Search

The Institute of Pharmacology of the University of Strasbourg played an eminent role in the development and international spread of pharmacology between 1872 and 1918. In this article, genealogy and biographies of key players are documented. Unfortunately, lack of data did not permit the complete biographical description of all scientists. Oswald Schmiedeberg played a decisive role in the global establishment of pharmacology, having trained most of the professors of his time. From Strasbourg, pharmacology spread into many countries including Germany, Austria, Switzerland, Italy, Norway, the UK, and the USA. The Institute of Pharmacology in Strasbourg played a major role in the establishment of both academic pharmacology and the modern pharmaceutical industry. The Institute of Pharmacology in Strasbourg also mirrors the history of Germany and France and the Nazi period.

The purpose of this article is the historical survey of the foundation and development of pharmacology in Tartu (Dorpat), Estonia. Pharmacology was founded in Tartu by Naunyn, Buchheim, and Schmiedeberg. Genealogy and biographies including selected references of pharmacologists and pupils, who acted from the very beginning to today as directors of the Department of Pharmacology, as well as its successor, the Institute of Pharmacology and Toxicology, are presented and commented. This history also illustrates the conditions that are important for the development of new scientific areas. It is not a central geographical location or a formal “center of excellence” with lots of financial resources but rather brilliant researchers with the right spirit and vision and academic freedom. The implications of the early history of pharmacology for the future of science are discussed.

Athineos Philippu, Department of Pharmacology and Toxicology, University of Innsbruck, Austria The eighth pharmacologic-historical Forum was held online in 2022 in Bonn during the Meeting of the DGPT. In this forum the personalities of Hans Dengler, Paul Martini, Manfred Göthert, and Rudolf Buchheim were honoured by describing their lives and scientific achievements.

The push-pull superfusion technique was used to investigate release of endogenous neurotransmitters and nitric oxide in various brain regions. The transmitters catecholamines, histamine, GABA, glutamate, as well and nitric oxide are released according to ultradian rhythms which generate fluctuations of vegetative functions such as blood pressure and arousal. More frequent infradian oscillations of neurotransmitter and nitric oxide release fates are implicated in mutual interneural control.

Use of the push-pull superfusing technique has shown that in the brain the release rates of endogenous catecholamines, GABA, glutamate and histamine are not constant but fluctuate temporally according to ultradian rhythms. Rhythmic fluctuations have been found in the posterior and anterior hypothalamus, the locus coeruleus, the nucleus of the solitary tract, the mammillary body and the medial amygdaloid nucleus of cats and rats. Similar fluctuations appear in the nitric oxide signal registered in the nucleus accumbens, as well as in the power of delta and theta waves of the EEG in the posterior hypothalamus. The EEG rhythmic fluctuations are generated in the arcuate nucleus because they disappear after its electrocoagulation. The frequency of the EEG fluctuations is increased, decreased or even abolished when catecholamine or histamine receptor agonists and antagonists are centrally applied showing that the EEG ultradian rhythm is controlled by catecholaminergic and histaminergic neurons. Moreover, the rhythmic fluctuations of delta and theta waves corelate negatively with those of histamine in the rat posterior hypothalamus. The possible role of these rhythmic fluctuations is discussed. Their potential importance for pharmacotherapy is still unknown.

In recent decades, consumption of psychostimulants has been significantly increased all over the world, while exact mechanisms of neurochemical effects of psychomotor stimulants remained unclear. It is assumed that the neuronal messenger nitric oxide (NO) may be involved in mechanisms of neurotoxicity evoked by psychomotor stimulants. However, possible participation of NO in various pathological states is supported mainly by indirect evidence because of its short half- life in tissues. Aim of this review is to describe the involvement of NO and the contribution of lipid peroxidation (LPO) and acetylcholine (ACH) release in neurotoxic effects of psychostimulant drugs. NO was directly determined in brain structures by electron paramagnetic resonance (EPR). Both NO generation and LPO products as well as release of ACH were increased in brain structures following four injections of amphetamine (AMPH). Pretreatment of rats with the non-selective inhibitor of NO- synthase (NOS) N-nitro-L-arginine or the neuronal NOS inhibitor 7-nitroindazole significantly reduced increase of NO generation as well as the rise of ACH release induced by AMPH. Both NOS inhibitors injected prior to AMPH had no effect on enhanced levels of LPO products. Administration of the noncompetitive NMDA receptor antagonist dizocilpine abolished increase of both NO content and concentration of LPO products induced by of the psychostimulant drug. Dizocilpine also eliminated the influence of AMPH on the ACH release. Moreover, the neurochemical and neurotoxic effects of the psychostimulant drug sydnocarb were compared with those of AMPH. Single injection of AMPH showed a more pronounced increase in NO and TBARS levels than after an equimolar concentration of sydnocarb. The findings demonstrate the crucial role of NO in the development of neurotoxicity elicited by psychostimulants and underline the key role of NOS in AMPH-induced neurotoxicity.

Background The pioneering work of Robert F. Furchgott, Luis J. Ignaro and Ferid Murad has led us to investigate whether nitric oxide (NO) is present in the brain, its origin and whether it possesses a functional role in brain structures. This review is mainly an outline of own findings obtained by using the push-pull superfusion technique. Method We have used the push-pull superfusion technique that makes it possible to determine quantitatively endogenous transmitters released from their neurons in the synaptic cleft. In some experiments, a NO sensor was inserted into the pushpull cannula for online determination of NO released in the synaptic cleft together with neurotransmitters. Results The release rates of endogenous NO are not constant but oscillate according to an ultradian rhythm with an apparent frequency of about 24 min per cycle. Similar rhythmic changes have been found in the release of neurotransmitters in several brain regions, as well as in the EEG delta band. Endogenous NO modulates the release of acetylcholine, glutamate, aspartate, GABA, serotonin, histamine in distinct brain areas. The release of adenosine is also increased by NO suggesting the synchronous release of ATP. Endogenous NO influences various brain functions such as blood pressure regulation and responses to stress. Recordings of evoked potentials revealed that NO plays a crucial role in the integration of afferent signals. Furthermore, NO in involved in amphetamine-induced neurotoxicity. Conclusion The multifarious influences of endogenous NO on central neuronal activity, brain functions and integration of afferent signals underpin its universal modulatory role in the brain.

