The lateral septal area is involved in the pressor pathway activated by microinjection of norepinephrine into the rat brain cingulate cortex

The cingulate cortex (CC) is involved in cardiovascular regulation. Microinjection of norepinephrine (NE) into the Cg3 area of the CC caused vasopressin release and pressor responses in unanesthetized rats. Microinjection of acetylcholine (ACh) into the lateral septal area (LSA) of unanesthetized rats caused similar vasopressin-related pressor responses. The LSA is anatomically connected to the CC and the paraventricular nucleus (PVN) of the hypothalamus, an important nucleus involved in vasopressin synthesis. Therefore, we attempted to verify if the cholinergic neurotransmission within the LSA is involved in the mediation of the pressor response to the microinjection of NE into the Cg3. Local pretreatment with lidocaine, muscimol, atropine or hemicholinium-3 microinjected into the LSA blocked the pressor response to the microinjection of NE injection into the Cg3. Conversely, pretreatment with physostigmine microinjected into the LSA potentiated the pressor response to NE injection into the Cg3. The present results indicate that the synapses in the LSA are part of the pressor pathway originating at the CC and that cholinergic neurotransmission within the LSA is involved in the mediation of the cardiovascular responses to the microinjection of NE into the Cg3.     

Peripheral pressor effects of sympathetic stimulation,noradrenaline, angiotensin II and vasopressin in Brattleboro rats

Summary The following study was designed to test the hypothesis that peripheral blood vessels of vasopressin deficient (Di/Di) rats are less responsive to pressor substances than normal rats. To address this question, pithed Di/Di and normal Long-Evans rats (LE) were exposed to intravenous injections of arginine-vasopressin, angiotensin II and noradrenaline. In addition, blood pressure increments and noradrenaline release in response to spinal cord stimulation in pithed Di/Di and LE rats were studied. The results show no abnormalities in peripheral vascular sensitivity to any of the pressor substances administered, nor was there any change in blood pressure and sympatho-adrenomedullary response to graded stimulation of the sympathetic outflow from the spinal cord. This study suggests that the failure of vasopressin deficient rats to recover from acute hemorrhage is not due to hyporesponsiveness of the peripheral vasculature to pressor agents but, rather, to the deficiency in the direct pressor effect of vasopressin.     

Mechanism of the CNS-mediated pressor response to intracerebroventricular injection of noradrenaline in unanaesthetized rats

Catecholamines administered intracerebroventricularly (i.c.v.) have cardiovascular effects mediated by the CNS. Although hypotension constitutes the more prominent response, an increase in blood pressure has also been reported after the intracerebroventricular injection of these amines. Anaesthesia interferes with pressor responses mediated by the CNS to a larger extent than with depressor mechanisms and constitutes one of the major factors influencing the pattern of response to the amines. The depressor response observed after the intracerebroventricular administration of noradrenaline is reversed into increases in blood pressure in awake animals. In the present experiment, the action of intracerebroventricularly injected noradrenaline was compared in anaesthetized and conscious rats. The results indicated that the pressor response in awake rats was not mediated by the sympathetic nervous system and involved the release of a pituitary humoral-factor, most probably vasopressin, whereas the depressor response observed in anaesthetized animals was not dependent on pituitary mediation. The involvement of histaminergic mechanisms in the CNS in the control of the pressor response to intracerebroventricularly administered noradrenaline in the rat is proposed.     

Mechanisms involved in the cardiovascular response to intracerebroventricular injection of noradrenaline and phentolamine.

