Sympathoinhibition by rilmenidine in conscious rabbits: involvement of alpha 2-adrenoceptors.

Cardiovascular and sympathetic nervous system effects of the mixed alpha 2-adrenoceptor and imidazoline receptor agonist rilmenidine were studied in conscious rabbits chronically instrumented for the recording of the firing rate of renal sympathetic fibers. Separate experiments were carried out on pithed rabbits with electrically stimulated (2 Hz) sympathetic outflow. Drugs were administered intravenously in a cumulative manner. In conscious rabbits, rilmenidine 0.1, 0.3 and 1.0 mg kg-1 dose-dependently lowered blood pressure, renal sympathetic nerve activity, heart rate and the plasma concentration of noradrenaline and adrenaline. The effect on blood pressure and plasma catecholamines was maximal after 0.3 mg kg-1 whereas heart rate and renal sympathetic nerve activity decreased further after rilmenidine 1.0 mg kg-1. Yohimbine 0.1 and 0.5 mg kg-1, when injected subsequently, attenuated and at the higher dose abolished all effects of rilmenidine. The effects of rilmenidine were also antagonized by the alpha 2-adrenoceptor antagonist 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imid azole HCl (RX821002; 0.1 and 0.5 mg kg-1). Yohimbine 0.1 and 0.5 mg kg-1 did not attenuate or attenuated only slightly the decrease of heart rate and renal sympathetic nerve activity produced by infusion of vasopressin. In pithed rabbits with electrically-stimulated sympathetic outflow, yohimbine 0.1 submaximally and yohimbine 0.5 mg kg-1 maximally increased the plasma noradrenaline concentration. The experiments show by direct measurement of sympathetic nerve firing and plasma catecholamines that rilmenidine causes sympathoinhibition in conscious rabbits, presumably through central sites of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotensive and bradycardic effects of talipexole (B-HT 920) in anaesthetized rabbits are antagonized by metoclopramide but not by yohimbine.

The interactions of talipexole (B-HT 920) and clonidine with selective alpha-adrenoceptor antagonists, yohimbine (alpha 2) and prazosin (alpha 1), as well as with dopamine receptor antagonists, metoclopramide (D2), domperidone (D2) and SCH23,390 (D1) were investigated in anaesthetized rabbits after i.v. administration. Both talipexole (0.03-0.1 mg/kg) and clonidine (0.01-0.03 mg/kg) dose-dependently induced hypotension and bradycardia. Talipexole had a shorter duration of action. The hypotensive effect of the alpha 2-adrenoceptor and D2 agonist talipexole (0.03 mg/kg) was antagonized by pretreatment with metoclopramide (3 mg/kg) or domperidone (0.3-3 mg/kg), but not with yohimbine (3 mg/kg), prazosin (0.1 mg/kg) or SCH23,390 (1 mg/kg). Its bradycardic effect was antagonized only by metoclopramide (3 mg/kg). The hypotensive and bradycardic effects of clonidine (0.03 mg/kg) were most effectively antagonized by yohimbine (0.3-3 mg/kg). These findings indicate that in anaesthetized rabbits after i.v. administration, talipexole may lower blood pressure by peripheral, and heart rate by central, dopamine D2 agonism.

Comparison of dexmedetomidine and midazolam sedation and antagonism of dexmedetomidine with atipamezole.

STUDY OBJECTIVE: To evaluate the effects of dexmedetomidine, an alpha-2 agonist, as an intravenous sedative drug and the effects of atipamezole, an alpha-2 antagonist, on recovery. DESIGN: Randomized, double-blind study with three parallel groups. An open dose-finding study preceded it to optimize the atipamezole dose. SETTING: Outpatient operating room at the gynecologic and obstetric university hospital in Helsinki, Finland. PATIENTS: Seventy-two healthy women scheduled for legal termination of pregnancy. INTERVENTIONS: Patients were assigned to one of three groups of 24 patients each to receive either dexmedetomidine 2 micrograms/kg and atipamezole 50 micrograms/kg; dexmetomidine 2 micrograms/kg and saline; or midazolam 0.15 mg/kg and saline. In addition to paracervical block, each patient received two different study drugs: study drug 1 was a sedative agent (either dexmedetomidine or midazolam), administered before the procedure. If the sedation was not deep enough and the patient reacted to the procedure, a low dose of propofol was administered. Study drug 2 was a reversing agent or a placebo, administered following the procedure. MEASUREMENTS AND MAIN RESULTS: The mean time to regain consciousness was shorter in the dexmedetomidine-atipamezole and the dexmedetomidine-saline groups compared with the midazolam group. Postoperative sedation, tested both by subjective and objective assessments, decreased more quickly in the dexmedetomidine-atipamezole group compared with the dexmedetomidine-saline and the midazolam groups. CONCLUSION: Atipamezole is an effective antagonist for reversing psychomotor impairment following dexmedetomidine sedation.

