Central Catecholamine Research Articles

Aspects of tolerability of centrally acting antihypertensive drugs.

Traditional centrally acting antihypertensives have been associated with a high incidence of adverse effects and are no longer recommended as first-line therapy. The newer imidazoline receptor agonists must overcome this reputation if they are to gain recognition as potential first-line agents for hypertension. Methyldopa, a centrally acting alpha(2)-agonist, is characterized by a number of serious adverse reactions that limit its use. Although unpredictable idiosyncratic or hypersensitivity reactions are uncommon, these include hepatitis, myocarditis, and hemolytic anaemia. Less serious problems such as abnormal liver function tests, positive Coombs test, drug-induced fever, and pancreatitis also occur. Central side effects include drowsiness, fatigue, lethargy, sedation, depression, psychotic reactions, nasal stuffiness, impotence, and exacerbation of Parkinsonism. In hypertensive men, methyldopa is less well tolerated than either captopril or propranolol, and up to 20% of patients discontinue therapy because of adverse effects. Clonidine acts primarily as an alpha(2)-agonist but also acts as an agonist at imidazoline receptors in the rostroventrolateral medulla. It is equipotent to most other antihypertensives but is considerably less well-tolerated in comparative trials. The principal adverse effects of clonidine are drowsiness, sedation, lethargy and dry mouth. Reserpine acts primarily by depleting central catecholamine neurotransmitter stores. It was very extensively used in early hypertension trials, but its central side effects of sedation, nasal stuffiness, and severe depression are now considered so undesirable that the drug is seldom prescribed. The imidazoline (I1) agonists moxonidine and rilmenidine act selectively and have very little central alpha(2)-agonist activity. In comparative studies against placebo and other reference antihypertensives, the only adverse effect consistently associated with these drugs was dry mouth (approximate placebo-corrected incidence 10%). Sedation was not pronounced. Withdrawal syndromes are complex pathophysiologic processes and occur with a variety of antihypertensive drugs. Cessation of therapy with clonidine and, to a lesser extent, methyldopa may result in a severe withdrawal syndrome characterized by restlessness, sweating, anxiety, tremor, palpitations, and headache. There may be a rapid rise in blood pressure, often with a true "rebound" to higher than pretreatment levels. Plasma and urinary catecholamine levels are increased, and fatalities have been reported. It is important to stress that such a syndrome has not been recorded, in animal or human studies, with either moxonidine or rilmenidine.

Blunted catecholamine responses after glucose ingestion in children with attention deficit disorder.

Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children with attention deficit disorder (ADD), but a physiologic mechanism has not been established. To address this issue, metabolic, hormonal, and cognitive responses to a standard oral glucose load (1.75 g/kg) were compared in 17 children with ADD and 11 control children. Baseline and oral glucose-stimulated plasma glucose and insulin levels were similar in both groups, including the nadir glucose level 3-5 h after oral glucose (3.5 +/- 0.2 mmol/L in ADD and 3.3 +/- 0.2 mmol/L in control children). The late glucose fall stimulated a rise in plasma epinephrine that was nearly 50% lower in ADD than in control children (1212 +/- 202 pmol/L versus 2228 +/- 436 pmol/L, p < 0.02). Plasma norepinephrine levels were also lower in ADD than in control children, whereas growth hormone and glucagon concentrations did not differ between the groups. Matching test scores were lower and reaction times faster in ADD than in control children before and after oral glucose, and both groups showed a deterioration on the continuous performance test in association with the late fall in glucose and rise in epinephrine. These data suggest that children with ADD have a general impairment of sympathetic activation involving adrenomedullary as well as well as central catecholamine regulation.