Intracerebroventricular (i.c.v.) injection of noradrenaline in anaesthetized and unanaesthetized rats caused a dose-related, bimodal change in blood pressure i.e. a fall after low doses (1–2 μg), variable responses after intermediate doses (4–6 μg) and a rise after higher doses (12–50 μg). The hypotensive response to the low dose of noradrenaline was shown to be mediated by central α-adrenergic receptors, since it was abolished by intracerebroventricular pretreatment with phentolamine. The pressor response to the higher dose was due to leakage of the catecholamine from the CNS to the periphery, as it was abolished by intravenous administration of phentolamine but not by prior ganglionic blockade with mecamylamine. Intracerebroventricular injection of 100 μg of phentolamine alone produced a fall in arterial pressure. This response was most likely due to diffusion of the α-adrenergic blocking agent to the peripheral circulation, since central injection of phentolamine attenuated the pressor response generated by intravenous administration of noradrenaline.     

Diminished pressor response to noradrenaline of the perfused tail artery of pregnant rats

A reduced pressor response of the perfused rat tail artery to various doses of noradrenaline (NA) occured during pregnancy and was most pronounced at day 7–8 of gestation. Progesterone pretreatment caused a similar reduction in non-pregnant rats, while oestradiol had no effect. It is suggested that the increased circulating progesterone level during pregnancy is responsible for the reduced NA response in vitro.     

Mucosal damage following electrical stimulation of the anterior cingulate cortex and pretreatment with atropine and cimetidine

Bipolar electrical stimulation of a restricted area of the anterior cingulate cortex in anesthetized rats produced stomach erosions. Pretreatment with atropine sulfate prevented the pathological effects of stimulation. Cimetidine was not effective in preventing the gastric damage. It was concluded that the pathological effects of electrical stimulation were cholinergically mediated, whereas, histamine-2 receptors were not involved.     

Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine,the prototype atypical antipsychotic

Rationale. Clozapine has been shown to increase extracellular dopamine (DA) and noradrenaline (NA) in the medial prefrontal cortex (mPFC). A recent study of ours suggested that extracellular DA in the PFC originates not only from dopaminergic but also from noradrenergic terminals, its release being controlled by α₂-adrenoceptors. Objectives. Since clozapine binds to α₂-adrenoceptors, the possibility that it might co-release DA and NA was studied. Methods. By means of microdialysis coupled to HPLC with electrochemical detection, the effect of clozapine on extracellular DA and NA in the mPFC, densely innervated by DA and NA, was compared to that in the occipital cortex, equally innervated by NA but receiving few DA projections. Results. Extracellular NA was found to be the same in the two cortices, consistent with homogeneous NA innervation. On the other hand, extracellular DA in the occipital cortex was only 29% lower than in the mPFC, in spite of the scarce dopaminergic innervation in the occipital cortex. Clozapine (10 mg/kg IP) increased extracellular DA and NA not only in the mPFC (by about 320% and 290%, respectively) but also in the occipital cortex (by 560% and 230%, respectively). Administration of the α₂-agonist clonidine (0.15 mg/kg) reversed the effect of clozapine in both cortices, while the D₂-agonist quinpirole (0.1 mg/kg IP) was ineffective. Conclusions. The results suggest that clozapine, by inhibiting α₂-adrenoceptors, co-releases DA and NA from noradrenergic terminals in the occipital cortex and that the same mechanism might be responsible for the concomitant increase of the two monoamines in the mPFC. Electronic Publication     

Is the pressor response to strychnine centrally mediated?

Intravenous administration of strychnine (0.003–0.300 mg · kg⁻¹) to curarized, chloralosed dogs induced hypertension and tachycardia. In spinal cord-transected dogs, intravenous administration of strychnine no longer elicited a rise in blood pressure and heart rate. Intracisternal injections of strychnine also produced hypertension and tachycardia but at lower doses. Similar results were obtained after intrathecal administration of strychnine in doses significantly different from those effective on intravenous and intracisternal administration. These findings suggest that the central nervous system may be involved in the haemodynamic changes induced by strychnine, but did not allow the site of action to be located.     

