2-adrenergic Agonist Clonidine Research Articles

Novelty seeking behavior in the rat is dependent upon the integrity of the noradrenergic system

These experiments were designed to investigate the role of the noradrenergic system in promoting investigation of novelty in rats. Behavior was monitored in a hole board equipped with photoelectric cells strategically placed so that locomotor activity, rearing and investigation of each of the holes could be quantified independently. Specially designed computer software permitted recording of the sequence and cumulative duration of the visits to specific holes throughout the session. Dose-response curves of the sedative effect of the α2 adrenergic receptor agonist clonidine were establised, a sedative effect being defined as a decrease in overall horizontal displacements, rearings and hole visits. After a one week interval, the rats were rerun in the holeboard, with novel objects placed in four of the nine holes. Previous experiments had shown that rats spend significantly more time investigating holes containing objects than empty holes in this apparatus and this was replicated here. Doses of clonidine which were below threshold for inducing any sedative effect (10 μg/kg) totally eliminated preference for holes with objects while having no effect on total time investigating the holes. A subsequent experiment showed that the β receptor antagonist propranolol (10 mg/kg) produced a similar effect. These results suggest that the noradrenergic system is implicated in stimulus seeking behavior and the post-synaptic β receptors are involved in mediating the behavior.

Blunted growth hormone response to clonidine in Gilles de la Tourette Syndrome

Noradrenergic mechanisms have been involved in the pathogenesis of Gilles de la Tourette Syndrome (GTS). Since the central α 2 adrenergic agonist clonidine is widely used as a therapeutic agent in GTS, the present study aimed at assessing whether GH release after clonidine, representing central α 2-adrenergic receptor sensitivity, was altered in GTS. After administration of 2 μg/kg body weight clonidine, the GH response was examined in nine drug-free, alcohol-abstinent GTS patients (eight men, one woman) and in nine age- and sex-matched abstinent healthy controls. A blunted response of GH release (<5 ng/ml) was observed in seven patients and the area under the curve (AUC) of the GH-release was significantly reduced ( p < .01) compared to controls. This finding indicates an involvement of the noradrenergic system in GTS.

Histamine H3-receptor-induced inhibition of duodenal cholinergic transmission is independent of intracellular cyclic AMP and GMP

1. The inhibitory effect of the histamine H3-receptor agonist ( R) α-methylhistamine on cholinergic neurotransmission was studied in the isolated guinea pig duodenum in the presence of different compounds which alter intracellular levels of cyclic nucleotides and of the G proteins blocker pertussis toxin. 2. The action of ( R) α-methylhistamine on electrically-evoked contractions was not modified either by forskolin and isobutylmethylxanthine (which increase cyclic AMP) or by zaprinast and methylene blue (which increase and decrease, respectively intracellular cyclic GMP). Drugs affecting cyclic nucleotide levels were also ineffective against the inhibitory effect of the α 2 adrenergic agonist clonidine. 3. Pertussis toxin significantly reduced the maximum inhibition induced by ( R) α-methylhistamine and clonidine, without influencing the effect of low concentrations of the above compounds; conversely it shifted to the right in a parallel way the inhibitory effect of adenosine. 4. These data suggest that H3-receptor-mediated inhibition of cholinergic transmission in the guinea pig duodenum is not linked to intracellular nucleotide changes. Moreover the signal transducing mechanism activated by ( R) α-methylhistamine involves pertussis toxin both sensitive and insensitive G proteins.

Influence of endogenous cholinergic tone and alpha-adrenergic pathways on growth hormone responses to His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in the dog.

