Noch ein Nachtrag zum Interesse der Pharmaindustrie am GABA-B-Rezeptor und seiner Wirkung:
In einem Review von 2007 werden die vielfältigen Wirkungen von Baclofen auf Angst und stoffliche Süchte hervorgehoben.
Aber leider, leider kann Baclofen nicht wegen seiner angeblichen Nebenwirkungen zur Therapie eingesetzt werden, sondern die PAMs(Positive Allosteric Modulators) müssen erforscht und natürlich patentiert werden.
D.h. alles, was wir versuchen durchzusetzen mit Baclofen in der Behandlung von Sucht, Angst und Depressionen ist der Pharmaindustrie bekannt, aber wird nicht gefördert bzw. beworben, weil es leider kein Patent für Baclofen gibt. Man mag sich den Zynismus gar nicht vorstellen bei den ca. 40.000 Menschen, die pro Jahr am Alkoholismus und seinen Folgekrankheiten alleine in Deutschland sterben.
Rechnet man ca. 10 Jahre bis zur Marktzulassung scheint so ein Patent schon mal hunderttausend Tote wert zu sein.
Die komplette Veröffentlichung findet ihr unter
http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed
Ein Auszug aus der Veröffentlichung zur Wirkung von Baclofen und PAMs findet ihr unten.
LG invorio
GABAB PAMs as Potential New Anxiolytics
The GABA system is well known to be involved in anxiety, as illustrated by the effect of benzodiazepines. However, the involvement of the GABAB receptor remained elusive for a long time due to the difficulty in assessing the effect of baclofen because of its above mentioned side effects. Anxiolytic effects of baclofen were however observed in some specific tests in rats, and also in humans [5, 17]. The generation of knockout mice deleted of either the GABAB1 or the GABAB2 gene confirmed a role of GABAB receptor in anxiety [17], as illustrated in several tests such as the light-dark box, the elevated plus maze or the elevated zero maze [18, 55]. In these same tests, the GABAB PAM GS39783 show strong anxiolytic activity, in contrast to baclofen [18, 55]. GS39783 was also efficient in reducing stress-induced hyperthermia [18], a test that could not be performed with baclofen due to its hypothermic action. Of most interest, the anxiolytic effect of GS39783 could still be observed after three weeks of treatment, demonstrating an absence of tolerence [55].
GABAB PAMs for the Treatment of Drug Addiction
The GABAB receptor is known for its role in modulating the reinforcing effect of abused drugs such as cocaine, heroin, alcohol, amphetamine and nicotine [15]. In rats, baclofen decreases self-administration of such drugs, and preclinical studies further indicated the potential of baclofen for the treatment of cocaine, alcohol and nicotine dependence. In support of these effects, baclofen attenuates the activation of limbic regions resulting from cocaine-associated cues as revealed by neuroimaging in humans [7]. However, the use of baclofen as a therapeutic strategy for these indications is limited due to its side effects. The effect of GABAB PAMs on drug dependence and reinforcement has therefore been studied recently as a potential alternative to baclofen.
Both CGP7930 and GS39783 were found to inhibit cocaine self-administration in rats responding to different schedule of reinforcement [71]. Moreover, GS39783 inhibits the reward-facilitating effect of acute cocaine administration, as assessed by the reward threshold in intracranial self-stimulation paradigm [70]. The positive action of GS39783 on cocaine addiction is further supported by the inhibition of most biochemical and behavioral effects of acute and chronic cocaine treatment [45]. These include increased locomotor activity, up regulation of cAMP-response-element-binding protein (CREB) and phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARP32) in the nucleus accumbens and dorsal striatum [45].
The GABAB PAMs were also shown to have beneficial effects in alcohol consumption in rats. Like baclofen, CGP7930 or GS39783 reduced ethanol drinking behavior in two types of inbred alcohol-preferring rats [46, 60]. Both acquisition and maintenance of alcohol dependence were largely inhibited by PAMs, similarly to baclofen.
These first data reveal that GABAB PAMs represent a novel therapeutic strategy for the treatment of drug addiction, a strategy that will certainly benefit from the anxiolytic activity of these molecules.