Localization of cholinergic neurons involved in the cardiovascular response to intrathecal injection of carbachol

Recent studies in this laboratory have demonstrated the ability of acetylcholine receptor agonists to produce systemic arterial pressor responses through stimulation of spinal muscarinic receptors. In urethane-anesthetized rats a new surgical procedure was employed to permit microinjection of drugs into the cerebrospinal fluid surrounding the medulla without significant redistribution to spinal sites and vice versa. Pretreatment with intracisternal (medullarylevel) injection of 10 μg of atropine significantly inhibited the expression of the pressor response produced by intrathecal injection of 5 μg of carbachol. This inhibition was due at least partly to the interruption of a medullary component of a spinobulbar pathway involving medullary muscarinic receptors. It was not due to redistribution of atropine from medullary to spinal sites since significant levels of atropine were not detected in the spinal cord after intracisternal injection of the drug. The remainder of the pressor response to intrathecal carbachol after medullary muscarinic receptor blockade was most likely due to interactions within the spinal cord itself.     

Effects of psychotropic drugs on pressor and behavioral responses to brain stimulation in unrestrained, unanesthetized rats

Electrical stimulation of the posterior hypothalamus (PH) and the mesencephalic reticular formation (MRF) in unanesthetized, unrestrained rats with chronic electrode implants and an arterial cannula elictied a rise in blood pressure accompanied by behavioral changes such as exploration, flight or escape responses. Pentobarbital inhibited both the pressor and behavioral responses to PH and MRF stimulation. Chlorpromazine, diazepam and imipramine depressed the pressor response to PH stimulation rather than that to MRF stimulation with affecting the behavioral responses. It is concluded from these results that chlorpromazine, diazepam and imipramine exert their action on the neural pathway involved in the pressor response rather than on that inducing behavioral responses, whereas pentobarbital affects more extended brain areas related to these neural systems.     

Increased levels of extracellular noradrenaline in the frontal cortex of rats exposed to naturalistic environmental stimuli: modulation by acute systemic administration of diazepam or buspirone

In vivo microdialysis was used to investigate the effects of an IP injection of diazepam or buspirone (each at 3 mg/kg) on spontaneous efflux of noradrenaline in rat frontal cortex, and on changes in efflux induced by naturalistic stress. After drug administration, rats either remained in their home cages or were transferred individually to a novel cage, 1 h later. The novel cage was brightly lit (1500 lux) and contained another, unfamiliar rat. After transfer to the novel cage, noradrenaline efflux was lower in diazepam-injected rats than in their vehicle-injected counterparts. However, in both case, stress caused a significant increase in efflux and the net increase was not affected by diazepam. Similarly, buspirone, which increased spontaneous efflux of noradrenaline, did not affect the net increase in efflux during stress. Neither compound modified locomotor activity in the novel cage. This suggests that any changes in noradrenaline efflux are unrelated to drug effects on non-specific arousal. It is concluded that generically unrelated anxiolytic agents can have different effects on spontaneous efflux of noradrenaline but do not modify the noradrenergic response to naturalistic stimuli.     

Effects of noradrenaline depletion in the brain on response to novelty in isolation-reared rats

RATIONALE: Social isolation from weaning in the rat produces a variety of neurochemical and behavioural effects in the adult that in part parallel changes seen in human schizophrenia. OBJECTIVES: The study investigated the effects of central noradrenaline (NA) depletion by the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the behaviour of isolation-reared rats. METHODS: Male Lister hooded rats were reared singly or in groups after weaning. During week 2, the rats were tested in photocell activity cages and were then injected with DSP-4 (25 mg/kg, IP). During week 4, rats were tested in the open field under the following conditions: open field alone, with two novel stimuli (T1), and with a familiar and a novel object (T2), and in the activity cages. RESULTS: DSP-4 significantly reduced cortical and hippocampal NA levels with no effect on the hypothalamus. Isolation-reared rats exhibited locomotor hyperactivity and reduced habituation to the testing arena, although their exploration of the novel objects in T1 was not significantly different from group-reared rats. DSP-4 treatment in group-reared rats increased inner zone activity in the open field but did not significantly affect the exploration of novel objects. DSP-4 treatment in isolates reduced exploration of objects at T2 while increasing exploration of the general environment. CONCLUSIONS: Isolation rearing influences the behavioural effects of central NA depletion. The results suggest isolation-induced changes in the central noradrenergic system in the isolated rat, supporting the view that early environmental factors can have long-term effects on central noradrenergic function as well as other neurotransmitter systems.     