Reduction of isoflurane anesthetic requirement by medetomidine and its restoration by atipamezole in dogs.

The isoflurane-sparing effect of the alpha 2-adrenergic agonist medetomidine (30 micrograms/kg of body weight, IV) was tested in 7 dogs, using a blinded, randomized-block study design. The baseline minimal alveolar concentration (MAC) of isoflurane was 1.18 vol% (95% confidence interval [0.97,1.39]). Medetomidine significantly (P < 0.003) reduced isoflurane MAC by 47.2%. Atipamezole (0.3 mg/kg, IV), an alpha 2-adrenergic antagonist, completely reversed the effect of medetomidine on isoflurane MAC. Atipamezole alone did not significantly alter isoflurane MAC. After medetomidine administration, marked bradycardia developed in all dogs and persisted for more than 2 hours. Mean arterial blood pressure increased acutely, but later decreased, and hypotension persisted for more than 2 hours. Atipamezole reversed the bradycardic and hypotensive effects of medetomidine. Results of this study indicate that medetomidine may be useful in clinical cases in which isoflurane MAC-reduction is desirable and that atipamezole might be used to reverse desirable and undesirable effects of medetomidine during isoflurane anesthesia.

Effects of dexmedetomidine on systemic and coronary hemodynamics in the anesthetized dog.

In addition to central effects, which are the basis of their use in anesthesiology, alpha 2-adrenergic agonists have direct peripheral cardiovascular effects. Dexmedetomidine (DM) has been found to depress cardiac function in dogs, even after autonomic denervation. The present experiments evaluated the effects of DM on coronary flow, myocardial oxygen extraction, and cardiac function in intact, open chest dogs under enflurane anesthesia. Heart rate (HR), mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP), the first derivative of systolic left ventricular pressure (dP/dtmax), and flow in the left anterior descending coronary artery (CBF) were measured and continuously recorded. Cardiac output (CO), plasma catecholamines (CA), hemoglobin and oxygen saturation in arterial, mixed venous, and coronary sinus blood were measured at intervals. Cardiac index (CI), systemic vascular resistance index (SVRI), regional coronary vascular resistance (CVR), and oxygen concentration differences across the systemic [C(a-v)O2], and coronary [C(a-cs)O2] circulations were calculated. DM doses of 0.25, 0.5, 1.0, 2.0, and 4.0 micrograms/kg were given IV at 20-minute intervals. Measurements and samples were taken at peak drug effects and just prior to the next dose. The alpha 2-antagonist atipamezole, 0.5 mg/kg, was given after the last dose of DM. DM caused immediate dose-dependent increases in SVRI, CVR, LVEDP, C(a-v)O2, and C(a-cs)O2, and decreases in HR, and CI, with recovery between doses. DP/dtmax declined after the first two doses and stabilized thereafter, as plasma CA fell to minimal levels. Atipamezole completely reversed all changes.(ABSTRACT TRUNCATED AT 250 WORDS)

ICI 147,798 causes insurmountable antagonism against T-0509, a selective beta 1-adrenoceptor agonist, but surmountable antagonism against isoproterenol.

In canine right ventricular muscle, the influence of ICI 147,798, a slowly dissociable beta 1-adrenoceptor antagonist, on the positive inotropic effect and cyclic AMP production of T-0509, a selective beta 1-agonist, and isoproterenol, a nonselective beta-agonist, were examined to elucidate the properties of the high- and low-affinity states or subtypes of beta 1-adrenoceptor. ICI 147,798 (1 x 10(-8) - 1 x 10(-5) M) produced biphasic concentration-response curves for the positive inotropic effect of T-0509 that were due to its insurmountable antagonism against the lower concentrations of T-0509. The maximum of the biphasic curves were almost the same as Camax. Analysis of hemiequilibrium antagonism by ICI 147,798 against T-0509 showed the dissociation constant (pKB) of ICI 147,798 to be approximately 8. On the other hand, ICI 147,798 produced a parallel rightward shift of the curves of isoproterenol. Schild analysis showed pA2 to be 7.98 +/- 0.04, suggesting competitive antagonism. The concentration-response curve for the increase in cyclic AMP elicited by T-0509 in the presence of 1 x 10(-6) M ICI 147,798 was also biphasic, but slightly depressed as compared with that of control, whereas that elicited by isoproterenol was shifted to the right. The positive inotropy and increase in cyclic AMP produced by T-0509 and isoproterenol in the presence of ICI 147,798 may be mediated by the low-affinity state of beta 1-adrenoceptor, which mechanism may be different from that producing the positive inotropy through the high-affinity state of beta 1-adrenoceptor.