His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6) is a synthetic peptide unrelated to any known hypothalamic-releasing hormone including growth hormone-releasing hormone (GHRH). Interestingly, this peptide induces a dose-related increase in plasma GH levels in all species tested so far. The aim of this study was to investigate the action of GHRP-6 alone or in combination with GHRH on GH release in dogs. In addition, the activation or blockade of endogenous cholinergic tone and alpha-1 adrenoceptors on GHRP-6-stimulated GH secretion was assessed. In adult Beagle dogs (n = 10), GHRP-6 (90 micrograms i.v.) increased basal GH levels from 2.6 +/- 1.5 to 14.4 +/- 3.1 micrograms/l (mean +/- S.E.M.) after 15 min. GHRH (50 micrograms i.v.) induced a GH peak of 9.7 +/- 2.2 micrograms/l at 15 min. The combined administration of GHRP-6 and GHRH strikingly potentiated canine GH release with a peak of 54 +/- 9.0 micrograms/l (P < 0.01). Pretreatment with the cholinergic agonist pyridostigmine (30 mg per os) increased GHRP-6-stimulated GH secretion (37.9 +/- 10.1 micrograms/l P < 0.05), while the muscarinic blocker atropine (100 micrograms i.v.) completely abolished (GH peak lower than 2 micrograms/l) the stimulatory action of GHRP-6. On the other hand, administration of the alpha-2 adrenergic agonist clonidine (4 micrograms/kg i.v.) increased basal plasma GH levels without affecting GH responses to GHRP-6.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha 2-adrenergic, but not imidazole, agonists activate NaCl cotransport in rabbit tracheal epithelial cells

The adrenergic agonist clonidine activates NaCl cotransport in rabbit tracheocytes. With the use of the high-affinity analogue p-[125I]iodoclonidine, binding of clonidine to cells was determined to fit a two-site model, with one site of high specificity for alpha 2-adrenergic (alpha 2-AR) and the other with a high affinity for I1-imidazol(in)e (I1) receptors. Total density of binding sites for both receptors was similar at 18 fmol/mg protein. Moxonidine displayed a 166-fold greater specificity for I1 receptors compared with cimetidine. Bumetanide-sensitive Na or Cl transport was stimulated by the alpha 2-AR agonists clonidine or guanabenz but not by the I1 agents cimetidine or moxonidine. I1 agonists-stimulated Na transport was detected only in the presence of bumetanide. Prazosin did not block clonidine-stimulated NaCl uptake or efflux, indicating the presence of an alpha 2A-AR subtype. Addition of clonidine either before or after incubation with l-isoproterenol or forskolin did not attenuate the time- and dose-dependent increase in adenosine 3',5'-cyclic monophosphate (cAMP) levels. Thus clonidine stimulates NaCl cotransport in rabbit tracheocytes through an alpha 2A-AR mechanism that does not require cAMP for signal transduction. In addition, I1-imidazol(in)e receptors stimulate Na transport in rabbit tracheocytes through an unidentified pathway.

Differential Nerve Block by the a2 Adrenergic Receptor Agonists Clonidine and Guanfacine

Differential Nerve Block by the a2 Adrenergic Receptor Agonists Clonidine and Guanfacine

Suppression of feeding induced by phenylephrine microinjections within the paraventricular hypothalamus in rats

Rats were treated with the alpha-2 agonist clonidine (4, 20 and 50 nMol) and with the alpha-1 agonist 1-phenylephrine (50, 100, 200 and 400 nMol). Phenylpropanolamine (PPA) is a phenythylamine anorectic drug that exerts direct agonist effects predominantly on alpha-1 adrenergic receptors, with some alpha-2 adrenergic activity. We recently reported that injection of PPA significantly suppressed feeding in rats. Prior studies have noted that into the paraventricular hypothalamus (PVN) microinjections of the alpha-2 adrenergic receptor agonist clonidine into the PVN induced feeding behavior in satiated rats. However, the effect on feeding of administration of alpha-1 adrenergic agonists within the PVN remains unknown. In the present study, unilateral guide cannulae aimed at the PVN were surgically implanted in adult male rats. In an initial 60 min feeding test conducted under free-feeding (“non-deprived”) conditions, each rat was found to eat significantly more food after injection of 25 nMol norepinephrine (NE) into the PVN. In subsequent tests, the feeding increased significantly to 4 nMol clonidine; however, feeding was suppressed by 50 nMol clonidine. Food intake after 20 nMol clonidine was not significantly different from that recorded after vehicle. In contrast, phenylephrine (100–400 nMol) reliably suppressed feeding behavior. In the final phase of the study, the rats ate significantly less food after injection of 160 nMol PPA into the PVN but consumed significantly more food after a final injection of 25 nMol NE into the PVN. These results suggest that the anorexic action of PPA may be linked to activation of alpha-1 adrenergic receptors within the PVN.