The push-pull superfusion technique (PPST) is a procedure for in vivo examination of transmitter release in distinct brain areas. This technique allows to investigate dynamics of transmitter release both under normal and experimentally evoked conditions. The PPST can be modified so that it is possible to determine release of endogenous transmitters simultaneously with electroencephalogram (EEG) recordings, recordings of evoked potentials or the on-line determination of endogenous nitric oxide (NO) released into the synaptic cleft. Because of the good time resolution, the method provides further the possibility to modify the collection periods of superfusates depending on the neuronal function that is analyzed. For instance, investigation of central cardiovascular control, behavioral tasks or mnemonic processes requires very short collection periods, because changes in transmitter release occur within seconds. Even more important is the time resolution when rates of transmitter release are correlated with evoked extracellular potentials or EEG recordings. This review provides an overview of the different devices which might be combined with the PPST and perspectives for future work.

Aims Nitric oxide (NO), is a simple but multifarious molecule. It is implicated in physiological and pathological processes within the striatum, mainly in the nucleus accumbens (NAc). The aim of the present study was to determine the origin of NO in the NAc of anaesthetized rats by applying various compounds known to modulate the release of NO when applied either systemically or locally. Main methods Real-time monitoring of NO was carried out by introducing an amperometric NO sensor into the outer tubing of a push–pull cannula. For local application of substances, the push–pull superfusion technique was used. Key findings An overdose of urethane (i.p.) or superfusion of the NAc with tetrodotoxin (TTX) led to a fall of NO release in the NAc. The NO synthase (NOS) inhibitors 7-nitroindazolmonosodiumsalt (7-NINA, neuronal NOS selective) and N-nitro- l -arginine ( l -NNA, NOS selective) decreased release of NO when applied i.p. or locally. Superfusion of the NAc with N-methyl- d -aspartate (NMDA) elicited a dose dependent increase of NO release. Significance Combination of an amperometric NO sensor for real-time monitoring of NO release with the push–pull superfusion technique showed that NO released in the NAc is, at least to a great extent, of neuronal origin. The enhanced release of NO elicited by locally applied NMDA demonstrates that activation of NMDA receptors facilitates NO synthesis, thus underlining the functionality of NO targets within the NAc.

Background and Purpose The influence of the neurotransmitter histamine on spontaneous and stimulation-evoked release of glutamate, aspartate, GABA and ACh in the nucleus accumbens (NAc) was investigated in vivo. Experimental Approach Using the push–pull superfusion technique, histaminergic compounds were applied to the NAc and neurotransmitter release was assessed. In some experiments, the fornix/fimbria of the hippocampus was electrically stimulated by a microelectrode and evoked potentials were monitored in the NAc. Key Results Superfusion of the NAc with the H1 receptor antagonist triprolidine (50 μM) decreased spontaneous outflow of glutamate, aspartate and ACh, while release of GABA remained unaffected. Superfusion with histamine elevated release of ACh, without influencing that of the amino acids. Electrical stimulation of the fornix/fimbria enhanced the output of amino acids and ACh within the NAc. The evoked outflow of glutamate and ACh was diminished on superfusion with triprolidine, while release of aspartate and GABA was not affected. Superfusion of the NAc with histamine intensified the stimulation-evoked release of glutamate and Ach. Histamine also elevated the stimulation-induced release of aspartate, without influencing that of GABA. Presuperfusion with triprolidine abolished the reinforced effect of histamine on stimulation-evoked transmitter release within the NAc. Conclusion and Implications Neuronal histamine activates H1 receptors and increases spontaneous release of glutamate, aspartate and ACh within the NAc. Stimulation of the hippocampal fornix/fimbria tract also enhances release of glutamate and ACh within the NAc and this effect is intensified by H1 receptor stimulation within the NAc. The latter effects, which are mediated by hippocampal afferences, might play an important role in mnemonic performance and in emotional processes such as anxiety and stress disorders. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/ 10.1111/bph.2013.170.issue-1

Background and Purpose Here, we have investigated whether learning and/or short-term memory was associated with release of ACh and glutamate in the rat nucleus accumbens (NAc). Additionally, neurotransmitter release in the NAc was assessed during facilitation of cognitive processes by antagonists of inhibitory histamine autoreceptors. Experimental Approach The olfactory, social memory test was used in combination with push–pull superfusion of the NAc. A male, juvenile rat was exposed twice to an adult male rat at intervals of 60 or 90 min, and release of ACh and glutamate was determined in the NAc of the conscious adult rat. Histamine receptor antagonists were applied i.c.v. Key Results First exposure of a juvenile rat to an adult rat increased ACh and glutamate release in the NAc of the adult rat. Repetition of exposure after 60 min did not change release of ACh and glutamate, while contact time to recognition (CTR) was shortened. Repetition of exposure after an interval of 90 min prolonged CTR and enhanced accumbal ACh and glutamate release rates. Injection (i.c.v.) of thioperamide (histamine H3 receptor antagonist) together with famotidine (H2 receptor antagonist), 80 min prior to second exposure, diminished CTR and abolished ACh and glutamate release when second exposure was carried out 90 min after the first one. Conclusions and Implications Histaminergic neurons per se facilitated short-term memory, without activation of cholinergic and/or glutamatergic neurons in the NAc of rats. Cholinergic and glutamatergic neurons within the NAc contributed to learning but not to recall of memory. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/ 10.1111/bph.2013.170.issue-1

Glutamate receptor activation participates in mediation of neurotoxic effects in the striatum induced by the psychomotor stimulant amphetamine. The effects of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on amphetamine-induced toxicity and formation of nitric oxide (NO) in both striatum and cortex and on induced transmitter release in the nucleus accumbens were investigated. Repeated, systemic application of amphetamine elevated striatal and cortical lipid peroxidation and NO production. Moreover, amphetamine caused an immediate release of acetylcholine and aspartate and a delayed release of GABA in the nucleus accumbens. Surprisingly, glutamate release was not affected. Dizocilpine abolished the amphetamine-induced lipid peroxidation and NO production in striatum and cortex and diminished the elevation of neurotransmitter release. These findings suggest that amphetamine evokes neurotoxic effects in both striatal and cortical brain areas that are prevented by inhibiting NMDA receptor activation. The amphetamine-induced acetylcholine, aspartate and GABA release in the nucleus accumbens is also mediated through NMDA receptor-dependent mechanisms. Interestingly, the enhanced aspartate release might contribute to NMDA receptor activation in the nucleus accumbens, while glutamate does not seem to mediate amphetamine-evoked transmitter release in this striatal brain area.

