Die Rolle des glutamatergen Systems bei Alkoholsucht

Zusammenfassung

In den letzten Jahren ist es gelungen, neue Tiermodelle zu entwickeln, die viele Aspekte von Alkoholismus darstellen. Diese Tiermodelle sind heute eine unverzichtbare Grundlage, um neurobiologische Mechanismen von abhängigem Verhalten zu untersuchen. Unterschiedliche Mechanismen sind in der Ausprägung von abhängigem Verhalten involviert: Neben Veränderungen im mesolimbischen/striatalen dopaminergen System und im opioidergen System spielen hauptsächlich adaptive molekulare Veränderungen im glutamatergen System eine entscheidende Rolle bei der Suchtentwicklung. Insbesondere stehen konditionierte Entzugsphänomene und stressbedingtes Rückfallverhalten in einem direkten Zusammenhang mit einem hypertrophen glutamatergen System. Aufgrund dieser Erkenntnisse wurde eine effiziente Pharmakotherapie für alkoholabhängige Patienten entwickelt. Acamprosat, ein funktioneller Glutamatantagonist und Glutamatmodulator, wurde bereits erfolgreich in der Klinik eingesetzt und niederaffine nichtkompetitive N-Methyl-D-Aspartate (NMDA-)Rezeptorantagonisten stellen die zweite Generation der Rückfallprophylaxen dar.

Abstract

New animal models have been developed which mimic several aspects of alcoholism. These models provide the basis to study the neurobiological mechanisms of “addicted behaviour”. At least two different neurobiological pathways which are involved in the development and maintenance of addicted behaviour have been identified. The first pathway involves the opioidergic system and probably the mesolimbic dopaminergic system and may induce alcohol craving and relapse due to the mood enhancing, positive reinforcing effects of alcohol consumption. A second pathway involves several components of the glutamatergic system (in particular NMDA receptors) and may induce alcohol craving and relapse by negative motivational states including withdrawal and stress. In particular conditioned withdrawal and stress-induced relapse are mediated by a hypertrophic glutamatergic system. Thus it has recently been shown that the NMDA receptor modulator acamprosate inhibits conditioned abstinence behaviour in rats. Although more systematic work is needed to fully define these different neurobiological pathways involved in addicted behaviour, preclinical studies have identified low affinity non-competitive NMDA receptor antagonists as a novel potential generation of anti-relapse compounds and clinical studies have already been initiated in order to test these compounds in alcoholic patients.

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