce a dose-dependent reduction in body temperature in the alpha2A, alpha2B and alpha2C AR WT control mice with ED50 values of 60.6+/-11.0, 16.2+/-2.5 and 47.2+/-9.1 microg kg(-1), i.p., respectively. In the alpha2A AR D79N mutants, Dex had no effect on body temperature at a dose (100 microg kg(-1), i.p.) that produced a significant reduction (-6.2+/-0.5 degrees C; P<0.01 vs vehicle) in temperature in WT controls. However, higher doses of Dex (300 and 1000 microg kg(-1), i.p) produced a small, but statistically significant decrease in temperature corresponding to -1.7+/-0.4 degrees C and -2.4+/-0.3 degrees C (both P<0.01 vs vehicle), respectively. In the alpha2B AR and alpha2C AR knock-out mice, Dex produced a dose-dependent reduction in body temperature with ED50 values of 28.4+/-4.8 (P>0.05 vs WT control) and 54.1+/-8.0 (P>0.05 vs WT control) microg kg(-1), respectively. 6. In conclusion, the data are consistent with the alpha2A AR being the predominant subtype involved in the mediation of the antinociceptive, sedative and hypothermic actions of Dex. This profile would appear to indicate that an alpha2A AR subtype selective analgesic will have a narrow therapeutic window, particularly following systemic administration.     

Influence of incubation time, inoculum size, and glucose concentrations on spectrophotometric endpoint determinations for amphotericin B, fluconazole, and itraconazole

Antinociception can be produced at the spinal level by activation of opioidergic, noradrenergic, and serotonergic systems. We tested the antinociceptive effects of combined activation of all three systems. Antinociception was assessed in the rat tail-flick test, and drugs were administered via an intrathecal catheter. Morphine, the norepinephrine uptake inhibitor desipramine, and serotonin produced antinociception of their own. The combination of subthreshold doses of morphine 1 microg and of desipramine 3 microg produced pronounced antinociception that was antagonized by yohimbine. The combination of subthreshold morphine with serotonin 50 microg or desipramine with serotonin caused only small antinociceptive effects. When morphine combined with desipramine was decreased to a subthreshold dose, we observed pronounced antinociception when a subthreshold dose of serotonin was added. A complex interaction can be supposed by results obtained with antagonists. The activation of all three neurotransmitter systems with small doses of agonists may represent an effective principle for pain control at the spinal level. IMPLICATIONS: Pain sensations are modulated at the spinal level by opioids, noradrenergic drugs, and serotonin. Using a rat model, we showed that the concurrent use of drugs from each of these classes produces good pain control at doses that should avoid the side effects associated with larger doses of each individual drug.     

Selectivity of atipamezole, yohimbine and tolazoline for alpha-2 adrenergic receptor subtypes: implications for clinical reversal of alpha-2 adrenergic receptor mediated sedation in sheep

The alpha2-adrenergic receptor antagonists, yohimbine, atipamezole and tolazoline, are used in veterinary medicine as reversal agents for the sedative/hypnotic effects of alpha2-agonists. Ruminants have increased sensitivity to the sedative/hypnotic effects of alpha2-agonists compared to other species. The receptors mediating the sedative effects of alpha2-agonists are located primarily on locus coeruleus neurons in the pons of the lower brainstem. Four pharmacological subtypes of the alpha2-adrenergic receptor (A,B, C and D) have been identified based on differences in ligand affinity. The aim of this study was to: 1) determine the pharmacological profile of atipamezole, yohimbine and tolazoline at the four alpha2-adrenergic receptor subtypes and; 2) determine whether these agents differ in their affinities at the alpha2-adrenergic receptor present in the sheep brainstem. In inhibition binding studies against the selective alpha2-adrenergic receptor ligand [3H]-MK-912, tolazoline showed the lowest affinity for all four alpha2-adrenergic receptor subtypes compared to yohimbine and atipamezole. The affinities of yohimbine and atipamezole were similar at the alpha2A-, alpha2B- and alpha2C-adrenergic receptors but differed by approximately 100 fold at the alpha2D-adrenergic receptor. Atipamezole had a 100 fold higher affinity at the alpha2D-adrenergic receptor when compared to yohimbine. To determine the ligand binding characteristics of these agents at the alpha2-adrenergic receptor in sheep brainstem, membranes were labelled with [3H]-MK-912 and inhibition competition curves were performed. Atipamezole showed approximately a 100 fold higher affinity for the sheep brainstem alpha2-adrenergic receptor compared to yohimbine which was similar to what was observed for the alpha2D-adrenergic receptor in PC12 cells transfected with RG-20. The results from these studies suggest that atipamezole has a high affinity for the alpha2D-adrenergic receptor that appears to be the receptor subtype in sheep brainstem.     

Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse

The sedative and anesthetic effects of ethanol and propofol when these drugs are coadministered are not known. Accordingly, we investigated the nature of the pharmacological interaction between ethanol and propofol during hypnosis and anesthesia in the mouse. Propofol, ethanol, and mixtures of the two were administered through the tail vein in male CD-1 mice (n = 162). The loss of righting response occurring 10 s after injection and persisting at least 10 s thereafter was defined as hypnosis, and lack of a motor response to tail clamping 60 s after injection was defined as anesthesia. The 50% effective dose (ED50) values for the hypnotic and anesthetic actions of the drugs were determined with quantal dose-response curves, using probit analysis. The pharmacological interactions were identified by the locations of ED50 values on their corresponding hypnosis and anesthesia isoboles. For each drug alone, the hypnotic and anesthetic ED50 values with 0.95 confidence intervals were 16.70 (11.98, 23.20) mg/kg and 25.02 (20.27, 31.29) mg/kg for propofol and 0.88 (0.81, 0.95) g/kg and 1.80 (1.45, 2.23) g/kg for ethanol, respectively. For the drugs in combination, the ED50 values for hypnosis with 0.95 confidence intervals were 6.98 (6.50, 7.49) mg/kg propofol with 0.61 (0.57, 0.66) g/kg ethanol, and for anesthesia were 10.55 (9.76, 11.42) mg/kg propofol with 0.93 (0.86, 1.05) g/kg ethanol, respectively. When plotted isobolographically, we found these combinations to be behaviorally additive both for hypnosis and anesthesia. Although a finding of synergism would have excluded the possibility of an identical mechanism of action for the drugs, elucidation of the molecular basis of the additivity must await further studies.     

Prostaglandin E1 suppresses tumor necrosis factor-alpha and interleukin-10 production by lipopolysaccharides-stimulated mononuclear cells

Previous studies have shown that the intravenous administration of yohimbine, an alpha 2 antagonist, increases norepinephrine turnover and has related anxiogenic effects in humans. We herein report that yohimbine also increases plasma neuropeptide Y (NPY) in healthy human subjects. This finding is consistent with previous reports in animals, but contrasts with a previously reported study in humans. NPY is a 36 amino acid peptide neurotransmitter located in sympathetic and nonsympathetic nerve fibers, as well as in brain structures such as the locus coeruleus, where it is colocalized with norepinephrine. NPY has been shown to inhibit locus coeruleus neuronal firing, decrease norepinephrine release, and increase postsynaptic noradrenergic signal transduction. When administered centrally, NPY also has anxiolytic properties. This study therefore suggests that yohimbine challenge may be useful in assessing NPY and noradrenergic system interactions in neuropsychiatric disorders such as panic disorder or post traumatic stress disorder in which noradrenergic system dysfunction has been observed.     

Effects of clonidine, dexmedetomidine and xylazine on thermal antinociception in rhesus monkeys

The antinociceptive effects of the s.c. administration of the alpha-2 agonists clonidine (0.0032-1.0 mg/kg), dexmedetomidine (0.001-0.032 mg/kg) and xylazine (0.1-3.2 mg/kg) were examined in the warm-water tail withdrawal assay in rhesus monkeys. The three agonists were dose-dependently effective in this assay; their potency order being dexmedetomidine > clonidine > xylazine. The alpha-2 antagonist idazoxan (0.1-3.2 mg/kg) caused dose-dependent and roughly parallel rightward shifts in the dose-effect curves for the three agonists. Apparent pA2 analysis with idazoxan yielded homogeneous values for the three agonists, supporting the notion that similar receptors mediate their antinociceptive effects. The opioid antagonist quadazocine (1.0 mg/kg) did not antagonize the antinociceptive effects of clonidine and xylazine, indicating that opioid receptors do not participate in the effects of the compounds in this assay. At dose ranges found to be effective in the antinociceptive assay, clonidine, dexmedetomidine and xylazine also dose-dependently caused sedation, muscle relaxation, bradycardia and moderate respiratory depression. The sedative, muscle relaxant and respiratory depressant effects of xylazine could be antagonized by idazoxan, suggesting that these effects may be mediated through alpha-2 receptors. These data indicate that the three imidazoline alpha-2 agonists, clonidine, dexmedetomidine and xylazine are effective s.c. in the warm-water tail withdrawal assay in rhesus monkeys, but only at doses that produce other behavioral and physiological effects.     

Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats

The effects of acute and chronic administration of cocaine on the antinociception and tolerance to the antinociceptive actions of mu-(morphine), kappa-(U-50,488H), and delta-([D-Pen2,D-Pen5]enkephalin; DPDPE), opioid receptor agonists were determined in male Swiss-Webster mice. Intraperitoneal injection of 40 mg/kg of cocaine by itself produced weak antinociceptive response as measured by the tail-fick test but the lower doses were ineffective. Administration of morphine (10 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (10 microg/mouse, ICV) produced antinociception in mice. Cocaine (20 mg/kg) potentiated the antinociceptive action of morphine and DPDPE but had no effect on U-50,488H-induced antinociception. Administration of morphine (20 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (20 microg/mouse, ICV) twice a day for 4 days resulted in the development of tolerance to their antinociceptive actions. Tolerance to the antinociceptive actions of morphine and U-50,488H was inhibited by concurrent treatment with 20 or 40 mg/kg doses of cocaine; however, tolerance to the antinociceptive action of DPDPE was not modified by cocaine. It is concluded that cocaine selectively potentiates the antinociceptive action of mu- and delta- but not of the kappa-opioid receptor agonist. On the other hand, cocaine inhibits the development of tolerance to the antinociceptive actions of mu- and kappa- but not of delta-opioid receptor agonists in mice.     

Effect of hypnotics on mice genetically selected for sensitivity to ethanol

It was previously shown that the rate of disappearance of blood ethanol was identical for two lines of mice selectively bred for differences in sleep-time after ethanol administration. The ED50 values for the loss of righting response with ethanol were significantly different at 3.64 g per kg for the SS line and 1.65 g per kg for the LS line. In the present study the mean sleep time is 367 sec for SS mice and 9342 sec for LS mice. The ED50 values remain essentially the same as previously reported. Unchanged LD50 values for ethanol, however, are not different at 4.8 g per kg for the SS and 4.5 g per kg for the LS line of mice. The ED50 value for loss for righting response following administration of methanol, butanol and t-butanol is approximately 2 fold greater for the SS line of mice than for the LS line. The ED50 values for sodium pentobarbital or ether in the 2 lines of mice for loss of righting response are virtually identical. In addition, the sleep-time values obtained after the administration of pentobarbital, chloral hydrate, trichloroethanol and paraldehyde are not significantly different. These data indicate that while the SS and LS lines of mice differ in central nervous system sensitivity to ethanol, methanol, butanol and t-butanol it is implied that they do no differ in central nervous system sensitivity to other hypnotic agents tested. Proof of this latter suggestion awaits determination of metabolic rates, and brain levels of these other depressants.     

Fluoxetine increases norepinephrine release in rat hypothalamus as measured by tissue levels of MHPG-SO4 and microdialysis in conscious rats

The selective serotonin uptake inhibitor fluoxetine (10 mg/kg i.p.) increased tissue levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4) in rat hypothalamus, indicating an increased release of norepinephrine. Microdialysis studies in conscious rats showed that fluoxetine (10 mg/kg i.p.) increased extracellular concentrations of norepinephrine as well as serotonin in the hypothalamus. In contrast, desipramine (10 mg/kg i.p.) increased extracellular concentration of norepinephrine but not serotonin in the hypothalamus. Consistent with its mechanism of being a selective serotonin uptake inhibitor, local perfusion of fluoxetine (10 microM) caused a 7-fold increase in hypothalamic extracellular serotonin and a small non-significant increase in extracellular norepinephrine. The subsequent systemic injection of fluoxetine (10 mg/kg s.c.) after local perfusion caused a 3-fold increase in extracellular norepinephrine, indicating that fluoxetine's action leading to an increase in extracellular norepinephrine was not occurring in the terminal areas of the hypothalamus but elsewhere in the brain, possibly cell bodies in the locus coeruleus.     