Serotonergic mechanisms within the locus coeruleus (LC) are thought to be important in various functions including the stress response. In this study we investigated a possible role of nitric oxide (NO) as an intermediary messenger in the regulation of the serotonin (5-HT) neurotransmission within the LC. Using the push-pull superfusion technique coupled with HPLC and electrochemical detection, the in vivo release of 5-HT was determined in time periods of 10 min in the LC of freely moving rats. Superfusion with three different NO donors, SIN-1 (linsidomine), S-nitroso-N-penicillamine (SNAP) or 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPANO) increased 5-HT release in the LC. Superfusion with the precursor of NO, L-arginine, for 1 h led to a sustained increase in 5-HT release. On the other hand, the NOS inhibitor N-methyl-L-arginine methyl ester (L-NAME) did not significantly change the release of 5-HT. Infusion of N-methyl-D-aspartate (NMDA) or kainic acid, as well as exposure of rats to noise stress or tail pinch increased the release of 5-HT in the LC. Superfusion with L-NAME prevented the increase in 5-HT outflow by all these procedures, while the inactive isomer D-NAME had no effect. Taken together, the results of this study suggest that the release of 5-HT in the LC is facilitated by NO. Under resting conditions inhibition of NOS does not appear to substantially influence the release of 5-HT in the LC. However, there seems to be a facilitatory nitrergic influence on serotonergic responses evoked by excitatory amino acid receptor stimulation or various stress stimuli.

Using intracerebral microdialysis in urethane-anaesthetized adult male Wistar rats, we monitored the effects of acute repetitive transcranial magnetic stimulation (rTMS; 20 trains of 20 Hz, 2.5 s) on the intrahypothalamic release of arginine vasopressin (AVP) and selected amino acids (glutamate, glutamine, aspartate, serine, arginine, taurine, gamma-aminobutyric acid) and the intrahippocampal release of monoamines (dopamine, noradrenaline, serotonin) and their metabolites (homovanillic acid, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid). The stimulation parameters were adjusted according to the results of accurate computer reconstructions of the current density distributions induced by rTMS in the rat and human brains, ensuring similar stimulation patterns in both cases. There was a continuous reduction in AVP release of up to 50% within the hypothalamic paraventricular nucleus in response to rTMS. In contrast, the release of taurine, aspartate and serine was selectively stimulated within this nucleus by rTMS. Furthermore, in the dorsal hippocampus the extracellular concentration of dopamine was elevated in response to rTMS. Taken together, these data provide the first in vivo evidence that acute rTMS of frontal brain regions has a differentiated modulatory effect on selected neurotransmitter/neuromodulator systems in distinct brain areas.

The aim of the present study was to investigate the importance of the serotonergic transmission in the locus coeruleus (LC) to conditioned fear. Rats were conditioned to fear by exposing them to noise signal (N), light signal (L) and electric foot shock (S) for 4 days. Control rats were exposed to the same events without receiving S. The LC was superfused with artificial cerebrospinal fluid (aCSF) through a push–pull cannula, and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) was determined in the superfusate. Motility, blood pressure (BP) and heart rate (HR) were telemetrically recorded. (1) The process of moving animals from their home cage into the grid-floor chamber transiently increased the release rate of 5-HT and the outflow of 5-HIAA in control and naive rats. In conditioned rats, 5-HT release was similarly increased during transfer but was permanently decreased in the grid-floor chamber. Control rats showed phases of enhanced motility in the chamber, while conditioned animals displayed continuous immobility. In naive rats, enhanced motility persisted in the novel environment. (2) Exposure of rats to N+L+S increased the release of 5-HT and the outflow of 5-HIAA to the same extent in conditioned and naive rats. These changes were associated with elevated motility, rise in BP and tachycardia. (3) In conditioned subjects, exposure to N+L in the fifth day led to a pronounced and sustained decrease in the release rate of 5-HT and to tachycardia, while no effects were observed in control rats or naive rats. The findings suggest that conditioned fear attenuates serotonergic neurotransmission within the LC. Telemetric recording of HR proves to be a valuable index for fear and stress processes.

We investigated the importance of endogenous amino acids in the locus coeruleus in inescapable electric shock and conditioned fear. In naive rats and in rats exposed to noise (N), light (L) and electric shock (S) or to N + L only, the locus coeruleus was superfused with artificial cerebrospinal fluid through a push-pull cannula and the release of GABA, taurine, glutamate, aspartate, serine and glutamine was determined in the superfusate by HPLC after derivatization with o-phthaldialdehyde. Locomotor activity, arterial blood pressure and heart rate were telemetrically monitored. The placement of naive rats or conditioned rats from their home cage to a chamber provided with a grid-floor for shock virtually did not change the release rates of the amino acids in the locus coeruleus. Motility was enhanced in naive and conditioned rats to a similar extent. Blood pressure and heart rate were enhanced in conditioned rats only. Exposure to N + L + S for 5 min greatly enhanced the release rates of all determined amino acids in the locus coeruleus. In conditioned rats the increase in release of most amino acids lasted longer than in naive rats. Electric shock also enhanced motility, blood pressure and heart rate. In conditioned rats, motility and cardiovascular changes were more pronounced and/or lasted longer than in naive rats. Exposure of conditioned rats to the conditioned stimuli N + L for 5 min led to an increased release of taurine and aspartate. The enhanced release of taurine lasted 30 min. Exposure to N + L did not affect the release rates of amino acids in naive rats. N + L did not influence motility but arterial blood pressure and heart rate were elevated in conditioned rats. The findings show that inescapable electric shock enhances the release of several amino acids in the locus coeruleus, while conditioned fear selectively increases the outflow of taurine and aspartate. Moreover, conditioned fear prolongs the response of excitatory and inhibitory amino acids to electric shock. The results suggest that an excitatory amino acid (aspartate) and an inhibitory amino acid (taurine) of the locus coeruleus are implicated in conditioned fear.