Regulation of Basal and Nursing‐Induced Secretion of Growth Hormone in the Neonatal Rat: The Involvement of Serotonergic, Muscarinic Cholinergic, Alpha2‐Adrenergic, Somatostatin and Growth Hormone‐Releasing Hormone Systems

Abstract Various neural factors are involved in the suckling-induced increase in serum growth hormone (GH) levels in neonatal rats, and, in the present study the serotonergic, cholinergic, somatostatin and GH-releasing hormone (GHRH) systems were investigated. The serotonin (5-HT) precursor 5-hydroxy-L-tryptophan (5-HTP) and the 5-HT receptor agonist quipazine maleate stimulated serum GH levels in 2-day-old rat pups separated from their mothers for 6 h. The increase in serum GH during suckling was further elevated by 5-HTP. The 5-HT antagonist cyproheptadine decreased serum GH levels in separated 2-day-old pups, and although it reduced the amplitude of the suckling-induced increase in serum GH concentration, it did not alter the increase in serum GH on a percentage basis. The effect of the cholinergic muscarinic antagonist atropine sulfate (ATR) was similar to that of cyproheptadine. Moreover, in separated pups, ATR prevented the increase in serum GH induced by 5-HTP. In contrast with 2-day-old pups, ATR completely eliminated the suckling-induced release of GH in 10-day-old rats. However, ATR failed to prevent GH release induced by the alpha(2)-adrenergic agonist clonidine HCI in 10-day-old male pups. While thyrotropin-releasing hormone increased serum GH levels, rat GHRH failed to alter serum GH levels either in separated or in suckled 2-day-old rat pups. Immunoneutralization for rat GHRH eliminated the increase in serum GH induced by clonidine HCI in 10-day-old pups, but (on a percentage basis) failed to prevent the GH-increasing effect of suckling in 2-day-old pups. While somatostatin failed to significantly decrease serum GH in separated 2-day-old pups, it effectively decreased serum GH levels in 2-day-old pups which were suckled. Cysteamine, which depletes hypothalamic somatostatin, increased serum GH in separated 2-day-old pups, and further increased the suckling-induced levels of serum GH. Cysteamine partially prevented the GH-decreasing effect of ATR. The present findings suggest that 1) the serotonergic and cholinergic systems are involved in the regulation of GH secretion as early as day 2 postpartum; 2) the serotonergic and cholinergic systems modulate the basal, and do not modulate the suckling-induced levels of serum GH; 3) the serotonergic system may exert its stimulatory influence on GH secretion only in the presence of a functional muscarinic cholinergic system; 4) the cholinergic system, at least in part, stimulates GH secretion via a cysteamine-sensitive system (probably by inhibiting somatostatin); 5) the cholinergic system is not functionally coupled with the alpha(2)-adrenergic system, which stimulates GH secretion via rat GHRH; 6) since in 10-day-old pups clonidine HCI was effective only in males, while suckling was effective in both sexes, the alpha(2)-adrenergic system is not involved in the suckling-induced increase of serum GH; and finally 7) neither somatostatin nor rat GHRH seem to be involved in the suckling-induced changes in serum GH. The findings are consistent with the hypothesis that the high circulating GH levels in the neonatal rat are due to alternative GH-releasing factors, perhaps thyrotropin-releasing hormone or gamma-aminobutyric acid. The neurohumoral mediator of the suckling-induced GH release in neonatal rats remains to be identified.

