Neurophysiology Research Group (Head: H. Prast)


- Gospava Gajc

Research in this group involves three major topics:

1. Neurophysiological basis of learning and memory

2. Physiology and pathophysiology of the nitric oxide system

3. Neuropharmacology of the nucleus accumbens

1. Neurophysiological basis of learning and memory

Some elementary processes which underly the ability of the brain to aquire, store and recall information are yet known in great detail. For example, the hippocampus and its subareas has been thoroughly investigated, and many neurotransmitters, mediators and signalling pathways involved in synaptic plasticity have been identified. In contrast, the knowledge about the contribution of several other brain areas to the different forms of learning and their intrinsic mechanisms is rather patchy. We investigate the role of the nucleus accumbens with respect to its subfields shell and core and the significance of the several neuron systems.

Another line of this research is the investigation of substances for cognition-enhancing properties. An important strategy in the brain impaired by cholinergic dysfunction is the enhancement of acetylcholine release. This can be achieved by ACHE inhibitors, but antagonists of H3 histamine receptors are also a promising approach.

Selected references

Prast H, Argyriou A, Philippu A (1996)
"Histaminergic neurons facilitate social memory in rats"
Brain Res: 734: 316-318

Argyriou A, Prast H, Philippu A (1998)
"Melatonin facilitates short - term memory"
Eur J Pharmacol: 349: 159-162

Prast H, Tran MH, Fischer H, Lamberti C, Grass K, Philippu A (1999)
"Histaminergic neurons modulate acetyl - choline release in the ventral striatum: importance of H3 histamine receptors"
Naunyn - Schmiedeberg's Arch Pharmacol: 360: 558-564

Prast H, Philippu A (2000)
"Improvement of memory by H3 receptor ligands?"
J OeGAI: 19: 13-15

Philippu A, Prast H (2001)
"Importance of brain histamine in locomotion, memory and EEG spectral power"
Behav Brain Res: 124: 151-159

Philippu A, Prast H (2002)
"Role of histaminergic and cholinergic transmission in cognitive processes"
Drug News and Perspectives: 14: 523-529

2. Physiology and pathophysiology of the nitric oxide system

Nitric oxide synthesized in neurons is a potent modulator of neurotrans-mission in the brain (1). For example, we have shown that nitric oxide enhances the release of neurotransmitters such as acetylcholine (2) and glutamate and facilitates neurotransmission (3, 4). Since nitric oxide might be involved in several pathologies such as neurodegenerative processes, it is of importance to study the mechanisms that lead to stimulation of nitric ox-ide synthesis (and raised oxidative stress).
In this line of research, we investigate in vivo the regulation of nitric oxide synthesis by neurotransmitter and receptor systems. We use an ampero-metric microsensor combined with a superfusion device for monitoring nitric oxide release under the influence of neuroactive substances in the brain area of interest.

Present topics

1. Does muscarinic M1 receptor activation lead to significant stimulation of nitric oxide synthesis?

2. Is nitric oxide required for M1 receptor-dependent signaling?

3. Are M1 receptors and nitric oxide involved in neurotoxic processes in striatum/nucleus accumbens?

Selected references

Prast H, Philippu A (1992)
"Nitric oxide releases acetyl­choline in the basal forebrain"
Eur J Pharmacol: 216: 139-140

Prast H, Fischer H, Werner E, Werner-Felmayer G, Philippu A (1995)
"Nitric oxide modulates the release of acetylcholine in the ventral striatum of the freely moving rat"
Naunyn Schmiedeberg's Arch Pharmacol: 352: 67-73

Prast H, Lamberti C, Fischer H, Tran MH, Philippu A (1996)
"Nitric oxide influences the release of histamine and glutamate in the rat hypothalamus"
Naunyn Schmiedeberg' s Arch Pharmacol: 354: 731-735

Prast H, Tran MH, Fischer H, Philippu A (1998)
"Nitric oxide - induced release of acetylcholine in the nucleus accumbens: Role of cyclic GMP, glutamate, and GABA"
J Neurochem: 71: 266-273

Kraus MM, Prast H (2001)
"The nitric oxide system modulates in vivo release of acetylcholine in the nucleus accumbens induced by stimulation of the hippocampal fornix / fimbria projection"
Eur J Neurosci: 14: 1105-1112

Kraus MM, Prast H. (2002)
"Involvement of the NO - cGMP system in excitatory amino acid and GABA release in the nucleus accumbens evoked by activation of the hippocampal fimbria"
Neuroscience: 112: 331-343

Prast H, Philippu A (2001)
"Nitric oxide as a modulator of neuronal function"
Prog Neurobiol: 64: 51-68

Bashkatova V, Kraus MM, Prast H, Vanin A, Rayevsky K, Philippu A (1999)
"Influence of NOS inhibitors on changes in ACh release and NO level in the brain elicited by amphetamine neurotoxicity"
Neuroreport: 10: 3155-3158

Kraus MM, Bashkatova V, Vanin A, Philippu A, Prast H (2002)
"Dizocilpine inhibits amphetamine-induced formation of nitric oxide and amphetamine - induced release of amino acids and acetylcholine in the rat brain"
Neurochem Res: 27: 229-235

Research Techniques

  • Monitoring of neurotransmitter release(acetylcholine, dopamine, amino acids) in rats an mice

  • Behavioural tasks on rats and mice (memory and cognition, and others)

  • Amperometric detection of nitric oxide release

  • Electrophysiological techniques
3. Neuropharmacology of the nucleus accumbens

Muscarinic acetylcholine receptors are of eminent significance for the balance between dopaminergic neurotransmission and other transmitter systems in regions of the basal ganglia, such as the nucleus accumbens. Dysfunctions of the cholinergic system including muscarinic receptors may contribute to cognive impairments and psychiatric disorders such as schizophrenia in which altered dopaminergic transmission has been implicated. Besides that, muscarinic receptors are of high importance as mediators of side effects of drugs.
However, the distinct role of the M receptor subtypes have not yet been satisfactorly elucidated. For example, the modulatory influence of the in striatum/accumbens highly abundant M4 receptor on the release of neurotransmitters is unknown. The main reason is that ligands with high selectivity for M receptors are hardly available. The exceptions are the MT-7 and MT-3 peptide toxins from the venom of the green mamba which are selective M1 and M4 receptor antagonists. .

Present topics

1. What is the role of M1 and M4 receptors in accumbal neurotransmission, particularly in glutamate, acetylcholine and dopamine release?

2. What is the significance of M1 and M4 receptors in nucleus accumbens for learning and memory and expression of behaviour?

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