To investigate whether impulses from chemoreceptors influence the release of catecholamines in the hypothalamus and the locus coeruleus, the two brain areas were superfused simultaneously and bilaterally with artificial cerebrospinal fluid through push-pull cannulae. The release of catecholamines was determined in the superfusate before and during chemoreceptor stimulation by bicarbonate solution saturated with carbon dioxide (CO2-NaHCO3) or KCN. Experiments were carried out on intact cats after carotid body denervation (CD). Intracarotid infusion of CO2-NaHCO3 increased arterial blood pressure and enhanced the release of noradrenaline but not dopamine in the posterior hypothalamus and the locus coeruleus. Following CD, the enhancing effect of CO2-NaHCO3 on the noradrenaline release in the posterior hypothalamus was abolished, while the effect on blood pressure was slightly enhanced. CD reversed the NaHCO3-induced release of noradrenaline in the locus coeruleus to a decreased noradrenaline outflow. Intracarotid infusion of KCN led to a fall in blood pressure. KCN increased the release rates of noradrenaline and, to a lesser extent, that of dopamine in the posterior hypothalamus, as well as the release of noradrenaline in the locus coeruleus. CD abolished the KCN-induced fall of blood pressure and the increased release of noradrenaline and dopamine in the posterior hypothalamus. Similar to CO2-NaHCO3, the enhancing effect of KCN on the noradrenaline release in the locus coeruleus was reversed following CD to a reduced noradrenaline outflow. Superfusion of the posterior hypothalamus and the locus coeruleus with KCN did not influence either blood pressure or the release rates of noradrenaline and dopamine in these brain areas. The findings show that impulses originating from chemoreceptors of the carotid body increase the release rates of the catecholamines in the posterior hypothalamus and the locus coeruleus, thus underlining the importance of catecholaminergic neurons of these brain areas in cardiovascular control.

To investigate the effect of nitric oxide (NO) on the release of serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), the posterior hypothalamus of the conscious rat was superfused through a push–pull cannula with drugs which either liberate NO, or inhibit NO synthase (NOS). The NO donors, linsidomine, diethylamine/nitric oxide (DEA/NO), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-glutathione (SNOG) and sodium nitroprusside influenced the release of serotonin in a biphasic way. Low concentrations of drugs diminished, while higher concentrations of these compounds enhanced the outflow of serotonin. The NOS inhibitors NG-methyl- l -arginine methyl ester ( l -NAME) and 7-nitroindazole (7-NINA) enhanced the serotonin release. A high concentration of l -NAME slightly diminished the outflow of serotonin. Inhibition of the guanylyl cyclase by oxodiazolo[4,3]quinoxaline-one (ODQ) abolished the changes in serotonin outflow induced by both low and high concentrations of linsidomine. The extracellular concentration of the 5-HIAA was not influenced by the compounds used. These data suggest that endogenous NO modulates the release of serotonin in a biphasic and cGMP-dependent way.

Previously, we have shown that in the presence of pargyline the release of serotonin (5-HT) in the locus coeruleus is modulated by various sensory stimuli and blood pressure fluctuations. The aim of the present study was to investigate whether local inhibition of monoamine oxidase (MAO) influences basal and stimulus-induced release of 5-HT in the locus coeruleus. For this purpose, the locus coeruleus was superfused in the absence and in the presence of the MAO inhibitor pargyline. Additionally, we examined whether the release of the 5-HT metabolite 5-hydroxy-indole acetic acid (5-HIAA) in the locus coeruleus is altered in response to stimuli. The locus coeruleus of the conscious rat was superfused through a push-pull cannula with artificial cerebrospinal fluid (CSF). 5-HT and 5-HIAA were determined in the superfusate. The basal release rate of 5-HT and the basal outflow of 5-HIAA averaged 2.0 fmol/min and 69 fmol/min, respectively. The basal release rate of 5-HT and the 5-HIAA outflow were tetrodotoxin (TTX)-sensitive. In the absence of pargyline, the sensory stimuli noise stress or tail pinch, applied for 10 min, increased 5-HT and 5-HIAA outflow by 50-70%. In contrast, an experimentally induced rise in blood pressure for 10 min enhanced 5-HT release by 50%, but had no effect on 5-HIAA outflow. The release of 5-HT and/or 5-HIAA elicited by sensory stimuli or a blood pressure rise was abolished by TTX. Addition of pargyline to the CSF enhanced 5-HT release fourfold and slightly decreased 5-HIAA outflow. These levels remained stable throughout the entire observation period of 8 h. In the presence of pargyline, 5-HT release elicited by noise, tail pinch and increase in blood pressure was enhanced. It is concluded that superfusion with pargyline enhances 5-HT release and reduces 5-HIAA outflow in the locus coeruleus. Furthermore, the ability of sensory stimuli and baroreceptor activation to enhance 5-HT release is preserved during a prolonged pargyline-induced increase in extracellular 5-HT. Since sensory stimuli enhanced, while baroreceptor activation did not influence 5-HIAA outflow, 5-HIAA is not a reliable index for short-term changes in the activity of serotonergic neurons in the locus coeruleus.

In the past 15 years the release of neurotransmitters and their metabolites in the locus coeruleus (LC) has been studied by using three approaches: microdialysis; push-pull superfusion; and voltammetry. These sophisticated techniques, which render it possible to follow the time course and magnitude of neurochemical changes in anaesthetized and conscious animals, have permitted great strides towards understanding neurotransmission in the LC. It appears that noradrenaline, known to be released in distant terminal fields, is also released in the somatodendritic area of LC neurons in response to drugs and physiological stimuli. Furthermore, determination of in vivo release enables the identification of functionally important neurotransmitter systems involved in relaying and integrating information reaching the LC via afferent neurons. As outlined in this review, the release rates of glutamate, aspartate, gamma-aminobutyric acid, glycine, 5-hydroxytryptamine and catecholamines, are modified in particular by arousing and stressful stimuli, pain, changes in cardiovascular homeostasis, as well as during opioid withdrawal or the sleep-wake-cycle. Profound interactions also occur between some of the neurotransmitters released during these situations. It appears that individual stimuli produce distinct neurochemical changes which contribute to the regulation of neuronal LC activity. Stimuli that activate LC neurons, such as pain, fall of blood pressure, noise, opiate withdrawal, do not produce a uniform response but modality-specific release patterns of excitatory and inhibitory neurotransmitters within the LC. From these studies and from existing neuroanatomical and electrophysiological data our knowledge of how neurotransmitters work in concert to regulate the functional state of LC noradrenergic perikarya in physiological and pathophysiological conditions is just emerging.