Active alpha 2 and beta adrenoceptors in lymphocytes from patients with chronic lymphocytic leukemia.

A single population of alpha 2 adrenoceptors was characterized in intact B lymphocytes from patients with chronic lymphocytic leukemia (B-CLL) by binding and saturation studies with 3H labelled yohimbine and by competition studies with alpha adrenergic antagonists. While the affinity of B-CLL alpha 2 adrenoceptors was low (KD: 9.81 nM-20.98 nM), each cell expressed a large number of receptors. No binding of the alpha 1 adrenoceptor antagonist prazosin was observed and the binding properties of beta adrenergic receptors (assayed with 3H-labelled dihydroalprenolol), were similar to those described for normal lymphocytes. Reaction of B-CLL with the beta adrenergic agonist isoproterenol raised the levels of cAMP in 11/13 patients tested, and in 8 of these, incubation with the alpha 2 adrenergic agonist clonidine prevented the effect and reduced the basal cAMP levels. The presence of active alpha 2 adrenoceptors on B-CLL lymphocytes may be involved in the regulation of metabolic pathways that affect cell functions and favor neoplastic growth.

Clonidine and PGE2 have different effects on Na+ and water transport in rat and rabbit CCD

We examined the effects of prostaglandin E2 (PGE2) and the adrenergic agonist clonidine on osmotic water permeability (Pf), lumen-to-bath 22Na+ flux (Jl----b), and transepithelial voltage (VT) in isolated perfused cortical collecting ducts (CCD) from rats and rabbits. Although PGE2 inhibited arginine vasopressin (AVP)-dependent Jl----b and Pf in CCDs from deoxycorticosterone (DOC)-treated and untreated rabbits, 0.1-10 microM PGE2 had no inhibitory effect on any of these transport parameters in CCDs from DOC-treated rats in presence of AVP. On the other hand, clonidine (1 microM in bathing solution) reversibly inhibited AVP-dependent Pf, Jl----b, and VT in the rat CCD by 30-40%, and 0.3 microM yohimbine, a specific alpha 2-adrenoceptor antagonist, reversed these effects. However, we were unable to demonstrate any inhibitory effect of 1-10 microM clonidine on Pf, Jl----b, or VT in the rabbit CCD using a variety of protocols. These results are consistent with the pattern of inhibition of AVP-dependent adenosine 3',5'-cyclic monophosphate (cAMP) production in the rat and rabbit CCD in that PGE2 inhibits both transport and cAMP production in the rabbit but not the rat CCD, and clonidine inhibits both transport and cAMP production in the rat but not the rabbit CCD [D. Chabardès, C. Brick-Ghannam, M. Montégut, and S. Siaume-Perez, Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): F43-F48, 1988].

Interaction between opiate subtype and alpha-2 adrenergic agonists in suppression of noxiously evoked activity of WDR neurons in the spinal dorsal horn.

Several studies have demonstrated synergistic antinociception following low-dose administration of morphine and alpha-2 adrenergic agonists at the spinal level. This study was carried out in order to identify the opiate subtypes that are likely to be involved in such synergistic suppression of noxiously evoked activity of wide-dynamic-range (WDR) neurons in the dorsal horn of the spinal cord. We also examined the effect of opiate antagonists and alpha-2 adrenergic antagonists on the suppression produced by opiate or alpha-2 adrenergic agonists. Extracellular activity of single WDR neurons in the spinal dorsal horn, which was evoked by a radiant heat stimulus (51 degrees C), was recorded in decerebrate, spinally transected cats. Agonists were administered spinally and antagonists intravenously. In the synergism study, ineffective doses of the moderately selective mu agonist morphine (25 micrograms), the delta agonist DADL (20 micrograms), and the selective delta agonist DPDPE (30 micrograms), when combined with an ineffective dose of the alpha-2 adrenergic agonist clonidine (5 micrograms) produced significant synergistic suppression of noxiously evoked WDR neuronal activity. However, the ineffective or slightly effective dose of the selective mu agonist DAGO (1 or 1.5 micrograms, respectively) did not show any synergistic action with clonidine. Furthermore, the synergism between morphine and clonidine was reversed by the selective delta antagonist ICI 174,864. We interpret these results to indicate that opiates interact at spinal delta receptors to produce a synergistic suppression of evoked WDR neuronal activity in the presence of spinal clonidine. An alternative explanation is that ICI 174,864 may interact in some way with alpha-adrenergic systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of thyroid hormone deficiency on noradrenergic circuitry: electrophysiological changes in intraocular hippocampus–locus coeruleus double transplants

