The potential neuroprotective mGluR-agonist L-CCG I lacks psychotomimetic effects following i.c.v. infusions and even counteracts MK-801 induced stimulation
Ulrich O. Kronthaler, Werner J. Schmid
Dept. Neuropharmacology, University of Tⁿbingen, Mohlstr. 54/1, 72074 Tⁿbingen, F.R.G.
Over the past years, research addressing the most prominent transmitter in the brain, i.e. glutamate, was confined to ionotropic glutamate receptors (iGluR), located postsynaptically. Recently there is a growing interest in a second family of glutamate receptors coupled to second messengers, the metabotropic glutamate receptors (mGluR), classified in 3 groups. In contrast to iGluR, mGluR are also expressed as autoreceptors. Pharmacological studies indicate, that these subtypes mediate presynaptic auto-inhibition and activation of group II mGluR has been shown to mediate neuroprotective effects. A very promising neuroprotective approach, i.e. reduction of neuronal activity by blockade the NMDA subtype of postsynaptic iGluR, is limited by possible psychotomimetic effects. For this reason, we tested whether reducing neuronal activity by activation of presynaptic group II mGluR would have similar side effects. One of the most selective agonists of group II mGluR is (2S,1'S,2'S)-2-(Carboxycyclopropyl)glycine (L-CCG I). In order to characterise effects of L-CCG I on motor behaviour, we conducted infusions into the lateral ventricle of rats and analysed locomotor behaviour in an open-field and sniffing behaviour in an experimental chamber. Both paradigms are predictive for psychotomimetic effects in humans.
L-CCG I induced 10 min after i.c.v. infusion a prominent sedation, as shown by reduced number of line-crossings (Fig. 1). In order to further characterise this effect, we tested whether L-CCG I counteracts the dose-dependent motor stimulation induced by blockade of NMDA receptors by MK-801, this was the case as shown in Fig. 2. Data from the experimental chamber are in line with the results from the open-field.
Obviously postsynaptic blockade of NMDA receptors and presynaptic reduction of glutamate release cause opposite behavioural effects, but with this approach, one may only speculate about the anatomical structures mediating these surprising effects. Nevertheless these results indicate, that a neuroprotective approach addressing the presynaptic terminals is probably not limited by psychotomimetic side effects. Moreover, combining this presynaptic approach with the highly efficient postsynaptic approach may counteract the psychomotomimetic side effects linked with the postsynaptic approach.
(Supported by DFG SFB 307 A4 and Graduiertenkolleg Neurobiologie)
Document created January, 9th 1997
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