The interactions between 5-hydroxytryptaminergic neurones and excitatory amino acid utilizing neurones were studied in the locus coeruleus of conscious, freely moving rats. The locus coeruleus was superfused with artificial cerebrospinal fluid through a push-pull cannula and 5-hydroxytryptamine (5-HT) was determined in the superfusate that was continuously collected in time periods of 10 min. Superfusion of the locus coeruleus with the NMDA receptor antagonist AP5 (10 μM), kynurenic acid (1 mM), or the AMPA/kainate receptor antagonist DNQX (10 μM) reduced the 5-HT release in the locus coeruleus. Superfusion with the agonists NMDA (50 μM), kainic acid (50 μM) or AMPA (10 μM) enhanced the release rate of 5-HT. AP5 (10 μM) blocked the stimulant effect of NMDA, while tetrodotoxin (1 μM) failed to influence the NMDA-induced release of 5-HT. In the presence of 10 μM DNQX, the releasing effect of 50 μM kainic acid was abolished. Pain elicited by tail pinch, as well as noise-induced stress, increased the release of 5-HT. Superfusion of the locus coeruleus with 10 μM AP5 reduced the tail pinch-induced 5-HT release. AP5 (10 μM) did not affect the noise-induced release of 5-HT which was reduced, when the locus coeruleus was superfused simultaneously with this concentration of AP5 and 1 μM kynurenic acid. DNQX (10 mM) failed to influence the release of 5-HT induced by tail pinch or noise. The findings suggest that 5-hydroxytryptaminergic neurones of the locus coeruleus are tonically modulated by excitatory amino acids via NMDA and AMPA/kainate receptors. The release of 5-HT elicited by tail pinch and noise is mediated to a considerable extent through endogenous excitatory amino acids acting on NMDA receptors, while AMPA/kainate receptors are not involved in this process. British Journal of Pharmacology (1998) 123, 746–752; doi:10.1038/sj.bjp.0701656

We investigated in conscious, freely moving rats whether the release of GABA, taurine and arginine in the hypothalamus is influenced by impulses originating from peripheral baroreceptors. The posterior hypothalamic nucleus was superfused with artificial cerebrospinal fluid through a push-push cannula and the release of amino acids was determined in the hypothalamic superfusate of control rats, as well as of rats after bilateral aortic denervation (AD). AD led to hypertension and increased the lability of arterial pressure. In sham-operated rats, intravenous infusion of phenylephrine increased blood pressure and the hypothalamic release of GABA and taurine. AD almost abolished the phenylephrine-induced release of the inhibitory amino acids. Similarly, the pressor response to hypervolaemia, elicited by blood injection, enhanced the release rates of GABA and taurine only in sham-operated rats. Baroreceptor unloading evoked either by intravenous infusion of nitroprusside, or by haemorrhage, decreased the release rates of GABA and taurine in sham-operated rats but not in AD rats. Electrical stimulation of the afferent aortic depressor nerve enhanced extracellular GABA and taurine in the posterior hypothalamic nucleus. The release rate of arginine was not influenced by alterations in baroreceptor activity either in sham-operated or in AD rats. The findings support the idea that, in the hypothalamus, GABA and taurine are involved in central blood pressure regulation. The release of these two amino acids seems to be driven tonically by baroreceptor impulses. Moreover, the findings indicate that the baroreceptors of the aortic arch play a crucial role in the mediation of changes in hypothalamic GABA and taurine outflow so as to counteract blood pressure fluctuations.

To investigate the function of serotonergic neurons within the locus coeruleus, this brain nucleus of conscious, freely moving rats was superfused with artificial cerebrospinal fluid through a push-pull cannula and the extracellular concentration of serotonin was determined in the superfusate. Serotonin release was increased by depolarization with veratridine (5 microM) or 80 mM K+, while superfusion with tetrodotoxin (1 microM) or systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin substantially diminished the release rate of serotonin in the locus coeruleus. The pressor response to intravenous infusion of noradrenaline (4 micrograms/kg/min) was associated with a pronounced increase in the release rate of serotonin. Superfusion of the locus coeruleus with tetrodotoxin (1 microM) abolished the increase in serotonin release evoked by the pressor response. A fall of blood pressure produced by intravenous administration of nitroprusside (150 micrograms/kg/min) or chlorisondamine (3 mg/kg) diminished the release rate of serotonin. Immobilization, noise (95 dB) or tail pinch increased the release of serotonin in the locus coeruleus and slightly elevated blood pressure. Chlorisondamine abolished the rise in blood pressure elicited by tail pinch without influencing the increased serotonin release. Tail pinch-induced serotonin release was abolished by superfusion with tetrodotoxin. The findings demonstrate that neuronal serotonin release in the locus coeruleus responds to cardiovascular and sensory stimuli, suggesting a function of serotonergic neurons in central blood pressure regulation, as well as in the modulation of locus coeruleus activity by stress and noxious stimuli.

Aims Thalamostriatal fibers are involved in cognitive tasks such as acquisition, learning, processing of sensory events, and behavioral flexibility and might play a role in Parkinson's disease. The aim of the present study was the in vivo electrochemical characterization of the projection from the lateral aspect of the parafascicular thalamus (Pfl) to the dorsolateral aspect of the nucleus accumbens (dNAc). Since nitric oxide (NO) plays a crucial role in striatal synaptic transmission, its implication in Pfl-evoked signaling within the dNAc was investigated. Main methods The Pfl was electrically stimulated utilizing paired pulses and extracellular potentials were recorded within the dNAc. Simultaneously, the dNAc was superfused using the push–pull superfusion technique for local application of compounds and for assessing the influence of NO on release of glutamate, aspartate and GABA. Key findings Stimulation of the Pfl evoked a negative-going component at 9–14 ms followed by a positive-going component at 39–48 ms. The early response was current-dependent and diminished by superfusion of the dNAc with tetrodotoxin, kynurenic acid or N G -nitro- l -arginine methyl ester (L-NAME), while 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPA/NO) increased this evoked potential. Transmitter release was inhibited by L-NAME and facilitated by PAPA/NO. Significance This study describes for the first time in vivo extracellular electrical responses of the dNAc on stimulation of the Pfl. Synaptic transmission within the dNAc on stimulation of the Pfl seems to be facilitated by NO.

