ANTISENSE STRATEGIES IN DOPAMINE-RECEPTOR PHARMACOLOGY

Recent advances in molecular biology have rovided pharmacologists the opportunity of developing an entirely new type of agent for studying a nd treating a variety of biological disorders. These agents, termed an tisense oligodeoxynucleotides, have as their target the messenger RNAs encoding specific proteins. They act by binding to selected portions of these mRNAs through complimentary interactions and thereby prevent the synthesis of these proteins. These novel pharmacological tools hav e the promise of being easier to design and being more selective and p redictable in their actions. In addition, insofar as agents targeted t o receptors for neurotransmitters are concerned, unlike the classical pharmacological agents, these new compounds may not lead to the upregu lation of the very receptors the drugs are designed to inhibit. The pr esent review summarizes briefly studies on the effect of oligodeoxynuc leotides antisense to the mRNAs encoding the various subtypes of the d opamine receptor. The studies show that oligodeoxynucleotides antisens e to the D-2 dopamine receptor when intracerebroventricularly into bra ins of rodents are rapidly taken up into the brain tissue, distributed to brain cells, and produce effects characteristic of highly selectiv e D-2 dopamine antagonists. The compounds also produced specific reduc tions in the levels of D-2 dopamine receptor mRNA and D-2 dopamine rec eptors. Similarly, injecting an antisense oligodeoxynucleotide targete d to the D-1 dopamine receptor mRNA produces effects characteristic of D-1 dopamine receptor antagonists. Other studies using these agents h as produced evidence that there is a small pool of receptors that turn over very rapidly and which constitute the functional pool of these r eceptors. The evidence suggests further that antisense oligodeoxynucle otides inhibit the synthesis of this small functional pool of dopamine receptors, thereby providing an explanation of why there is often dis cordance between changes in dopaminergic function and changes in the l evels of dopamine receptors. Studies of antisense oligodeoxynucleotide s targeted to the other subtypes of dopamine receptor may help reveal the biological roles that these and other newly discovered subtypes of neurotransmitter receptors have. They may also provide an entirely ne w and potentially more selective therapeutic regimen for altering the functions of these receptors.