S. William Tam

Unique properties of norepinephrine release from terminals arising from the locus coeruleus: high potassium sensitivity and lack of linopirdine (DuP 996) enhancement.

The dose-response of K+ to elicit the release of norepinephrine (NE), acetylcholine (ACh), dopamine (DA) and serotonin (5-HT) from rat brain slices was examined. Cerebral cortical and hippocampal [3H]NE release had steeper K+ dose-response curves than those observed for apparent hippocampal [3H]ACh, striatal [3H]DA and striatal [3H]5-HT release. In contrast, the apparent release of [3H]NE from the hypothalamus had a K+ dose-response curve similar to those observed for the release of [3H]ACh, [3H]DA and [3H]5-HT. Linopirdine, a drug which enhances K(+)-stimulated release of [3H]Ach, [3H]DA and [3H]5-HT, had no effect on cerebral cortical [3H]NE release even at submaximal K+ stimulation. Hippocampal [3H]NE release was also not affected by linopirdine, however the compound significantly enhanced K(+)-evoked [3H]NE release from hypothalamic slices. These data point to unique properties of [3H]NE release from terminals arising from the locus coeruleus (i.e. those found in the cerebral cortex and hippocampus) when compared to [3H]NE release from terminals derived from the lateral tegmentum (i.e. those found in the hypothalamus) and the release properties of other neurotransmitters. The relative high K+ sensitivity of NE release from coerulear terminals may be related to the lack of linopirdine effects on cerebral cortical and hippocampal [3H]NE release.

Preclinical Evaluation of Linopirdine: Neurochemical and Behavioral Effects

The observation that profound losses in neocortical cholinergic innervation (Davies and Maloney, 1976; Perry et al., 1978; Whitehouse et al., 1982; Coyle et al., 1983) occur in Alzheimer’s disease (AD) and data pointing to the importance of cholinergic function to learning and memory in animals (El-Defrawy et al, 1985; Watson et al. 1985, Hepler et al., 1985) have led to what has been called the cholinergic hypothesis of AD. This hypothesis states that the cholinergic losses observed in AD lead, at least in part, to the cognitive and mnemonic deficits observed in the disease. However, with the wide range of neurochemical alterations now documented in AD the cholinergic hypothesis appears to be an oversimplification (Price, 1986; D’Amato et al., 1987; Struble et al., 1987).

Neurotransmitter Release Enhancement as a Possible Therapy for Neurodegenerative Diseases: Update on Linopirdine (DUP996)

Cholinergic approaches to palliate the symptoms of Alzheimer’s disease (AD) have focussed on the discovery and development of direct cholinergic agonists or cholinesterase inhibitors. As an alternative approach to develop drugs that bolster compromised cognitive processes, increasing presynaptic release of acetylcholine (ACh) offers another means of enhancing cholinergic activity. The aminopyridines have long been known to increase neurotransmitter release, but these compounds increase release under basal as well as stimulated conditions. Nickolson et al. (1990) hypothesized, however, that compounds which specifically enhance stimulated ACh release would prove to be superior therapeutic agents. Their efforts to identify compounds which enhance K+-stimulated and not basal release of ACh led to the discovery of linopirdine (DuP996), an agent which has undergone clinical evaluation for its efficacy in AD patients.