To investigate the influence of nitric oxide (NO) on the release of histamine and glutamate, the anterior hypothalamus of anaesthetized rats was superfused through a push-pull cannula either with artificial cerebrospinal fluid (CSF) or with various drugs dissolved in CSF. Hypothalamic superfusion with the NO-donating compounds linsidomine (200 mumol/l) or diethylamine-NO (DEANO, 100 mumol/l) led to a pronounced and sustained decrease in the histamine release rate, whereas the release rate of glutamate was enhanced. Superfusion with the inhibitor of NO synthase L-NG-nitro-L-arginine methyl ester (L-NAME, 200 mumol/l) increased the histamine release rate. The inhibitory effect of 200 mumol/l linsidomine was abolished by atropine (10 mumol/l). Superfusion with the glutamate receptor agonists glutamate (100 mumol/l) or N-methyl-D-aspartate (NMDA, 50 mumol/l) enhanced the histamine release rate. In the presence of linsidomine, the releasing effect of NMDA was not changed. These findings demonstrate that the release of histamine in the hypothalamus is diminished by endogenous NO. This effect of NO on histamine release seems to be due to enhanced release of acetylcholine from vicinal cholinergic neurons via stimulation of muscarinic acetylcholine receptors located presynaptically on histaminergic neurons. The NO-induced glutamate release seems to exert a subordinate stimulatory effect on histamine release. Finally, the inhibition of histamine release by NO is not due to blockade of NMDA receptors.

Biogenic amines and amino acids have been implicated in central cardiovascular homeostasis. Initially drugs were injected into the brain and their effects on blood pressure were investigated. Other approaches allowed endogenous neurotransmitters released in the extracellular space of brain structures involved in cardiovascular regulation to be identified. As Nicolas Singewald and Athineos Philippu outline, even slight disturbances in blood pressure and/or isovolaemia lead to marked changes in the release rates of biogenic amines and amino acids in various brain structures. Blood pressure homeostasis is maintained with the participation of several brain regions and neurotransmitters which possess the same or opposing functions when released from CNS neurones.

The push-pull technique was used to investigate the effects of neuroactive compounds and experimentally induced blood pressure changes on the release of endogenous serotonin in the posterior hypothalamic area of the rat. Hypothalamic superfusion with artificial cerebrospinal fluid which contained 80 mM K+ or 1 microM veratridine enhanced the rate of serotonin release. Superfusion with tetrodotoxin (5 microM) led to a pronounced decrease in the serotonin release rate. Increases in blood pressure elicited by intravenous infusions of noradrenaline (3-4 micro g/kg/min) or phenylephrine (10 microg/kg/min) enhanced the release of serotonin in the hypothalamus. Similarly, the serotonin release rate was enhanced by hypervolaemia. Decreases in blood pressure elicited by intravenous administration of nitroprusside (30-40 microg/kg/min) or chlorisondamine (3 mg/kg) reduced the release of serotonin. Likewise, the serotonin release rate was decreased by hypovolaemia. With one exception (hypothalamic superfusion with tetrodotoxin) neither neuroactive drugs, nor experimentally elicited blood pressure changes modified the release rate of the metabolite 5-hydroxyindoleacetic acid (5-HIAA). These findings show that changes in blood pressure lead to counteractive alterations in the release of serotonin. Thus, serotoninergic neurons of the posterior hypothalamus seem to be involved in the homeostasis of blood pressure by exerting a hypotensive function. At least in the hypothalamus, the concentration of 5-HIAA in the superfusate does not seem to be a reliable marker for the activity of serotoninergic neurons.

The EEG signal of the area hypothalami posterior (PH) was recorded in the urethane anaesthetized rat. The main characteristic of the EEG in this brain region was intermittent oscillations of high amplitude in the delta and theta frequency bands. Oscillations of the alpha and beta frequency bands showed comparatively lower variations. Time distribution analysis of the EEG spectral power revealed that the delta and theta rhythms appeared and disappeared according to an ultradian rhythm with a frequency of approximately 1 cycle per 100 min. No significant rhythm was found in the alpha and beta band. The rhythm frequency of neuronal activity in the PH is very similar to the ultradian frequency of pulsatile neurotransmitter release in the PH demonstrated previously.

The posterior hypothalamus of conscious, freely moving rats was superfused with artificial cerebrospinal fluid through a push-pull cannula and the release of amino acids was determined in the superfusate. Under basal conditions, the release rates of taurine, GABA and glutamate fluctuated according to ultradian rhythms with different frequencies. Hypothalamic superfusion with veratridine or high concentrations of potassium choride enhanced the release rates of taurine, GABA and glutamate in a concentration-dependent way. Tetrodotoxin decreased the basal release rates of the three amino acids. The release of arginine was not influenced significantly by these compounds. A fall of blood pressure elicited by intravenous infusion of nitroprusside decreased the release rates of GABA and taurine and enhanced the release of glutamate. Infusion of noradrenaline increased blood pressure and release rates of GABA and taurine, while the release of glutamate was not influenced. Neither the pressor, nor the depressor responses to drugs influenced the release of arginine in the hypothalamus. It is concluded that the inhibitory amino acids taurine and GABA released from hypothalamic neurons possess a tonic hypotensive function. The excitatory amino acid glutamate, released from glutamatergic neurons of the hypothalamus, seems to possess a hypertensive function in counteracting a fall of blood pressure.

Inactivation of GABA was inhibited by gamma-vinyl GABA (GVG) and the effects of the increased GABA level in the brain on blood pressure and body weight of spontaneously hypertensive rats (SHR) and normotensive rats (WKY) were investigated. When started at the age of 8 weeks or 5 weeks, treatment of SHR and WKY with GVG (150 mg/kg, s.c.) for several weeks did not influence systolic blood pressure. In 1-week old SHR, treatment with GVG (up to 150 mg/kg, s.c.) abolished the rise in blood pressure until animals were 8 weeks old. Thereafter, arterial blood pressure started to increase but it remained distinctly lower than that in untreated animals. When started at the age of 1 week, treatment with GVG for 7 weeks did not influence arterial blood pressure in WKY. GVG delayed increase in body weight in SHR and WKY, irrespective of their age. GVG greatly increased GABA levels in the hypothalamus, frontal cortex, brainstem and rest of the brain in both WKY and SHR. It is concluded that an increase in the GABA level in the brain leads to a delay in the development of hypertension in young SHR. Hence, development of genetic hypertension seems to be susceptible to activation of the GABAergic system in a very early critical phase only.