Modulation of the levels of ouabain-like compound by central catecholamine neurons in rats

Catecholamine regulates the Na +,K +-ATPase activity in the central nervous system and the Na +,K +-ATPase has been shown to have endogenous ligands (ouabain-like compound; OLC). To examine the relationship between OLC and central adrenergic neurons, we evaluated the effects of central sympathectomies with intracerebroventricular (i.c.v.) injection of 6-hydroxydopamine (6-OHDA; 250 μg) on brain and plasma OLC levels and brain catecholamine levels. In centrally sympathectomized rats, hypothalamic OLC content and plasma OLC level were significantly decreased by 90% ( P < 0.01) and 70% ( P < 0.01), respectively, in accordance with reduced brain norepinephrine content compared with control rats pretreated by i.c.v. injection of vehicle (ascorbic acid). On the other hand, peripheral sympathectomy with a similar manner did not affect plasma OLC level at all. These findings suggest that central adrenergic neurons may be involved in the synthesis and/or release of circulating OLC.

Interactions of angiotensin II with central catecholamines.

There is a large body of anatomical and functional evidence supporting an interaction between brain angiotensin and central catecholamine systems. Angiotensin II AT1 receptors have been identified on dopamine containing cells in the substantia nigra and striatum of human brain using receptor autoradiography. Using in vivo microdialysis we have demonstrated that locally administered angiotensin II stimulates dopamine release from the striatum of conscious rats. Since some angiotensin receptor antagonists and angiotensin converting enzyme inhibitors can cross the blood brain barrier it is possible that they interact with the brain catecholaminergic systems.

Lesions of the afferent catecholaminergic pathways inhibit the temporal activation of the CRH and POMC gene expression and ACTH release induced by human interleukin-1beta in the male rat.

A number of recent studies have suggested that interleukin-1beta (IL-1beta) is a major mediator contributing to the recruitment of the hypothalamo-pituitary-adrenal (HPA) axis following infectious aggressions. Central catecholamines modulate the response of the HPA axis. To investigate the importance of the afferent catecholaminergic pathways in a pathophysiological situation, we used the intraperitoneal (i.p.) IL-1beta injection (mimicking peripheral infections) and we investigated the effects on the HPA responses to IL-1beta of bilateral neurotoxic (6-OHDA) deletion of the ventral noradrenergic ascending bundle (VNAB-X). The VNAB is an essential stimulating pathway linking the brainstem and the paraventricular nucleus (PVN). We determined the time courses of a number of HPA variables up to 240 min after i.p. injection of IL-1beta. We followed: plasma ACTH and corticosterone (CORT) concentrations, AP POMC nuclear primary RNA transcripts, AP POMC nuclear intermediate transcript RNA, AP POMC cytoplasmic mRNA, and hypothalamus (HT) CRH cytoplasmic mRNA. Compared to sham-lesioned male rats, VNAB-X animals displayed: (1) a reduced increase in plasma ACTH, and to a lesser extent in CORT throughout the experimental period with a 85% inhibition at the peak (90 min); (2) an increase in AP POMC primary nuclear transcript and in AP POMC nuclear intermediate transcript RNAs which last 60 min, instead of sustained significantly higher levels up to 240 min; (3) a similar, although reduced inhibition in the corresponding POMC cytoplasmic mRNA; (4) an almost complete abolishment of the marked biphasic rise in HT CRH mRNA. In conclusion, activation of the HPA axis by peritoneal IL-1beta challenge involves CRH-producing neurons, and afferent catecholaminergic innervation of the PVN plays a crucial role in the signaling machinery linking the peritoneal aggression to the HPA axis.