Pharmaco-histochemical evidence of the existence of dopamine nerve terminals in the limbic cortex

With a recent modification of the Falck-Hillarp technique using glyoxylic acid perfusion and Vibratome sectioning in combination with pharmalogical models for the selective demonstration of dopamine stores, evidence has been obtained that there exist large numbers of previously unknown systems of dopamine nerve terminals in the limbic cortex, e.g. in the gyrus cinguli, the entorhinal cortex and the amygdaloid cortex. No evidence for the existence of dopamine cell bodies in these areas was obtained.     

Inhibition of N-methyl-d-aspartate- and kainate-evoked noradrenaline release in human cerebral cortex slices by ethanol

Summary The effect of ethanol on the release of noradrenaline evoked by various stimuli was investigated in human cerebral cortical slices from patients undergoing neurosurgery. The slices were preincubated with [³H]noradrenaline and then superfused. Tritium overflow was stimulated by exposure to N-methyl-d-aspartate (NMDA; in slices superfused without Mg²⁺), kainic acid, veratridine or by increasing the K⁺ concentration.The NMDA evoked tritium overflow was concentration-dependently inhibited by ethanol; an inhibition by 37% occurred at 48 mmol/l ethanol. This ethanol concentration was not yet effective when kainic acid was used for stimulation, but ethanol 150 mmol/l strongly inhibited the tritium overflow evoked by kainic acid as well. The tritium overflow evoked by veratridine or high K⁺ was not affected by ethanol in the concentration range investigated.These findings are compatible with the suggestion that the NMDA receptor and, with less susceptibility, the kainate receptor are sites of action underlying the effect of ethanol in the human brain.Send offprint requests to M. Göthert at the above address     

Subchronic milnacipran treatment increases basal extracellular noradrenaline concentrations in the medial prefrontal cortex of rats

In this study, we investigated the acute effects of milnacipran, a serotonin–noradrenaline reuptake inhibitor, following subchronic treatment with milnacipran (30 mg/kg periorally for 7 days) on extracellular noradrenaline, dopamine and serotonin concentrations in the medial prefrontal cortex. Subchronic administration of milnacipran produced significantly higher basal levels of extracellular noradrenaline. Acute milnacipran administration following subchronic milnacipran treatment for 7 days produced a greater increase in extracellular noradrenaline than a single dose of milnacipran alone. The present results suggest that subchronic milnacipran treatment enhances noradrenergic neural transmission beyond that achieved with acute administration of milnacipran alone, but has no effect on serotonergic or dopaminergic neural transmission.     

Nociceptin inhibits noradrenaline release in the mouse brain cortex via presynaptic ORL1 receptors