Male Sprague-Dawley rats underwent sinoaortic denervation (SAD) or sham operation. We examined changes in the release rates of GABA, glutamate and arginine in the locus coeruleus (LC) elicited by experimental blood pressure increases (i.v. noradrenaline infusion for 3 min, 4 microg kg(-1)min(-1)) or decreases (i.v. sodium nitroprusside infusion for 3 min, 150 microg kg(-1)min(-1)). The release of the neurotransmitters was monitored by the push-pull superfusion technique. Mean blood pressure did not differ between sham-operated and SAD rats but blood pressure lability was greatly enhanced in SAD rats and accompanied by increased basal release of glutamate in the LC. GABA release was not affected. A rise in blood pressure induced by noradrenaline enhanced GABA release in the LC of sham-operated rats. This effect was abolished by SAD. Glutamate release did not respond to hypertension either in SAD or in sham-operated rats. Nitroprusside led to a fall in blood pressure which was more pronounced and lasted longer in SAD than in sham-operated rats. In SAD rats, glutamate release was enhanced by nitroprusside. The depressor response had no effect on glutamate release in sham-operated rats. GABA release did not respond to this stimulus in either SAD or sham-operated rats. SAD and blood pressure changes did not influence the release rate of arginine. In conclusion, experimental hypertension increases GABAergic activity in the LC by stimulating peripheral baroreceptors. In SAD rats, augmented blood pressure lability seems to be at least partly due to elevated glutamate outflow within the LC.

The social memory test was used so as to investigate whether brain histamine is involved in short-term memory. Histamine injected intracerebroventricularly (i.c.v.) decreased investigation time of a juvenile rat by an adult rat. A similar effect was elicited by i.c.v. administration of histidine. Compared with the control animals, rat pretreatment with alpha-fluoromethylhistidine (FMH), which inhibits neuronal synthesis of histamine, prolonged recognition time. The H3-receptor agonist immepip also prolonged investigation time, while the H3-antagonist thioperamide exerted the opposite effect. Treatment with histidine increased, while treatment with FMH decreased histamine levels in various brain regions. It is concluded that histamine released from histaminergic neurons facilitates short-term memory.

In addition to differences in their blood pressure, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) are known to differ in their emotional behaviour. The neurochemistry underlying these differences is not well understood. In the present study the release rates of the two main regulatory amino acids in the locus coeruleus, glutamate and gamma-aminobutyric acid (GABA), were monitored in WKY rats and SHR to investigate whether basal and/or challenged neurotransmission differs between these strains. The strains differed in their basal blood pressure (WKY 102+/-2 mmHg, SHR 140+/-4 mmHg), as well as in their emotional behaviour, since WKY rats displayed enhanced anxiety-related behaviour in the open field test (time in centre: WKY 197+/-40 s/30 min, SHR 741+/-93 s/30 min). Basal glutamate and GABA release rates did not differ between WKY rats and SHR. A rise in blood pressure induced by intravenous infusion of noradrenaline for 10 min enhanced GABA release in WKY rats by 60%, while no effect was observed in SHR. Glutamate release did not respond to experimental hypertension in both strains. Intravenous infusion of sodium nitroprusside led to a fall in blood pressure, which was less pronounced and was of shorter duration in WKY rats than in SHR. The depressor response had no effect on amino acid release in the locus coeruleus of both strains. Mild stress induced by noise or tail pinch led to slight rises in arterial blood pressure (10 mmHg and 20 mmHg respectively), which were similar in WKY rats and SHR. Tail pinch enhanced the release rates of glutamate and GABA in the locus coeruleus of WKY rats and SHR; however, no strain differences were noted. Noise stress did not significantly influence amino acid release. These findings demonstrate that SHR and WKY rats differ in GABAergic neurotransmission, which is revealed in response to specific cardiovascular challenges, but not to mild stressors. The observed lack of GABA response to blood pressure elevation in SHR may reflect a disturbed mechanism counteracting high blood pressure, possibly contributing to hypertension in this strain.

The aim of the present study was to elucidate whether amphetamine modulates the output of the neurotransmitters glutamate, aspartate, GABA and acetylcholine (ACh) in nucleus accumbens (NAc) as well as the formation of lipid peroxidation (LPO) and nitric oxide (NO). D,L-amphetamine (AMPH, 5 mg/kg, i.p., 4 times every 2 h) was injected into anaesthetized rats and the release of neurotransmitters in the NAc, tissue content of NO and LPO products were determined. While AMPH increased the release of aspartate, GABA and ACh in the NAc, the glutamate release was not affected. Levels of NO and LPO products were elevated in striatum and cortex. Pretreatment with the neuronal NO synthase inhibitor 7-nitroindazole (50 mg/kg, i.p.) was highly effective in abating the rise of the neurotransmitter release and NO generation but failed to influence the intensity of LPO elicited by the AMPH administration. These findings suggest that activation of NO synthesis is a potent factor in the AMPH-induced neurotransmitter release and that activation of NO synthesis and LPO by AMPH are not parallel processes.

Mutual modulatory and functional interactions exist between the histaminergic and cholinergic systems in the brain. The activity of histaminergic neurons is permanently modulated by neighboring cholinergic neurons via muscarinic M(1) receptors, cholinergic transmission by histaminergic neurons through H(1), H(2), H(3A) and H(3B) receptors. In the nucleus accumbens, glutamatergic neurons originating from the hippocampus modulate cholinergic transmission in a direct way via stimulation of NMDA receptors located on cholinergic neurons. Additionally, glutamatergic neurons of the hippocampus modulate the activity of cholinergic neurons in an indirect way by stimulating histaminergic neurons within the nucleus accumbens. Reciprocal regulatory influences and neurotransmission are subjected to the global modulatory influence of nitric oxide. Both histaminergic and cholinergic systems in the nucleus accumbens are implicated in the response to aversive stimuli. Memory acquisition is associated with activation of cholinergic transmission in the nucleus accumbens, while stimulation of histaminergic neurons facilitates memory in a way that is independent of the cholinergic system. Hence, both histaminergic and cholinergic transmission within the nucleus accumbens and interactions between the two systems seem to play a predominant role in cognition.

