Neuroendocrine and behavioral effects of antisense oligonucleotides.

In addition to traditional morphological and functional strategies, including physiological and pharmacological tools, innovative approaches are necessary to investigate molecular, cellular and neuroendocrine correlates of behavior. Neuroendocrine as well as behavioral regulation, particularly in mammals, is a priori complex at multiple levels, justifying the use of various complementary techniques. Among them, antisense targeting has proven to be a valuable tool for studying peptide and protein functions in vivo even in the intact brain, which provides a particular challenge but also a promise for those interested in antisense targeting. On the one hand, both the blood–brain barrier and the heterogeneity of the brain make efficient and selective antisense targeting difficult to achieve. But on the other hand, the brain as a whole or even an individual neuron with its capability of producing hundreds of biologically active neuropeptides and receptor and other proteins may be particularly amenable to the use of antisense approaches, especially when few specific traditional pharmacological agents exist. In neuroendocrinology those antisense studies dominate that focus on neuropeptides and receptors of neuropeptides or steroids. The number of such studies using antisense targeting in vivo peaked in 1994 and 1995, with about 20 papers published in each of those years (in 1993, about 5 papers were published and in 1996, about 15). This development, which is similar for corresponding behavioral studies (including those on autonomic effects; from 1993 to 1996 about 10, 30, 25 and 20 papers respectively were published), appears to be normal for a new and promising technique and reflects the initial enthusiasm just as much as its subsequent more expert use and the realization of considerable pitfalls. The antisense papers published so far in behavioral neuroscience (including autonomic effects) have described effects on (order according to the number of published papers) antinociception, motor regulation, feeding and drinking, reproductive behaviors, anxiety, learning and memory, and on cardiovascular and temperature regulation. By weighing the advantages and disadvantages of antisense targeting, this short review is aimed at stimulating and qualifying the reader to use antisense oligodeoxynucleotides (ODN) in vivo to study mechanisms underlying the regulation of neuroendocrine systems and behavior. Although a detailed methodological discussion is beyond the scope of this article and the methodology has already been reviewed by others (1–8), some of the problems we are facing in the actual application of antisense ODN to the brain of conscious rats are briefly discussed in terms of administration, chemical modification, proper controls, mechanisms of antisense action and specificity in vivo. Furthermore, this review will highlight the literature on antisense effects on neuroendocrine systems and behavioral performance, with emphasis on those studies that include both neuroendocrine and behavioral parameters as well as our own attempts in this direction.