Alterations in central catecholamines associated with immune responding in adult and aged mice

Central catecholamine alterations associated with immune activity are similar to those seen following stressor exposure. Inasmuch as aged animals exhibit more pronounced stressor-provoked alterations of central amines relative to younger animals, it was of interest to determine whether immune challenge would similarly induce more pronounced central amine variations in older animals. Fifteen-month old CD-1 mice challenged with 10 7 sheep red blood cells (SRBC) revealed an equivalent peak splenic plaque-forming cell response (4 days after antigen challenge) to that of 3-month-old mice challenged with 10 6 cells. Neither plasma adrenocorticotropic hormone (ACTH) nor corticosterone levels varied over days following immunization, although ACTH levels were generally higher in the older mice. In both age groups reductions of hypothalamic and locus coeruleus norepinephrine (NE) and increased accumulation of the metabolite MHPG coincided with (or preceded by 24 h) the peak immune response. However, increased accumulation of MHPG in the hypothalamus was greater and occurred earlier in the locus coeruleus of the aged mice. Likewise, at or about the time of peak immune responses nucleus accumbens dopamine (DA) levels were reduced and metabolites elevated in both age groups, while in the prefrontal cortex only DA metabolite levels were elevated. These data are commensurate with previous findings showing that SRBC inoculation may influence central neurotransmitters and that such effects correspond with the time of the peak immune responses. Moreover, in so far as hypothalamic NE utilization is concerned, it seems that the effects of SRBC inoculation are more pronounced in aged animals.

Stress-induced activation of prefrontal cortex dopamine turnover: blockade by lesions of the amygdala

Stress consistently has been found to activate peripheral and central catecholamine systems. Dopamine (DA) turnover in the prefrontal cortex is especially sensitive to stress produced by relatively mild footshock, conditioned fear, or exposure to a novel cage. Because lesions of the central nucleus of the amygdala block the effects of both stress and fear in many experimental paradigms, the present study evaluated whether such lesions would block stress-induced increases in prefrontal dopamine turnover using either mild footshock or novelty as stressors. In Experiment 1 electrolytic lesions of the central nucleus of the amygdala attenuated the increase in the dopamine metabolite homovanillic acid (HVA) in the prefrontal cortex evaluated in post-mortem tissue normally produced by footshock. In Expriment 2 similar lesions attenuated the increase in dopamine turnover in the prefrontal cortex using a different stressor, novelty, and a different measure of dopamine turnover, DOPAC/DA ratios. These data provide further evidence for the critical role of the amygdala in stress.

Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain

Changes in the level of glutamine synthetase (GS), an enzyme chiefly found in glial cells, were investigated in the brains of rats treated with modafinil, an awakening drug interfering with central catecholamine function. Two hours (waking period) and 7 h (recovery period) after intra-peritoneal injection of 128 mg/kg modafinil, a significant increase in the level of GS protein was observed by immunotitration in both the locus coeruleus (+30%) and in the frontoparietal cortex (+50%). No changes were observed with 64 mg/kg of modafinil. Gs mRNA was quantified in the entire cortex by Northern blot hybridization using an oligonucleotidic GS cDNA probe. A significant increase in the GS-mRNA level (+70%) was observed in the CX of rats 2 h after injection of 128 mg/kg modafinil; the level tended to return to control values 7 h later during the recovery period. The level of glial acid fibrillary protein (GFAP), an astroglial marker, was unchanged after modafinil treatment. These changes in GS levels after modafinil treatment are discussed in terms of neuron-glia interactions in the regulation of brain metabolism during pharmacologically induced wakefulness, excluding possible stress effects.

Generalized presence of a PEC-60-like peptide in catecholamine neurones.

PEC-60, a 60-residue intestinal peptide structurally related to the pancreatic secretory type of trypsin inhibitor, has been isolated, characterized and molecularly cloned. It shows biological activity as a hormone in both the gastrointestinal tract and in the immune system. We now report immunohistochemical evidence suggesting its neural localization exclusively within central and peripheral catecholamine (CA) neurones. PEC-60-like immunoreactivity was present in cell bodies, dendrites and nerve terminals of virtually all catecholamine neurones examined and including the noradrenergic gland cells of the adrenal medulla. PEC-60-like immunoreactivity was not seen, however, within the tyrosine hydroxylase-positive but CA-negative arcuate neurones producing growth hormone releasing hormone. The findings open up the possibility that a PEC-60-like peptide may represent a generalized co-transmitter in the peripheral and central CA neurones.