Acetylcholine modulates histaminergic transmission via M(1) receptors. On the other hand, cholinergic transmission is modulated by neighbouring histaminergic neurons via H(1), H(2) and H(3) receptors. Dopaminergic and GABAergic neurons are also involved in these modulatory mechanisms. Furthermore, the release of histamine is modulated by glutamatergic neurons and nitric oxide of neuronal origin. The release of histamine in the brain oscillates according to circadian, slow ultradian and fast ultradian rhythms. Ultradian fluctuations have also been observed in the theta- and delta-frequency bands of the EEG spectral power. Simultaneous recordings of histamine outflow and EEG in the hypothalamus revealed that the ultradian histamine release rhythm coincides temporally with ultradian fluctuations in the EEG spectral power. Histamine receptor ligands used in pharmacotherapy, like H(1) and H(2) antagonists, modify the frequency of the EEG fluctuations. Brain histamine seems to be involved in memory processes, since inhibition of histamine synthesis deteriorates, while H(3) antagonists, histamine and histidine improve short-term memory. The latter finding may open new horizons in pharmacological treatment of memory disorders.

The gas NO is a messenger that modulates neuronal function. The use of NO donors and NO synthase inhibitors as pharmacological tools revealed that this free radical is probably implicated in the regulation of excitability and firing, in long-term potentiation and long-term depression, as well as in memory processes. Moreover, NO modulates neurotransmitter release. In vivo and in vitro studies have shown that, in all brain structures investigated, endogenous NO modulates the release of several neurotransmitters, such as acetylcholine, catecholamines, excitatory and inhibitory amino acids, serotonin, histamine, and adenosine. In most cases, enhanced NO level in the tissue increases the release of neurotransmitters, although decreasing effects have also been observed. Cyclic 3′–5′ guanosine monophosphate and glutamate mediate the modulation of transmitter release by NO. Recent observations suggest that the release of some transmitters is dually influenced by NO. Thus, besides modulation by presynaptically located auto- and heteroreceptors, NO released from nitrergic neurons seems to play a universal role in modulating the release of transmitters in the brain.

Intravenous bolus injection of KCN (40 microg) elicited brief but pronounced tachypnea, bradycardia and pressor response, and led to a 37% increase in 5-hydroxytryptamine (serotonin) (5-HT) release in the locus coeruleus (LC) of freely moving rats. Slow infusion of KCN (15 microg/min) for 10 min induced only a slight pressor response, but increased the respiration rate (+39 breaths/min), as well as 5-HT release in the LC (+60%) throughout the infusion. In rats with transected chemoreceptor afferents, neither injection or infusion of KCN changed 5-HT release, suggesting that in intact animals, the effect on extracellular 5-HT was due to activation of peripheral chemoreceptors. In summary, we report that peripheral chemoreceptor activation enhances 5-HT release in the LC, indicating that 5-HT might be involved in the modulation of LC activity by ascending chemosensory information.

To reveal the functional importance of amino acid neurotransmission in the amygdala (AMY) of conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, the in vivo release of glutamate (GLU) and GABA in this brain structure was studied using the push-pull superfusion technique. Basal GLU and GABA release rates in the AMY were comparable in SHR and WKY rats, although arterial blood pressure (BP) in SHR (152+/-6 mmHg) was higher than in WKY rats (102+/-4 mmHg). Neuronal depolarization by superfusion with veratridine enhanced the release of GLU and GABA to a similar extent in both rat strains. On the other hand, exposure to noise stress (95 dB) for 3 min led to a tetrodotoxin-sensitive increase in GLU release in the AMY of SHR, but not WKY rats. The concurrent pressor response to noise was enhanced in SHR as compared to WKY rats. A rise in BP induced by intravenous infusion of phenylephrine for 9 min had no effect on amino acid release in the AMY of both strains. The data suggest an exaggerated stress response of glutamatergic neurons in the AMY of SHR as compared with WKY rats, which might be of significance for the strain differences in the cardiovascular and behavioural responses to stress. The results also show that, in both rat strains, glutamatergic and GABAergic neurons in the AMY are not modulated by baroreceptor activation. Moreover, hypertension in adult SHR does not seem to be linked to a disturbed synaptic regulation of glutamatergic or GABAergic transmission in the AMY.

Noradrenaline turnover has been found to be increased in the locus coeruleus of young spontaneously hypertensive rats (SHR). There is also evidence that the noradrenergic projection from the locus coeruleus to the posterior hypothalamus contributes to the development of genetic hypertension. To investigate whether the release of noradrenaline and dopamine in the locus coeruleus is modified in genetic hypertension, this brain region of adult SHR and normotensive Wistar-Kyoto (WKY) rats was superfused with artificial cerebrospinal fluid through a push-pull cannula. Dopamine and noradrenaline released in the superfusate were determined radioenzymatically. There was no difference in the basal release of noradrenaline and dopamine in the locus coeruleus of conscious, anaesthetized or diazepam-treated adult WKY rats and SHR. In conscious animals, a rise in blood pressure elicited by intravenous infusion of phenylephrine enhanced the release of noradrenaline and dopamine in both strains to the same extent. Intravenous infusion of sodium nitroprusside elicited a fall in blood pressure and also increased to the same degree the release of noradrenaline and dopamine in the locus coeruleus of normotensive and hypertensive conscious rats. In anaesthetized rats, baroreceptor activation by phenylephrine decreased the release of noradrenaline and dopamine, while sodium nitroprusside lowered blood pressure and enhanced the release rates of the two catecholamines. Treatment of conscious rats with diazepam (10 mg/kg, i.p., 120 min prior to starting collection of the superfusate) abolished the phenylephrine-evoked release of catecholamines observed in conscious animals. The sensory stimulus tail pinch led to a slight increase in blood pressure. In conscious animals, this aversive stimulus led to enhanced release of noradrenaline and dopamine that lasted longer in SHR than in WKY rats. The release of catecholamines evoked by tail pinch was abolished in rats treated with diazepam, as well as in anaesthetized animals. Our findings show that in adult rats, genetic hypertension does not modify the release of noradrenaline and dopamine in the locus coeruleus. Since in anaesthetized rats increases in blood pressure diminish, while decreases in blood pressure enhance, the release of noradrenaline and dopamine, it seems that both amines possess a counteracting, hypertensive function in the rat locus coeruleus. When baroreceptor activation by phenylephrine is carried out on conscious animals, stress predominates and the release of catecholamines is enhanced. This study demonstrates the importance of the noradrenergic system of the locus coeruleus in central cardiovascular control and in emotional, stress and pain-regulating processes.