Distribution of muscarinic receptor subtypes in rat brain from postnatal to old age.

In an effort to understand the developmental changes in the distribution of muscarinic receptor subtypes (m1-m5), specific brain regions from juvenile (16-day-old), young (21-day-old) and adult (90-day-old) rats were analyzed using subtype-selective antibodies. These studies revealed significant age-dependent changes in the four brain regions examined. In cortex, an area associated with higher cognitive functions, significant increases of m2 and m4 receptors occurred between juvenile and adult rats. In the striatum, the level of m4 receptor increased with age whereas the m1, m2 and m3 receptors had reached mature levels within the first 16 days. Small but significant changes occurred in the cerebellum with a decrease in m1, m3 and m4 receptor subtypes. In contrast to other brain regions, the hippocampus displayed consistent expression levels of muscarinic receptor subtypes. Suggesting that this brain region, which is involved in the foundation of numerous neural networks, requires a full complement of muscarinic receptors at a very early age. Muscarinic receptors have been shown to be important in a number of behavioral activities, including learning and memory. The changes observed in the age-dependent expression of these receptors most likely play an important role in how acetylcholine produces its effects in vivo.

Felbamate, a novel antiepileptic drug, reverses N-methyl-D-aspartate/glycine-stimulated increases in intracellular Ca2+ concentration.

Felbamate, 2-phenyl-1,3-propanediol dicarbamate, is a novel, orally active anticonvulsant that has recently been approved for the treatment of Lennox-Gastaut syndrome and partial onset seizures in the United States. Felbamate is active in a broad range of animal anticonvulsant tests. Although its mechanism of action has yet to be fully elucidated, felbamate appears to act by inhibiting the spread of seizures and elevating seizure threshold. One proposed mechanism of action for felbamate is via the NMDA receptor complex. Previous studies have demonstrated the ability of felbamate to inhibit glycine binding at the NMDA receptor complex. The present study examined the effects of felbamate on NMDA/glycine-stimulated increases in intracellular calcium (Ca2+) using cultured rat hippocampal neurons. The results of these experiments demonstrate that felbamate inhibits NMDA/glycine-stimulated increases in intracellular Ca2+ with a minimal effective concentration of 100 microM.

Characterization of the binding of SCH 39166 to the five cloned dopamine receptor subtypes.

Characterization studies were conducted on the five cloned dopamine receptor subtypes (D1-D5) using the novel D1-selective antagonist, SCH 39166, as well as other related benzazepines and dopaminergic agents. The results demonstrate that SCH 39166 exhibits saturable, high-affinity binding to the D1 and D5 receptors, but binds with low affinity to the D2, D3, and D4 receptors. In contrast, the D2 antagonist haloperidol showed low affinity for the "D1-like" receptors and high affinity for the "D2-like" receptors. A series of agonists was also evaluated and the D5 receptor subtype displayed a two-site fit for the endogenous agonist dopamine, as well as for the agonist apomorphine. Differences in agonist binding among the D1-like receptors reflect the importance of the nonconserved amino acid substitutions.