Functional influence of the central noradrenergic system on the skin conductance activity in rats

Pharmacological studies on neuroleptics and amphetamine strongly suggest that some dysfunction of the central catecholamine system may play a key role in the pathogenesis of schizophrenia. Our previous studies have demonstrated that intraventricular administration of 6-hydroxydopamine, a selective neurotoxin of the catecholamine neuron, can reproduce schizophrenia-like abnormalities in the skin conductance activity. In the present experiments, effects of pharmacological modulation of the central noradrenergic activity were studied in rats. Stimulation of the central noradrenergic activity by yohimbine (0.6 mg/kg, i.m.) slowed down the habituation of the skin conductance response (SCR) and increase the spontaneous fluctuation of the skin conductance (SF), while inhibition of the activity by clonidine (0.06 mg/kg, i.m.) accelerated or obliterated the SCR and decreased the SF frequency. If the functional significance of the central noradrenergic system lies in vigilance control, the present results are consostent with classical theory in psychophysiology: the habituation rate of SCR and the frequency of SF are correlated well with each other and both indices reflect arousal level. The disorder of the system should produce not only these psychophysiological abnormalities but also psychological disturbances; i.e., overarousal and underarousal syndromes. Therefore, the dysfunction of the noradrenergic system might constitute an essential aspect of schizophrenic disorder.

Central catecholamine alterations induced by stressor exposure: analyses in recombinant inbred strains of mice

Stressors increase plasma corticosterone concentrations and the turnover of norepinephrine (NE) and dopamine (DA) in some brain regions. However, appreciable interindividual and interstrain differences exist in this respect. The present investigation assessed the NE and DA changes induced by uncontrollable footshock in the BALB/cByJ and C57BL/6ByJ mice and seven recombinant inbred strains. Stressor exposure indeed provoked strain dependent alterations of plasma corticosterone, hypothalamic and mesocortical NE, as well as mesocortcolimbic DA. The profile of stressor effects in the recombinant strains with respect to the NE alterations, the mesocortical DA changes, as well as plasma corticosterone was commensurate with a polygenic mode of inheritance. The data were related to behavioral changes induced by stressors in these strains of mice, as well as to the contribution of the brain amines to stressor-induced behavioral changes.

The suprachiasmatic nucleus controls the circadian rhythm of heart rate via the sympathetic nervous system

The mammalian suprachiasmatic nucleus (SCN) controls a wide variety of circadian behavioral and physiological processes. The specific motor output pathway(s) by which these diverse processes are controlled are unknown. The only established motor output of this system is the regulation of pineal melatonin synthesis via the sympathetic nervous system. It is therefore possible that other peripheral circadian rhythms are regulated similarly. To address this issue, body temperature (BT), general activity (GA), wheel-running activity (WR), and heart rate (HR) were recorded in laboratory rats, and the effects of SCN lesion (SCNX) and of pharmacological sympathectomy with guanethidine (GUAN) on these multiple circadian rhythms were determined. The SCNX abolished circadian patterns in all motor outputs, whereas sham animals showed robust rhythms in all measures. In contrast, guanethidine, which depleted peripheral but not central catecholamine content, selectively reduced HR circadian rhythmicity. Other rhythms (BT, GA, and WR) were unaffected. These results suggest that the SCN influences some peripheral targets via circadian regulation of the sympathetic nervous system, and other circadian outputs are regulated via different, unknown pathways.

