Brain mapping: topography of neurons and their transmitters involved in various brain functions.

Use of the demanding techniques microdialysis or push-pull superfusion makes it possible to identify neurons in distinct brain areas involved in central control of peripheral functions, thus enabling brain mapping. Investigations with the push-pull superfusion technique have shown that mainly catecholaminergic neurons of the posterior and anterior hypothalamus, the locus coeruleus, and the nucleus of the solitary tract are of crucial importance for blood pressure regulation. Experimentally induced blood pressure changes also modify the release of histamine, glutamate, and taurine in the posterior hypothalamus and of serotonin in the locus coeruleus. Furthermore, histaminergic neurons of the nucleus accumbens are involved in memory, serotonergic neurons of the locus coeruleus in response to noxious stimuli, while nitric oxide of striatum has been implicated in neurotoxicity elicited by amphetamines. The involvement of several neurons in one brain function is discussed.

History of pharmacology:2 - The Institute of Pharmacology of the University of Strasbourg: genealogy and biographies.

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.

History of pharmacology: 1-the Department of Pharmacology of the University of Tartu (Dorpat): genealogy and biographies.

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.

Eighth pharmacologic-historical forum.

SCOPE, HISTORICAL OVERVIEW AND PERSPECTIVES: 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.

Neurotransmitters are released in brain areas according to ultradian rhythms: Coincidence with ultradian oscillations of EEG waves.

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.

Role of nitric oxide in psychostimulant-induced neurotoxicity.

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.

Nitric Oxide: A Universal Modulator of Brain Function.

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.

Use of Push-Pull Superfusion Technique for Identifying Neurotransmitters Involved in Brain Functions: Achievements and Perspectives.

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.

Origin of endogenous nitric oxide released in the nucleus accumbens under real-time in vivo conditions.

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.

Influence of parafascicular thalamic input on neuronal activity within the nucleus accumbens is mediated by nitric oxide - an in vivo study.

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.

Sinoaortic denervation abolishes blood pressure-induced GABA release in the locus coeruleus of conscious rats.

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.

Dizocilpine inhibits amphetamine-induced formation of nitric oxide and amphetamine-induced release of amino acids and acetylcholine in the rat brain.

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.