The effects of thyroid hormone deficiency on the noradrenergic innervation of hippocampus from locus coeruleus (LC) were examined using intraocular double transplants in albino rats. Fetal brainstem pieces containing the nucleus LC were transplanted to the anterior chamber of the eye of thyroidectomized and normal recipients and the brain grafts were allowed to mature for 8 weeks. Pieces of fetal hippocampal formation were introduced into the anterior eye chamber and placed in contact with the LC grafts or placed in previously operated eyes. As evidenced by high performance liquid chromatography, hippocampal transplants in contact with a brainstem graft gradually became hyperinnervated by noradrenergic fibers from these grafts. The levels of norepinephrine were lower in single control grafts and in double grafts in thyroidectomized animals than in control double grafts. Extracellular recordings of single neuronal activity were performed in hippocampal transplants in all 3 groups after 10-14 months in oculo. Superfusion with the α2- adrenergic agonist clonidine and the α-adrenergic antagonist phentolamine elicited significant increases in discharge rate of hippocampal neurons in control double transplants, but not in single hippocampal grafts or in double grafts in thyroidectomized hosts. The β-adrenergic antagonist timolol did not change the neuronal firing rate in any of the 3 groups. Superfusion with penicillin over single hippocampal transplants caused long-lasting increases in slow-wave activity. This increased bioelectric activity remained after the cessation of drug application. A similar increase in slow-wave activity was found in hyperinnervated control double transplants only when penicillin was combined with clonidine or phentolamine. However, the hippocampal portion of double grafts in thyroidectomized recipients readily responded to penicillin with seizures and/or interictal spiking. The data presented here suggest that chronic lack of thyroid hormones leads to significant disturbances of the central noradrenergic transmission in isolated LC-hippocampal circuits.

Enhanced susceptibility to kindling by chlordimeform may be mediated by a local anesthetic action

The formamidine pesticides amitraz and chlordimeform have recently been shown to be potent proconvulsants (Gilbert 1988). Two main neuroactive properties have been identified as mediators of formamidine neurotoxicity, alpha-2 adrenergic agonism and local anesthetic actions. These two proposed mechanisms of formamidine action were contrasted using electrical kindling of the amygdala. Male rats were administered 0, 10 and 40 mg/kg of the local anesthetic lidocaine, 0, 0.01 and 0.10 mg/kg of the alpha-2 adrenergic agonist clonidine or 0, 10 and 30 mg/kg chlordimeform, IP, once per day. After each injection, kindling stimulation was delivered through chronically-implanted electrodes. The high dosage of chlordimeform and both dosages of lidocaine enhanced the rate of kindling development (mean sessions to stage 5 seizures = 8.6 +/- 1.16, 10.15 +/- 1.04 and 8.5 +/- 0.95, respectively) relative to controls (mean = 14.59 +/- 1.36). Afterdischarge (AD) durations were increased over the first seven sessions by both treatments, but the total cumulative AD did not differ from controls. Clonidine, by contrast, delayed kindling development (mean 27.57 +/- 1.97) and shortened the mean AD duration over the first seven sessions. These data provide support for a local anesthetic action of chlordimeform and stand in contrast to several recent demonstrations of alpha-2 activity of formamidines as a primary contributor to formamidine toxicity.

