Potentiation by DL-α-aminopimelate of the inhibitory action of a novel mGluR agonist (L-F₂CCG-I) on monosynaptic excitation in the rat spinal cord

Abstract

1. Neuropharmacological actions of all the possible stereoisomers of 3′,3′-difluoro-2-(carboxycyclopropyl)glycine (3′,3′-difluoro-CCG) were compared with those of the corresponding 2-(carboxycyclopropyl)glycine (CCG) isomers in the isolated spinal cord of newborn rats. (2S,1′S,2′S)- and (2S,1′R,2′S)-2-(2-carboxy-3,3-difluorocyclopropyl)glycine (L-F₂CCG-I and L-F₂CCG-IV) were the most potent in causing depolarization, their threshold concentrations being approximately 1 μM.

2. The depolarization evoked by L-F₂CCG-I (30 μM) was depressed by (+)-α-methyl-4-carboxyphenylglycine (MCPG, 1 mM (n=4)) to 17±3% of the control: this depolarizing action was not decreased by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 100 μM), and only slightly decreased by high concentrations of D-2-amino-5-phosphonopentanoic acid (D-AP5, 100 μM), suggesting that L-F₂CCG-I activates mainly metabotropic glutamate receptors.

3. L-F₂CCG-I preferentially depressed the monosynaptic component of the spinal reflex approximately 3 times more effectively than (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG-I). The depressant action of L-F₂CCG-I (0.2 μM–0.7 μM) on monosynaptic excitation was antagonized by (2S,1′S,2′S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG, 0.3 mM–1 mM) and (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4, 0.3 mM).

4. DL-α-Aminopimelate (10 and 100 μM) selectively potentiated the depression of monosynaptic excitation caused by L-CCG-I (0.2 μM) and L-F₂CCG-I (0.1 μM). The actions of (2S,1′R,2′R,3≈prime;R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (50 nM–0.2 μM), L-2-amino-4-phosphonobutanoic acid (L-AP4) (0.3–1 μM), (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) (1–7 μM) and baclofen (0.1–0.7 μM) were unaffected by DL-α-aminopimelate. The threshold concentration for the potentiating actions of DL-α-aminopimelate was 3 μM.

5. The depolarization induced by quisqualate (3 μM, 10 s application) was increased to 115±2% and 137±5% of the control values during combined application of quisqualate with either 30 μM or 100 μM DL-α-aminopimelate, respectively.

6. Following the application and subsequent washout of L-F₂CCG-I, DL-α-aminopimelate (3–100 μM) decreased the amplitude of the monosynaptic component of spinal reflexes in a concentration-dependent manner, indicating a 'priming' effect of L-F₂CCG-I.

Full Text

The Full Text of this article is available as a PDF (360.9 KB).