The purpose of this research is to study the role of the brainstem and spinal cord in motor dysfunction, such as tremor and hyperreflexia, which are signs frequently associated with neurological disorders, such as Parkinson's and Alzheimer's Disease. Brainstem-mediated tremor was attenuated by blocking alpha-1 adrenergic receptors with phenoxybenzamine and prazosin, supporting the conclusion that the descending noradrenergic system facilitates motor outflow at the level of the spinal cord. Blockade of dopaminergic, beta-adrenergic and alpha-2 adrenergic receptors augment tremor, suggesting a reciprocal role for these different catecholaminergic receptor types of the mediation of tremor. In subsequent experiments, intrathecal application of noradrenergic receptor antagonists also attenuated tremor. We have also found that the intrathecal administration of a glutamate receptor antagonist blocks tremor, which is consistent with the accepted belief that motor outflow is mediated by an excitatory amino acid neurotransmitter. Our conclusions about the modulatory role of norepinephrine in tremor are further supported by recent studies on the acoustic startle reflex, which is also mediated in the brainstem and spinal cord. We report that pretreatment with alpha-adrenergic antagonists decreases the magnitude of the startle reflex and decreases the augmentation of the reflex produced by neurotoxic probes. Additional experiments have discovered that the activation of 5-HT1 receptors augments tremor. Other studies have found that augmentation of the startle reflex by 5-HT1 agonists, 8-OHDPAT and N,N-DMT, is attenuated by pretreatment with metergoline, a mixed 5HT1/5HT2 receptor antagonists, and is not affected by ketanserin, a 5-HT2 antagonist. Quipazine, a 5HT2 agonist, decreases the magnitude of the startle reflex, an effect blocked by pretreatment with ketanserin, but not by metergoline. We plan to study the role of descending monoaminergic pathways in the habituation and sensitization of the acoustic startle reflex, which are believed to be mediated within the brainstem and spinal cord.