Antagonism of medetomidine-induced ataxia in rats by yohimbine, aminophylline and caffeine.

The actions of the alpha 2-antagonist yohimbine and methylxanthines aminophylline and caffeine were evaluated in reversing ataxia, increase in landing foot splay (LFS), produced by the alpha 2-agonist medetomidine in male rats. Medetomidine at 0.1 and 0.15 mg/kg, i.p. increased LFS by 42.9 and 69.6%, respectively. The peripherally acting alpha 2-agonist ST91 (0.125 to 0.5 mg/kg, i.p.) did not significantly affect the LFS. Intraperitoneal injection of yohimbine at 0.5 and 1 mg/kg, aminophylline at 25, 50 and 100 mg/kg, and caffeine at 25 and 50 mg/kg significantly antagonized medetomidine (0.15 mg/kg, i.p.)-induced ataxia. Yohimbine was more effective (100 and 111%) than the methylxanthines (28 to 72%) in reversing medetomidine ataxia. Aminophylline and caffeine, but not yohimbine, significantly reduced LFS in non-medetomidine treated rats. The data suggested that medetomidine ataxia in rats could be specifically antagonized by yohimbine and to a lesser extent by aminophylline and caffeine.

Alpha 2-adrenergic receptor agonist effects on supraventricular and ventricular automaticity in dogs with complete atrioventricular block.

Complete atrioventricular block was induced in 26 pentobarbital-anesthetized dogs to determine the effects of the alpha 2-adrenergic receptor agonists, xylazine and medetomidine, on supraventricular and ventricular automaticity. Prazosin and atipamezole, alpha-adrenoceptor antagonists, were administered to isolate alpha 1- or alpha 2-adrenoceptor effects. Six dogs served as controls and were given glycopyrrolate (0.1 mg/kg of body weight, IV) and esmolol (50 to 75 micrograms/kg/min, IV) to induce parasympathetic and beta 1-adrenergic blockade, respectively. Eight dogs were given sequentially increasing doses of xylazine (n = 5), 0.000257 mg (10(-9)M) to 25.7 mg (10(-4)M) and medetomidine (n = 3), 0.000237 mg (10(-9)M) to 2.37 mg (10(-5)M) after parasympathetic and beta 1-adrenergic blockade. Twelve dogs were given xylazine (n = 6, 1.1 mg/kg, IV) or medetomidine (n = 6, 0.05 mg/kg, IV) after parasympathetic and beta 1-adrenergic blockade. Three dogs given xylazine and 3 dogs given medetomidine were administered prazosin (0.1 mg/kg, IV) followed by atipamezole (0.3 mg/kg, IV). The order of prazosin and atipamezole was reversed in the remaining 3 dogs given either xylazine or medetomidine. Complete atrioventricular block and administration of glycopyrrolate and esmolol resulted in stable supraventricular and ventricular rates over a 4-hour period. Increasing concentration of xylazine or medetomidine did not cause significant changes in supraventricular or ventricular rate. Xylazine and medetomidine, in the presence of the alpha-adrenoceptor antagonists, prazosin (alpha 1) and atipamezole (alpha 2), did not cause significant changes in supraventricular or ventricular rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical capture of free-ranging cattle: immobilization with xylazine or medetomidine, and reversal with atipamezole.