Modification of quasi-morphine withdrawal with serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal

Methylxanthines produce a quasi-morphine withdrawal syndrome (QMWS) in opiate naive rats. Additionally, methylxanthine-induced suppression of conditioned behavior in rats is reversed by the alpha 2 adrenergic agonist clonidine which also attenuates true opiate withdrawal and the QMWS. Therefore, the operant behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) provide a model with which to study mechanisms involved in the expression of opiate withdrawal. In order to examine the role of serotonin (5-HT) in the rate-decreasing effects of IBMX on operant behavior, the 5-HT precursor 5-hydroxytryptophan, and 5-HT reuptake blocker fluoxetine were administered in combination with IBMX to rats performing a fixed-ratio 30 operant for food reinforcement. Both drugs failed to reverse the behavioral suppression caused by relatively low doses of IBMX, suggesting that elevated 5-HT neurotransmission contributes to, rather than attenuates, the QMWS. The relatively selective 5-HT2 antagonists mianserin and pirenperone blocked the IBMX-induced suppression, whereas the classic 5-HT antagonist methysergide had no effect. The results indicate that the operant behavioral effects of IBMX and possibly the QMWS may be mediated by serotonergic mechanisms.

Effect of alpha-2 adrenergic receptor stimulation on short-circuit current across isolated skin of the toad Bufo Arenarum

1. The effect of the alpha-2 adrenergic agonist clonidine on short-circuit current (SCC) across isolated skins of Bufo arenarum toads was investigated. 2. Clonidine inhibited basal SCC in a dose-dependent manner. 3. Blockade of the effect of clonidine on basal SCC by the selective alpha-2 antagonist yohimbine supports the hypothesis that the inhibitory effect is mediated by the stimulation of alpha-2 adrenergic receptors. 4. The fact that the inhibitory effect of clonidine is higher in skins with spontaneous positive SCC than in the negative ones, and that the alpha-2 agonist was unable to alter amiloride-induced negative SCC suggests that the inhibitory effect of clonidine may probably be mediated by inhibition of sodium transport.

Noradrenergic and serotonergic receptor system function in panic disorder and depression.

Recent studies which have utilized the administration of neurotransmitter agonists and antagonists to study presynaptic and postsynaptic receptor system function in panic disorder and major depression are reviewed. In panic disorder, patients have been found to be overly sensitive to the alpha-2 adrenergic agonist clonidine, and the alpha-2-adrenergic antagonist yohimbine, but they have relatively normal responses to tryptophan, the precursor of serotonin, and MCPP, a directly acting serotonin agonist. In depression, patients appear to have relatively normal responses to clonidine and yohimbine except for some supersensitivity to yohimbine effects on blood pressure and subjective symptoms. In contrast to the panic disorder patients, depressed patients demonstrate a neuroendocrine subsensitivity to tryptophan. Taken together, these studies suggest a relative abnormality in the alpha-2-adrenergic regulation of the noradrenergic system in panic disorder and a subsensitivity of the serotonergic system in depression. The pharmacologic treatment response in panic disorder and depression is similar in that both conditions respond to tricyclic antidepressants and monoamine oxidase inhibitors, but different in that panic disorder does not respond to atypical antidepressants such as trazodone and bupropion, but does respond to benzodiazepines, in contrast to depression. The possible mechanisms involved in producing these findings and the methods to more fully study possible receptor system abnormalities in these illnesses are discussed.