A fourth type of opioid receptor, termed ORL₁, has been cloned and nociceptin (also known as orphanin FQ) has been identified as an endogenous ligand at this receptor. We examined whether nociceptin affects the release of noradrenaline in the brain. For this purpose, cerebral cortex slices from the mouse, rat or guinea-pig were preincubated with [³H]noradrenaline and then superfused with medium containing desipramine and rauwolscine. Tritium overflow was evoked electrically (0.3 Hz) or by introduction of Ca²⁺ 1.3 mM into Ca²⁺-free K⁺-rich (15 mM) medium. Nociceptin 1 μM reduced the electrically evoked tritium overflow from mouse, rat and guinea-pig brain cortex slices by 80, 71 and 36%, respectively. Naloxone 10 μM did not change the effect of nociceptin. All subsequent experiments were performed on mouse brain cortex slices and in the presence of naloxone 10 μM. The concentration-response curve of nociceptin (maximum inhibition by 80%, pEC₅₀ 7.5) was shifted to the right by the non-selective ORL₁ receptor antagonist naloxone benzoylhydrazone and the selective ORL₁ receptor antagonist [Phe¹ψ(CH₂-NH)Gly²]-nociceptin(1–13)NH₂ (pA₂ 6.6 and 7.2, respectively). Naloxone benzoylhydrazone did not affect the evoked overflow by itself whereas [Phe¹ψ(CH₂-NH)Gly²]-nociceptin(1–13)NH₂ caused an inhibition by maximally 35% (pEC₅₀ 7.0; intrinsic activity α 0.45). The inhibitory effect of [Phe¹ψ(CH₂-NH)Gly²]-nociceptin(1–13)NH₂ was counteracted by naloxone benzoylhydrazone. Nociceptin also reduced the Ca ²⁺ -evoked tritium overflow in mouse brain cortex slices superfused in the presence of tetrodotoxin. This effect was also antagonized by naloxone benzoylhydrazone, which, by itself, did not affect the evoked tritium overflow. In conclusion, nociceptin inhibits noradrenaline release more markedly in the mouse than in the rat or guinea-pig brain cortex. The effect of nociceptin in the mouse brain cortex involves ORL₁ receptors, which are located presynaptically on noradrenergic neurones. Received: 19 June 1998 / Accepted: 17 July 1998     

Analysis of the pressor response to the K+ channel inhibitor 4-aminopyridine

The cardiovascular response to the K(+) channel inhibitor 4-aminopyridine in anaesthetized rats was analysed. 4-Aminopyridine produced a biphasic pressor response. First, it increased blood pressure, total peripheral vascular resistance, cardiac output and stroke volume. Nitric oxide synthase (NOS) inhibitor augmented the tension response; reserpine, phentolamine, propranolol, scopolamine, atropine, adrenalectomy, indomethacin, angiotensin AT(1) and endothelin ET(A) receptor antagonists had no effect. Subsequently, heart rate increased, but total peripheral vascular resistance was no longer elevated. Reserpine and propranolol abolished the tachycardia. An elevated late tension occurred after propranolol and NOS inhibitor but not reserpine or phentolamine+NOS inhibitor. The peripherally acting 3,4-diaminopyridine produced similar responses. 4-Aminopyridine contracted isolated aortic rings also after denudation. These results are compatible with that the immediate tension response resulted from closure of vascular smooth muscle K(+) channels, and that closure of presynaptic K(+) channels in peripheral sympathetic nerves subsequently activated noradrenaline release, beta-adrenoceptors and tachycardia, while nitric oxide counter-acted a concomitant alpha-adrenergic vasoconstriction.     

Ethylketocyclazocine decreases noradrenaline release and blood pressure in the rabbit at a peripheral opioid receptor

Summary Rabbits were pithed and their sympathetic outflow was stimulated electrically via the pithing rod. Arterial blood pressure, heart rate, the endogenous plasma noradrenaline level, the plasma ³H-noradrenaline clearance and the noradrenaline release rate (the rate of entry of endogenous noradrenaline into the plasma) were determined. Ethylketocyclazocine 0.1 mg kg^–1+0.02 mg kg^–1 h^–1 and 1 mg kg^–1 + 0.2 mg kg^–1 h^–1 but not 0.01 mg kg^–1+ 0.002 mg kg^–1 h^–1 decreased blood pressure, the endogenous plasma noradrenaline level and the noradrenaline release rate. The effects of ethylketocyclazocine 1 mg kg^–1+ 0.2 mg kg^–1 h^–1 were antagonized by naloxone 1 mg kg^–1 + 0.5 mg kg^–1 h^–1. Given alone, naloxone caused no change. It is concluded that ethylketocyclazocine inhibits action potential-evoked release of noradrenaline from postganglionic sympathetic neurones, and hence can lower blood pressure, by a peripheral effect, possibly mediated by opioid receptors at the terminal axons.     

Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors

Summary The effects of histamine and related drugs on the evoked tritium overflow from superfused rat brain cortex slices preincubated with³H-noradrenaline were determined. Tritium overflow was stimulated electrically (3 Hz; slices superfused with normal physiological salt solution) or by introduction of CaCl₂ 1.3 mmol/l (slices superfused with Ca²⁺-free medium containing K⁺ 20 mmol/l).Histamine slightly decreased the electrically evoked^H overflow in slices superfused in the presence of desipramine. The degree of inhibition obtained with histamine was doubled when both desipramine and phentolamine were present in the superfusion medium (pIC₁₅ 6.46). Under the latter condition, the evoked overflow was inhibited by the H₃ receptor agonist R-(–)--methylhistamine and its S-(+) enantiomer (pIC₁₅ 7.36 and 5.09, respectively), but was not affected by the H₂ receptor agonist dimaprit and the H₁ receptoragonist 2-thiazolylethylamine (both at up to 32 µmol/l). The concentration-response curve of histamine was shifted to the right by the H3 receptor antagonists thioperamide, impromidine and burimamide (apparent pA₂ 8.37, 6.86 and 7.05, respectively), by the H₂ receptor antagonist ranitidine (apparent pA₂ 4.27) and was not affected by the H₁ receptor antagonist dimetindene (32 µmol/l). The inhibitory effect of R-(–)--methylhistamine on the evoked overflow was also counteracted by thioperamide. Given alone, none of the five histamine receptor antagonists affected the evoked overflow. In the absence of desipramine plus phentolamine, impromidine and burimamide facilitated the electrically evoked³H overflow whereas thioperamide had no effect. The facilitatory effects of impromidine and burimamide were abolished by phentolamine, but not affected by desipramine. The concentration-response curve of noradrenaline for its inhibitory effect on the evoked overflow was shifted to the right by impromidine and burimamide, but not influenced by thioperamide (apparent pA₂ 5.24, 5.04 and <6.5, respectively; experiments carried out in the presence of desipramine). In slices superfused with Ca²⁺-free K⁺-rich medium containing tetrodotoxin, desipramine plus phentolamine, the tritium overflow evoked by introduction of Ca²⁺ was inhibited by histamine; the concentration-response curve of histamine was shifted to the right by thioperamide.The present study shows that the inhibitory effect of histamine on noradrenaline release in the rat brain cortex involves presynaptic H₃ receptors and that the degree of inhibition is increased in the presence of phentolamine. The H₃ receptor antagonists impromidine and burimamide are weak ₂-adrenoceptor antagonists. Send offprint requests to E. Schlicker at the above address     

Changes in electrophysiological properties and noradrenaline response in vas deferens of diabetic rats

The purpose of this study was to study changes in the sympathetic nerves of the vas deferens in 10-week-old streptozotocin-induced diabetic rats. To assess the activity of autonomic neurons, we recorded the amplitude and frequency of spontaneous junction potentials in vasa deferentia from age-matched controls and streptozotocin-induced diabetic rats. No change in the resting membrane potential of the smooth muscle of the vas deferens was found in streptozotocin-induced diabetic rats. The frequency of spontaneous junction potentials was significantly increased in the streptozotocin-induced diabetic rats and their amplitude was also markedly increased. The dose–response curve for the contractile response of the vas deferens to noradrenaline was significantly shifted to the right and the apparent affinity (pD₂ value) was significantly decreased in streptozotocin-induced diabetic rats. These results suggest that degeneration of sympathetic neurons may occur in the vas deferens of 10-week streptozotocin-induced diabetic rats and that the greater amplitude of the spontaneous junction potentials may be related to an increase in Ca²⁺ mobilization, though the increase in Ca²⁺ mobilization does not lead to an enhanced contractile response.