Twenty-nine free-ranging Norwegian cattle were captured with xylazine (n = 20) or medetomidine (n = 9) using a tranquilizing gun, and the time from darting to recumbency (induction time) was recorded. Twenty-eight animals were given atipamezole IV 15-100 min after darting, and the effects of the antagonist were evaluated. Blood samples (n = 19) for haematology and serum chemistry were collected within 10 min after immobilization was induced. Xylazine (0.55 +/- 0.18 mg/kg; mean +/- SD; n = 18) or medetomidine-HCl (0.039 +/- 0.10 mg/kg; n = 8) induced complete immobilization after a single darting with sternal or lateral recumbency, the induction times being 9.6 +/- 3.8 and 12.0 +/- 6.8 min, respectively. No difference in the clinical effects of the two drugs was observed. Rapid reversal was achieved with 0.057 +/- 0.017 and 0.077 +/- 0.019 mg/kg of atipamezole-HCl in xylazine- and medetomidine-treated animals, respectively. All the animals stood within 2 min after IV administration of the antagonist. Seven animals showed signs of excitement shortly after reversal, but these side-effects were of brief duration. Heavy resedation with relapse into recumbency was seen 3-4 h after reversal in two cows captured with xylazine, while moderate resedation was observed in two medetomidine-treated animals 2 h after reversal. Except for the plasma glucose concentration, which was elevated in both xylazine- and medetomidine-treated animals, the mean values of the haematological and plasma chemical parameters were within the reference ranges established for Norwegian cattle.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of medetomidine sedation by atipamezole in pigs.

The efficacy of atipamezole as a medetomidine antagonist was evaluated in pigs. The atipamezole doses (intramuscularly) were 80, 160, 320 and 480 micrograms/kg of body weight, which were one, two, four and six times higher than the preceding medetomidine dose (80 micrograms/kg, intramuscularly). Atipamezole effectively reversed medetomidine-induced sedation, and the optimal action was seen at doses of 160 and 320 micrograms/kg. Recovery from sedation was quick and smooth, and adverse effects such as hyperactivity or tachycardia were minimal with either dose.

Single and repeated doses of the vasodilator/beta-adrenergic antagonist, carvedilol, block cirazoline- and isoproterenol-mediated hemodynamic responses in the conscious rat.

The purpose of this study was to evaluate the effects of carvedilol, a beta 1&2-adrenergic blocker and vasodilator, on cirazoline-mediated changes in arterial blood pressure and isoproterenol-mediated changes in heart rate after acute and chronic administration. Conscious, chronically instrumented male Sprague-Dawley rats were injected with carvedilol (1 mg/kg, IV), prazosin (0.3 mg/kg, IV), or propranolol (1 mg/kg, twice daily for 8 days. After administration of the first dose of carvedilol on day 1, the vasopressor response to cirazoline (60 +/- 3 mmHg predrug) and the isoproterenol-induced tachycardia (152 +/- 13 beats/min predrug) were blocked (e.g., 7 +/- 4 mmHg postdrug and 11 +/- 3 beats/min postdrug, respectively). After the administration of carvedilol on day 8, the cirazoline vasopressor response was 2 +/- 1 mmHg and the isoproterenol-induced tachycardia was 4 +/- 3 beats/min, indicating effective alpha 1- and beta-adrenergic blockade after chronic dosing with carvedilol. Prazosin blocked the cirazoline-induced vasopressor response on both days 1 and 8 but had no effect on the isoproterenol-induced tachycardia. Propranolol blocked the isoproterenol-induced tachycardia on both days 1 and 8 but had no effect on the cirazoline vasopressor response. These data indicate that only carvedilol effectively blocked both alpha- and beta-adrenergic hemodynamic responses and that the antagonism of these responses with carvedilol was not diminished after chronic dosing of twice-a-day treatment for 8 days.

Cardiovascular responses of sinoaortic-denervated rats to intracerebroventricular injection of alpha 1- and alpha 2-adrenoceptor agonists.