The effects of idazoxan combined with 30% nitrous oxide on the jaw-opening reflex in the rat

In rats, the jaw-opening reflex is elicited by activation of a nociceptive receptor by the electric stimulation of the tooth pulp. This study was undertaken to assess the effects of 30% nitrous oxide and 30% nitrous oxide with idazoxan, an alpha 2-adrenergic antagonist, on this reflex. Each rat received electric stimulation for the jaw-opening reflex at 3, 5, 7, 10, 15, and 20 min after both the start of inhalation and the withdrawal of 100% oxygen or 30% nitrous oxide in oxygen. Idazoxan, 400 micrograms/ kg, was administered intravenously at the start of the inhalation period. Amplitudes significantly decreased during inhalation of nitrous oxide, but they returned gradually to control levels after cessation of nitrous oxide inhalation. In the cases of 100% oxygen, 100% oxygen with idazoxan, and 30% nitrous oxide in oxygen with idazoxan, amplitudes did not change from controls during and after 30% nitrous oxide inhalation. The latency remained unchanged irrespective of the treatment. Since in rats the degree of inhibition by 30% nitrous oxide in oxygen is partially diminished by administration of idazoxan, we conclude that nitrous oxide affects an alpha 2-adrenergic receptor in the central nervous system.     

Norepinephrine induces expression of c-fos mRNA through the alpha-adrenoceptor in rat aortic rings

We examined whether norepinephrine at pharmacologically relevant doses induces increased expression of c-fos mRNA in rat aortic rings. c-fos mRNA was expressed at norepinephrine concentrations known to cause minimum and maximum contraction of rat aorta in vitro. At the concentration known to cause maximum contraction, norepinephrine produced a marked and sustained increase of c-fos mRNA expression. Induction of c-fos was blocked completely by the alpha 1-adrenergic antagonist prazosin, partially by the alpha 2-adrenergic antagonist yohimbine, and not at all by the beta-adrenergic antagonist propranolol. A prazosin inhibition curve showed that 1 nmol/L prazosin inhibited 10 micromol/L norepinephrine induced c-fos expression by 40%. At the pharmacologic dose known to cause maximum contraction, norepinephrine induces c-fos mRNA expression through the alpha-adrenoceptor in rat aortic rings.     

The effect of dexmedetomidine on nutrient organ blood flow

The alpha 2-adrenergic agonist dexmedetomidine decreases not only heart rate, myocardial contractility, and oxygen demand, but also cardiac output (Q). To investigate whether this reduction in Q could critically impair perfusion of individual organs, we studied the effect of dexmedetomidine on nutrient blood flow to the heart, brain, kidney, spleen, skin, intestine, liver, and arteriovenous anastomoses using the radioactive microsphere technique. Studies were conducted in 14 dogs with an open chest and anesthetized with either chloralose/urethane (CU) or fentanyl/halothane (FH), to create different baseline conditions. Hemodynamic variables, organ blood flow, arterial and mixed venous oxygen, and lactate content were measured before and after administration of 0.1, 1, and 10 micrograms/kg dexmedetomidine intravenously (IV). After 10 micrograms/kg dexmedetomidine Q decreased in both groups by 50%. The decrease in blood flow varied greatly between the organs. While flow through arteriovenous anastomoses and skin decreased by 70% to 90%, renal blood flow decreased by 30%, cerebral blood flow only when baseline blood flow was high (FH dogs), and left ventricular blood flow only in the CU group, where the largest decrease in hemodynamic variables occurred. Oxygen consumption decreased only in CU dogs, but so did arterial lactate levels. These data indicate that dexmedetomidine causes considerable redistribution of Q, predominantly reducing blood flow to less vital organs and shunt flow.     

Antidepressant treatment and chemical sympathectomy fail to modulate alpha 1-adrenoceptor sensitivity in mouse eye

The mydriatic response to alpha 1-adrenergic agonists was used as a functional index of postsynaptic alpha 1-adrenoceptors in mouse iris dilator muscle. Topical ocular application of methoxamine or phenylephrine caused dose-related mydriasis which was inhibited by pretreatment with prazosin or phentolamine. Chemical sympathectomy with topical 6-hydroxydopamine (6-OHDA) produced supersensitivity to phenylephrine but not methoxamine. Daily antidepressant treatment for 14 days with desipramine (10 mg/kg, i.p.), amitriptyline (10 mg/kg, i.p.), fluoxetine (2 mg/kg, i.p.), or moclobemide (40 mg/kg, i.p.) did not alter the response to methoxamine. Central alpha 1-adrenoceptors labelled with [3H]prazosin were similarly unaffected except for a modest downregulation produced by fluoxetine. These results demonstrate that postsynaptic alpha 1-adrenoceptors in mouse CNS and iris dilator muscle are refractory to manipulations known to alter their sensitivity in other tissues.