Attenuation of isobutylmethylxanthine-induced suppression of operant behavior by pretreatment of rats with clonidine

Administration of 3-isobutyl-1-methylxanthine (IBMX) to rats performing a FR30 operant for food reinforcement produces a does-dependent suppression of behavior. Operant behavior suppressed by 5 mg IBMX/kg is attenuated by pretreatment, 30 min before the operant session, with the α 2 adrenergic agonist clonidine (5–30 μg/kg). Clonidine itself causes a dose-dependent reduction in FR30 responding prior to the administration of IBMX. However, doses of clonidine which also suppressed responding were not more effective than lower doses in attenuating the suppresion of operant behavior caused by IBMX, perhaps due to postsynaptic or nonspecific actions of clonide. Methylxanthines, alone or in combination with the opiate antagonist naloxone, produce signs of opiate withdrawal. This quasi-morphin withdrawalsyndrome may be useful in studies of either the development or expression of opiate withdrawal. Since clonidine attenuates the rate-suppressant effect of IBMX, it is likely that a significant component of IBMX's behavioral effects are due to increases in NE neurotransmission. These results are similar to those obtained with true opiate withdrawal in rats, strengthening the idea that suppression of operant behavior by IBMX involves mechanisms in common with opiate withdrawal. It may be a useful way of objectively studying the expression of the withdrawal syndrome in the absence of opiates and/or a way of determining if a drug can selectively block withdrawal.

Effect of estrogen on the growth hormone response to the alpha-adrenergic agonist clonidine in women with menopausal flushing.

The serum GH response to the alpha 2-adrenergic receptor agonist clonidine (0.15 mg, iv) was measured in 8 postmenopausal women with hot flushes before and during treatment with the conjugated estrogen premarin (1.25 mg, orally daily for 4 weeks), 9 normal premenopausal women, and 12 normal men. The men had a significantly greater GH response than did the age-matched premenopausal women (P less than 0.05). The mean individual peak GH response was significantly higher in the premenopausal compared with the postmenopausal women (P less than 0.05). Premarin decreased the number of hot flushes (P less than 0.01), but had no effect on the GH response to clonidine. These results suggest that estrogens do not enhance alpha 2-adrenergic mechanisms that regulate GH secretion and that improvement in menopausal flushing after estrogen therapy is not mediated by an effect on central alpha 2-adrenergic function.

Noradrenergic effects on rat visual cortex: Single-cell microiontophoretic studies of alpha-2 adrenergic receptors

The catecholamine noradrenaline has been proposed to modulate the excitability of cortical neurons, and such a regulation may be mediated by specific adrenergic receptors. We characterized, using electrophysiological recordings, the types of responses of single cells in the rat visual cortex (areas 17 and 18) to the iontophoretic application of adrenergic agents. For the majority of spontaneous and visually-driven cells sampled, noradrenaline decreased the firing frequency, and in some cases of visually-driven cells could increase the signal/noise ratio. These effects were also documented after the application of the alpha-2 adrenergic agonists clonidine and oxymetazoline, and could be reduced or blocked by a previous ejection of the specific alpha-2 antagonist idazoxan. The present study supports a role for alpha-2 adrenoceptors in the modulation of sensory inputs to the visual cortex.

Early clinical experience with clonidine in spinal spasticity.

The centrally active, alpha-2 adrenergic receptor agonist clonidine was given to 12 spinal cord injury patients with problematic spasticity not adequately controlled by recognized spasmolytic drug therapy. Five patients had an excellent reduction and 2 patients had some reduction in clinical spasticity (average dose 0.39 mg daily). Four of the 7 responders discontinued clonidine because of adverse reactions after an average of ten weeks of therapy. Three responders have continued to tolerate the drug well with excellent control of spasticity for 18 to 34 months. Five patients had no change in clinical spasticity (average dose of 0.24 mg daily). Three of the non-responders discontinued clonidine because of adverse reactions after an average of three weeks of therapy. Significant associated adverse reactions included syncopal seizures (3), cerebrovascular accident (1), deep vein thrombosis (1), autonomic hyperreflexia (3), lethargy/drowsiness (3), and nausea/vomiting (1). Possible mechanisms of action for clonidine to affect spasticity and the unstable cardiovascular system of quadriplegics is discussed. While spinal cord injured patients with severe spasticity may benefit from clonidine, great caution is recommended during its use until further study establishes safe parameters of administration and efficacy is confirmed on controlled studies.