The aim of the present work was to analyse the cardiovascular responses induced by i.c.v. administration of the alpha 1- and alpha 2-adrenoceptor agonists, phenylephrine and clonidine, respectively, in conscious normal and sinoaortic-denervated rats. Sinoaortic denervation involves changes in central and peripheral catecholaminergic pathways. Clonidine (1-10 micrograms) produced a dose-dependent rise in blood pressure and a bradycardiac response in sham-operated animals, whereas in sinoaortic-denervated rats it provoked a brief rise in blood pressure followed by a marked fall as well as bradycardia. The responses involved mostly activation of central alpha 2-adrenoceptors, but the blood pressure responses induced by clonidine in sinoaortic-denervated rats may also have involved alpha 1-adrenoceptors. The bradycardia induced by the alpha 2-agonist in both groups of rats involved preferentially central alpha 2-adrenoceptors but also partially stimulated alpha 1-adrenoceptors. Phenylephrine, at a dose of 10-60 micrograms, induced a rise in blood pressure and a bradycardiac response while 90 micrograms produced a biphasic pressure response (early transient rise followed by a fall) as well as bradycardia in both sham-operated and sinoaortic-denervated animals. Phenylephrine activated alpha 1-adrenoceptors in every case, but the fall in blood pressure and the bradycardia also involved alpha 2-adrenoceptors. The responses were significantly higher in the sinoaortic-denervated rats than in the sham-operated. Our findings suggest that arterial baroreceptor reflexes can modify the effects of alpha-agonists initiated in the central nervous system. Sinoaortic denervation preparations enable one to unmask the depressor response to clonidine and also demonstrate the true magnitude of the phenylephrine response.

Immobilization of mink (Mustela vison) with medetomidine-ketamine and remobilization with atipamezole.

Four groups of mink were immobilized with medetomidine-HCl (MED) 0.1 mg/kg + ketamine (KET) 5 or 7.5 mg/kg at different ambient temperatures. The induction time, degree of immobilization and analgesia, rectal temperature, heart and respiration rates were recorded at intervals throughout the immobilization period. The animals were then given atipamezole-HCl (ATI) 0.5 mg/kg for reversal at different times after injection of MED/KET and the effects of the antagonist were evaluated. Subcutaneous administration of MED/KET induced complete immobilization in all 20 animals, and the highest dose was considered suitable for major surgery. Prolonged immobilization at low ambient temperatures (-10 to +5 degrees C) caused severe hypothermia in all animals. The mean rectal temperature had dropped to 37.8 degrees C and 32.1 degrees C at 15 and 85 min, respectively, after injection of MED/KET, significantly lower than the corresponding values for animals immobilized at room temperature. Intramuscular administration of ATI 20 or 40 min after injection of MED/KET rapidly remobilized the animals without apparent side-effects. Administration of ATI to animals recovering spontaneously 90 min after injection of MED/KET induced thermogenesis (shivering) in animals immobilized at a low ambient temperature, while no such effect was seen in animals immobilized at room temperature. One hour after injection of ATI, the rectal temperatures of all treated animals had returned to normal and there were no signs of abnormal behaviour.

Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole.

Dexmedetomidine is an alpha 2-adrenergic agonist that decreases central sympathetic activity and reduces the anesthetic requirement for halothane. We evaluated the effect of dexmedetomidine on neurologic and histopathologic outcome from incomplete cerebral ischemia in the rat. Anesthesia was maintained with a 25-micrograms.kg-1.h-1 fentanyl infusion combined with 70% nitrous oxide. Incomplete ischemia was produced by unilateral carotid artery ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Arterial blood gas tensions, pH, and head temperature were maintained at normal levels during the experiment. Four ischemic groups were tested: group 1 (n = 15) received an intraperitoneal (ip) saline injection (control); group 2 (n = 10) received an ip injection of 10 micrograms/kg dexmedetomidine 30 min before ischemia; group 3 (n = 10) received 100 micrograms/kg dexmedetomidine; and group 4 (n = 10) received 100 micrograms/kg dexmedetomidine plus 1 mg/kg atipamezole (an alpha 2-adrenergic antagonist). Neurologic outcome was evaluated for 3 days using a graded deficit score. Histopathology was evaluated in coronal section in caudate and hippocampal tissue segments. Dexmedetomidine (10 and 100 micrograms/kg) significantly decreased plasma catecholamines and improved neurologic and histopathologic outcome in a dose-dependent manner compared to control rats (P less than 0.05). Atipamezole abolished the decrease in catecholamines and the improvement in outcome seen with dexmedetomidine, confirming that these effects were mediated by alpha 2-adrenergic receptors. It is concluded that alpha 2-adrenoreceptor stimulation decreases sympathetic activity and decreases ischemic injury in a model of incomplete cerebral ischemia.

Stimulation of food intake in rats by the alpha 2-adrenoceptor agonists xylazine and detomidine.