Amphetamine facilitation of win-shift radial-arm maze retention: The involvement of peripheral adrenergic and central dopaminergic systems

In these experiments we examined the role of peripheral and central catecholamine systems in mediating the memory-improving effects of 4-OH amphetamine and d-amphetamine in an eight-arm radial maze task. Sotalol (a peripherally acting β-adrenergic antagonist), propranolol (a peripherally and centrally acting β-adrenergic antagonist), or haloperidol (a dopaminergic antagonist) was administered prior to injection of amphetamine. Rats were first allowed to obtain food pellets placed in four of the eight maze arms and then were returned to their home cages. After a delay, food pellets were placed only in the four arms that were blocked prior to the delay, and each rat was returned to the maze and given access to all eight arms. Entries into the baited arms were scored as correct responses. On the experimental day, the animals received intraperitoneal injections of 0.9% saline, Sotalol (5.0 mg/kg), propranolol (2.0 mg/kg), haloperidol (0.5 or 1.0 mg/kg), or a combination of propranolol (2.0 mg/kg) and haloperidol (0.5 mg/kg) 10 min before training, and subcutaneous injections of either saline, d-amphetamine (1.0 mg/kg), or 4-OH amphetamine (2.0 mg/kg) immediately after they completed four alley entrances. Retention was tested 18 h later. Posttraining administration of 4-OH amphetamine or d-amphetamine produced a significant improvement in retention relative to saline controls (p < .01). Sotalol and propranolol significantly blocked the improvement in retention produced by 4-OH amphetamine (p < .05), but not that produced by d-amphetamine. However, the effect of d-amphetamine on retention was completely blocked by 1.0 mg/kg of haloperidol (p < .01). The combined administration of propranolol (2.0 mg/kg) and the lower dose of haloperidol (0.5 mg/kg) did not attenuate the retention-enhancing effects of d-amphetamine. These findings suggest that the memory-improving effects of posttraining amphetamine are mediated by influences involving peripheral adrenergic and central dopaminergic systems.

Evaluation of the behavioral effects of peptides related to neuropeptide Y

Neuropeptide Y (NPY) selectively increases the hyperpolarizing effect of noradrenaline in central noradrenergic neurones of the nucleus locus coeruleus (LC).’ This potentiation is based on the interaction between NPYreceptors and q-adrenoceptors at a step before the common signal transduction mechanism which includes G proteins (G, or G,) and inwardly rectifying potassium charme1s.l The membrane potential of rat LC neurones was recorded in a midpontine slice preparation. Noradrenaline was applied from a micropipette with pressure pulses of increasing duration. Shorter pulses inhibited the spontaneous firing, while longer pulses in addition hyperpolarized the membrane. NPY, its C-terminal fragment NPY (16-36) and peptide YY (PYY) all potentiated the effect of noradrenaline, while [Leu3’, Pro34]NPY was inactive. These results are compatible with the presence of Y,-type NPY-receptors at the cell somata of LC neurones. When the spontaneous firing was prevented by passing continuous hyperpolarizing current via the recording electrode, focal electrical stimulation evoked a synaptic depolarization (PSP) followed by a hyperpolarization (IPSP). The PSP is basically due to the release of excitatory amino acids and y-aminobutyric acid from afferent fibres, while the IPSP is due to the release of noradrenaline from recurrent axon collaterals or dendrites. NPY inhibited the IPSP, but did not change the PSP. Under the same conditions NPY time-dependently potentiated the effect of noradrenaline applied by pressure pulses. Hence, NPY appears to have a dual effect in LC neurones. On the one hand it potentiates the action of exogenously applied or endogenously released noradrenaline via Y&ype somatic NPY-receptors. On the other hand it inhibits the release of noradrenaline via presynaptic NPY-receptors. 1. Illes, P. and Regenold, J. T. Interaction between neuropeptide Y and noradrenaline on central catecholamine neurons.

