Knockouts future

Using superfusion experiments, electrophysiological techniques, pithed animal preparations, and experiments in which transmitter release was determined indirectly via the end-organ response (e.g., twitch response of vas deferens preparations), numerous presynaptic opioid receptors have been identified (Table 2). For the identification of the receptors, classical drug tools were used for future studies, knockout mice (now available for each of the four opioid receptor subtypes) and special nucleotides (e.g., antisense oligodeoxynucleotides or short interfering... 

To better understand the roles of individual serotonin receptor subtypes in modulating the neural circuitry of complex behavior, a number of groups have generated "knockout" mice lacking individual serotonin receptor subtypes over the last decade. Overall, 10 (at least 14) serotonin receptor subtypes have been knocked out in mice, as well as several genes that regulate the development and activity of serotonin neurons (e.g., Pet-1, the serotonin transporter, and tryptophan hydroxylase). We review these studies, discuss their relevance to the pathophysiology of neuropsychiatric disorders, and close with a perspective on where the field may head in the future. 

Cathepsin L-deficient mice show decreased levels of enkephalin in the brain, with reduction by approximately one half (22). In addition, enkephalin brain levels are also reduced by about one half in PC2-deficient mice (28). These results support dual roles for both cathepsin L and PC2 in enkephalin production. Ongoing studies indicate multiple neuropeptides that are substantially decreased by more than 50% in the brain and endocrine tissues of cathepsin L knockout mice (Eunkelstein et al., submitted for publication). With the observed alterations in brain neuropeptides, it will be of interest in future studies to assess the behavioral effects of the loss of neuropeptides in cathepsin L knockout mice. Cathepsin L knockout mice are viable and show phenotypes of hair loss and cardiac myopathy (29, 30). The mechanism for these functional effects of cathepsin L deficiency could possibly involve neuropeptides. New and continued investigations of neuropeptides in cathepsin L knockout mice will provide knowledge of the relative roles of cathepsin L in the production of particular neuropeptides. 

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