Effects of the alpha 2-adrenoceptor agonists xylazine and detomidine on food intake in freely feeding male rats were evaluated. Intraperitoneal (i.p.) injection of xylazine (0.25-3 mg/kg) and detomidine (25 and 50 micrograms/kg) significantly increased the 2 and 24 h food intake from control values. Treatment of rats with the alpha 2-adrenoceptor antagonist yohimbine (1 mg/kg, i.p.) 15 min before xylazine (0.5 mg/kg, i.p.) or detomidine (50 micrograms/kg, i.p.) significantly inhibited the increase in food intake. Yohimbine treatments alone at 0.5, 1 and 2 mg/kg, i.p. did not significantly change the 2 and 24 h food intake from control values. The results suggest that the alpha 2-agonists xylazine and detomidine enhance food intake in rats.

Rapid reversal of alpha 2-adrenoceptor agonist effects by atipamezole in human volunteers.

1. The ability of atipamezole, a specific and selective alpha 2-adrenoceptor antagonist, to reverse the pharmacological effects induced by the alpha 2-adrenoceptor agonist dexmedetomidine was studied in six healthy male volunteers. Each volunteer received in four sessions in a randomized and single-blind manner three different doses (6.7 micrograms kg-1, 27 micrograms kg-1 and 67 micrograms kg-1) of atipamezole or saline placebo as 5 min i.v. infusions preceded by a fixed i.v. dose of dexmedetomidine (0.67 micrograms kg-1). 2. Dexmedetomidine caused profound sedation, with the subjects actually falling asleep. This was effectively reversed by the two highest doses of antipamezole. 3. Dexmedetomidine reduced salivary flow on average by 70%. A rapid and full reversal of this effect was seen after the highest dose of antipamezole. 4. Hypotension induced by dexmedetomidine was also effectively antagonized by atipamezole. Bradycardia was very modest after dexmedetomidine in this study, and thus no reversal of alpha 2-adrenoceptor agonist-induced bradycardia could be demonstrated. 5. Plasma noradrenaline concentrations were reduced by 80% by dexmedetomidine. This was effectively antagonized by atipamezole, and the highest dose caused a 50% overshoot in plasma noradrenaline concentrations over the basal levels. 6. It is concluded that the effects of dexmedetomidine are effectively reversible by atipamezole. A dose ratio of 10:1 for atipamezole:dexmedetomidine was clearly insufficient for this purpose, but ratios in the range of 40:1 to 100:1 were found to be effective in the current experimental situation.

Chemical restraint-reversal with medetomidine and atipamezole in veterinary small animal practice: a survey on the opinions of the dog owners and veterinarians.

The opinions of animal owners and practising veterinarians concerning a new restraint-reversal medication (medetomidine-atipamezole) for dogs were obtained by two questionnaires in connection with a clinical study. Four alternative answers to each statement question scored as "completely agree", "somewhat agree", "somewhat disagree" and "completely disagree". The questionnaires were completed by 21 veterinarians and 245 dog owners. The overall response to the treatment was clearly positive. Both groups had a favourable attitude towards drug use with mean combined scores (from 1 to 4; 4 = most favourable) of 48.1 (max 56) for the dog owners and 39.2 (max 52) for the veterinarians. Only a little information was gained about the background of negative sentiments. Some pet owners (19%) opposed to medication on a priori grounds, some (26%) reacted strongly to the dizziness of their animals and some owners (21%) complained because of general anxiety before, during and after their pets were treated.

Alpha 2-noradrenergic modulation of hippocampal theta activity.

The purpose of the present study was to determine the role of norepinephrine in the generation of hippocampal theta activity. Experiments were performed on urethane-anesthetized rats, implanted with recording electrodes in the dentate gyrus and stimulating electrodes in the dorso-medial posterior hypothalamus. The effects of norepinephrine on hippocampal theta activity was studied by directly infusing norepinephrine and other noradrenergic agents into the hippocampus. Norepinephrine microinfusion produced a decrease in the amplitude of theta activity as observed in the polygraph chart record. Subsequent spectral analyses demonstrated a decrease in power at peak theta frequencies, as well as a decrease in power at frequencies between 20-25 Hz (noise). The inhibitory effect of norepinephrine on hippocampal type 2 theta activity was found to be mediated by alpha 2-adrenergic receptors. Microinfusions of an alpha 2 agonist (detomidine) mimicked the effects produced by norepinephrine, whereas alpha 1 and beta agonists were ineffective. The inhibitory effect of detomidine was blocked by microinfusions of an alpha 2 antagonist (tolazoline), which indicates that the site of action was specific to the noradrenergic alpha 2 receptor.