Cardiovascular responses and central catecholamines in streptozocin-diabetic rats

Brain catecholamine levels, spinal cord levels of the norepinephrine metabolite methoxy-hydroxy-phenylglycol (MHPG), and heart rate were measured in nondiabetic and streptozocin-diabetic rats after sham surgery or bilateral carotid ligation. Although carotid ligation increased heart rate in both diabetic and nondiabetic rats, in diabetic animals the response did not differ from the response to sham surgery. Carotid ligation increased epinephrine concentrations in the medulla/pons of diabetic animals but was not associated with alterations in other central catecholamines. In all diabetic rats spinal ratios of MHPG/norepinephrine (an index of noradrenergic activity) were higher than in nondiabetics, and the change in heart rate (post-surgical-pre-surgical rate) correlated inversely with hypothalamic dopamine (R = -0.60). In sham-operated diabetic rats there were high inverse correlations of the change in heart rate with medullary epinephrine and of pre- and post-surgical heart rate with spinal MHPG/NE (R = -0.87 to -0.95). Central catecholamines and heart rate were not correlated in nondiabetic animals and correlated only weakly when nondiabetic and diabetic animals were pooled. Correlations in diabetic animals were usually abolished or reduced by carotid ligation. These findings suggest a link between central catecholamines and heart rate in diabetic rats subjected to surgical stress. Whether catecholaminergic neurons contribute to abnormal chronotropic responses in diabetic rats or respond to stimuli that affect both heart rate and neural function remains to be determined.

Microdialysis as a Method to Measure Central Catecholamines during Exercise

Microdialysis as a Method to Measure Central Catecholamines during Exercise

Selective administration of nicotine into catecholaminergic regions of rat brainstem stimulates adrenocorticotropin secretion

Nicotine (Nic) is a potent stimulus for ACTH secretion, and this response appears to be mediated by central catecholamine secretion. We have previously shown that fourth ventricular administration of Nic rapidly elevated plasma ACTH levels, that a nicotinic cholinergic antagonist, mecamylamine, instilled into the fourth ventricle inhibited the ACTH response to iv Nic, and that Nic stimulated norepinephrine secretion in the hypothalamic paraventricular nucleus. Thus, the present investigations sought to identify Nic-responsive regions in the brainstem that give rise to ascending catecholaminergic afferents resulting in ACTH secretion. Chronic brain and jugular cannulae were implanted, and Nic (50 nl over 30 sec) was infused into the locus coeruleus (LC), nucleus of the solitary tract (NTS -C2 or -A2 regions), C1, or A1 cell regions of freely moving, adult male rats. Injection of Nic (free base, 0.25-10 micrograms) into either the C2 or A2 region of NTS resulted in a dose-dependent increase in plasma ACTH. In contrast, C1 was unresponsive and A1 only showed responses to the highest doses of Nic (5 or 10 micrograms). In LC, Nic in doses of 2.5 micrograms or higher was required to elevate plasma ACTH. This dose is approximately 10-fold greater than that required in NTS-A2. Finally, mecamylamine (0.25 mg/kg body wt, iv), administered 2 min before Nic, abolished the ACTH responses in both C2 and A2 and significantly reduced the 7-min peak ACTH response in LC (P < 0.05). In summary, microinjection of Nic selectively activated the brainstem regions under investigation, with a rank order of sensitivity to Nic that was NTS-A2 > NTS-C2 > LC > A1 > C1 = cerebrospinal fluid. Therefore, systemically administered Nic appears to activate multiple catecholaminergic brainstem regions that are involved in mediating ACTH secretion.

Selective administration of nicotine into catecholaminergic regions of rat brainstem stimulates adrenocorticotropin secretion.

