Neuronal circuits and mechanisms involved in the cognitive enhancing properties of α7nAChR modulators

Datum

12.03.2012

Zeit

15:00 - 16:00

Sprecher

Jens D. Mikkelsen Senior Scientist, MD, PhDNeurobiology Research UnitRigshospitalet, Copenhagen University Hospital, Denmark

Sprache

en

Hauptthema

Physik

Andere Themen

Physik

Host

Prof. Dr. Peter Brust, Institut für Radiopharmazie, Abteilung Neuroradiopharmaka

Beschreibung

Alpha7 nicotinic acetylcholine receptor (α7nAChR) selective agonists have been reported to exhibit pro-cognitive effects in patients with schizophrenia (SCZ). We have carried out behavioural, biochemical and neuroanatomical studies in the rat to investigate the neuronal systems and mechanisms involved in this effect. Systemic administrations of a number of α7 nAChR agonists produce an increase in c-Fos activation in the prelimbic region of the PFC as well as in cholinergic cells of the basal forebrain projecting directly to the PFC. This increase in gene expression is mediated via the cholinergic neurons in the basal forebrain, because a selective lesion of the cholinergic input to the PFC eliminates c-Fos induction after administration of an α7nAChR agonist. Furthermore, intra-PFC infusion of SSR180771 led to a dose-dependent increase in local extracellular glutamate as measured by a microelectrode array. These data strongly suggest that the cholinergic input from the basal forebrain is essential in the cognitive effects seen after systemic administration of α7nAChR agonists. Importantly, effects of α7nAChR agonists in behavioural models have only been seen in animals with induced prefrontal dysfunction. These models include pre-administration of phencyclidine (PCP) or kynurenine (KYN) the precursor of kynurenic acid (an endogenous, astrocyte-derived, antagonist of α7nAChR whose levels are increased in the brains of schizophrenics). Pre-treatment with the α7nAChR agonist SSR180711 returned the performance of cognitively impaired mice and rats back to control levels. While the effects of α7nAChR agonists have been examined after a single administration, more chronic treatments are applied in the clinic. Noteworthy, the α7nAChR is rapidly desensitised, but this is not followed by tolerance in vivo. Rather the receptor levels increase under these conditions.

Letztmalig verändert: 11.03.2012, 08:35:06