Nicotine (Nic) is a potent stimulus for ACTH secretion, and this response appears to be mediated by central catecholamine secretion. We have previously shown that fourth ventricular administration of Nic rapidly elevated plasma ACTH levels, that a nicotinic cholinergic antagonist, mecamylamine, instilled into the fourth ventricle inhibited the ACTH response to iv Nic, and that Nic stimulated norepinephrine secretion in the hypothalamic paraventricular nucleus. Thus, the present investigations sought to identify Nic-responsive regions in the brainstem that give rise to ascending catecholaminergic afferents resulting in ACTH secretion. Chronic brain and jugular cannulae were implanted, and Nic (50 nl over 30 sec) was infused into the locus coeruleus (LC), nucleus of the solitary tract (NTS -C2 or -A2 regions), C1, or A1 cell regions of freely moving, adult male rats. Injection of Nic (free base, 0.25-10 micrograms) into either the C2 or A2 region of NTS resulted in a dose-dependent increase in plasma ACTH. In contrast, C1 was unresponsive and A1 only showed responses to the highest doses of Nic (5 or 10 micrograms). In LC, Nic in doses of 2.5 micrograms or higher was required to elevate plasma ACTH. This dose is approximately 10-fold greater than that required in NTS-A2. Finally, mecamylamine (0.25 mg/kg body wt, iv), administered 2 min before Nic, abolished the ACTH responses in both C2 and A2 and significantly reduced the 7-min peak ACTH response in LC (P < 0.05). In summary, microinjection of Nic selectively activated the brainstem regions under investigation, with a rank order of sensitivity to Nic that was NTS-A2 > NTS-C2 > LC > A1 > C1 = cerebrospinal fluid. Therefore, systemically administered Nic appears to activate multiple catecholaminergic brainstem regions that are involved in mediating ACTH secretion.

Comparison of the Effects of Losulazine and Reserpine on Central Aminergic Neurons

The purpose of this study was to examine the effects of both acute and chronic administration of the peripheral sympatholytic antihypertensive agent losulazine on central dopaminergic, noradrenergic, and 5-hydroxytryptaminergic neurons in the rat. For comparison, the acute effects of reserpine were also examined. Acute systemic administration of losulazine produced marked dose- and time-dependent decreases in dopamine and norepinephrine concentrations in regions outside the blood-brain barrier (i.e., the median eminence, intermediate lobe, and neural lobe), that were accompanied by an increase in plasma concentrations of prolactin and α-melanocyte-stimulating hormone. By comparison, losulazine caused a relatively modest, transient depletion of dopamine and norepinephrine (but not 5-hydroxytryptamine) in regions of the brain protected by the blood-brain barrier (i.e., the striatum, nucleus accumbens, and dorsomedial nucleus of the hypothalamus). In contrast to losulazine, acute systemic administration of reserpine caused a prolonged depletion of dopamine, norepinephrine, and 5-hydroxytryptamine in all brain and pituitary regions examined. These results suggest that regional differences in the response of aminergic neurons to acute administration of losulazine and reserpine reflect differences in the ability of these drugs to penetrate the blood-brain barrier. Chronic systemic administration of losulazine produced a similar decrease in dopamine and norepinephrine in the median eminence, intermediate lobe, and neural lobe, suggesting that tolerance does not develop to the ability of losulazine to deplete catecholamines in these regions. Chronic losulazine administration also decreased dopamine concentrations in the striatum, and norepinephrine concentrations in the dorsomedial nucleus, suggesting that losulazine may have cumulative effects on central catecholamine neurons terminating in these brain regions.

Atrial natriuretic factor inhibits noradrenaline release in the presence of angiotensin II and III in the rat hypothalamus

1. Atrial natriuretic factor effects on neuronal noradrenaline release evoked by angiotensin II or III and high potassium solution plus angiotensin II and III in the rat hypothalamus were studied. 2. Atrial natriuretic factor (10 nM) did not modify spontaneous noradrenaline release. On the other hand, the atrial factor diminished the increase of noradrenaline release induced by both angiotensin II (1 microM) or angiotensin III (1 microM). 3. Ten nanomolar ANF reduced the amine output induced by 100 nM KCl. Both angiotensins enhanced the 3H-noradrenaline secretion stimulated by high potassium solutions. When atrial natriuretic factor was added to the medium containing the depolarizing KCl solution plus angiotensin II or III (1 microM), the diminishing effects were greater than when the atrial factor was added to the depolarizing solution alone. 4. Our results suggest that atrial natriuretic factor effects on noradrenaline release, evoked by angiotensin II, III and KCl, may be involved in the regulation of the central catecholamine pathways and sympathetic activity.