Kenny J. Simansky, Ph.D.
Professor
Ph.D. (1979) University of Iowa
Phone: 215-762-8141
Email: kenny.simansky@drexelmed.edu
This laboratory is involved in analyzing the neural pathways, neurochemical mechanisms and physiological processes responsible for the behavioral actions of drugs. The research projects focus on three areas: 1) neurochemical regulation of the reward circuitry in the brain in normal function, in addiction and in models for testing actions of psychiatric drugs; 2) interactions between the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) and brain/gut peptides in regulating eating and drinking; and 3) development of novel pharmacological strategies for enhancing recovery of motor function after injury to the spinal cord.
Serotonergic function in eating and drinking. Serotonergic drugs such as fenfluramine (e.g., Redux“) reduce eating and body weight in humans. Although this specific agent has been problematic in clinical use due to adverse effects, 5-HT receptors remain targets for developing antiobesity agents. Peripheral administration of 5-HT itself decreases consumption of food and increases water intake in laboratory animals. Our pharmacological experiments have established that two subtypes of serotonergic receptor (5-HT1-like, possibly 5-HT7--and 5-HT2) mediate the ability of 5-HT to reduce feeding. Studies have been conducted in vitro to localize potential sites for the satiating effect of 5-HT. These experiments have identified a 5-HT2 mechanism for serotonergic contraction of the pylorus of the gut. The specific anatomical locus of these 5-HT2 receptors, the interaction of 5-HT and peptides in the pylorus and the role of the pylorus in serotonergic control of feeding are being investigated by using autoradiographic, pharmacological and surgical methods. Other studies are identifying the neuronal circuitry supporting 5-HT-induced changes in ingestion. These experiments established that an intact abdominal vagus nerve is necessary for 5-HT to stimulate drinking but not for satiety actions in feeding. Denervation of peripheral sensory neurons by systemic injections of capsaicin and destruction of the area postrema in the brainstem did reduce the satiety effect of 5-HT. Thus, current studies are focusing on the roles of spinal visceral afferents and medullary brainstem pathways in translating peripheral serotonergic signals to inhibit eating.
Serotonergic neurons in the brain are also implicated in the inhibitory control of eating. For years, investigators attributed this ingestive function to 5-HT innervation of the hypothalamus. More recently, work from this laboratory and elsewhere suggested that sites in the brainstem are critical for serotonergic drugs to produce satiety. For example, we demonstrated that infusion of CP-93,129, a direct agonist at 5-HT1B receptors, into the parabrachial nucleus of the brainstem inhibited eating. The figure below shows the distribution of these receptors labeled by 125 I-iodocyanopindolol in the parabrachial region of the rat brain (scp, superior cerebellar peduncle; lPBN, lateral parabrachial nucleus; mPBN, medial parabrachial nucleus; *=site of infusion). Significantly, CP-93,129 also reduced eating after infusion into the paraventricular nucleus of the hypothalamus but the drug was 50-fold more potent in the PBN. We are now mapping the distribution of sites in the brainstem and hypothalamus that respond to satiety actions of 5-HT1B and 5-HT2C agonists. We are also studying the neurochemical circuitry responsible for integrating peripheral, brainstem, hypothalamic and telencephalic regions in 5-HT-related satiety. These experiments use strategically placed lesions, local infusion of pharmacological agonists and antagonists, infusion of oligodeoxynucleotide probes that are antisense to 5-HT receptor mRNA, expression of early immediate genes for peptide markers of cellular response and traditional anatomical methods. We are conducting parallel studies in rabbits and in mice in this NIMH-sponsored project.
Stimulating mu receptors for enkephalin and other opioids in the PBN increases eating. Beta-endorphin, enkephalin and endomorphin are opioid neurotransmitters/neuromodulators that act at mu-opioid receptors in the brain. Stimulation of these receptors produces analgesia, euphoria, increased eating especially of very palatable foods, changes in respiration and other physiological responses. The particular response depends upon the specific region within the brain that is stimulated. We have determined recently that activating mu receptors within the parabrachial nucleus increases eating. Current research is defining the interaction of this opiatergic circuitry with other neuropeptides and with serotonergic neurons.
The nucleus accumbens and associated circuitry mediates reward and this system is relevant for understanding affective states in normal function and disease. The nucleus accumbens (NAC) is segregated into two components (shell and core) that coordinate the processing of motivational properties of natural rewards (e.g., sweet-tasting substances) and drugs of abuse with the motor responses to obtain and consume these rewards. A newly-funded program (NIDDK) is studying the neurochemical mechanisms within this circuitry that underlies environmental control of behavior involved in seeking food and drugs (i.e., craving). As part of this project, we are investigating mechanisms implicated in the actions of drugs that affect eating and that treat depression, anxiety and schizophrenia. This project is in collaboration with Drs. Aloyo, Romano and Harvey in this department.
Recovery of function after spinal cord damage. In collaboration with Drs. Murray, Gizster, Fischer and Tessler, in the Department of Neurobiology and Anatomy, we are investigating new approaches for promoting regeneration and recovery of function after damage to the spinal cord. Our principle contribution to this NIH-sponsored Program Project led by Dr. Murray is exploring the ability of serotonergic drugs to enhance recovery after complete transection of the cord. Recently, we demonstrated that serotonergic agonists that act directly at 5-HT2 receptors enhance the ability of neural transplants to improve motor function in spinal rats. Current studies are testing the hypothesis that the 5-HT2C subclass of receptors, specifically, is involved in this therapeutic action. Furthermore, we are assessing whether appropriately designed 5-HT agonists can promote recovery without transplants.
Selected Publications:
Adipudi, V. and Simansky, K. J. Lesions of the area postrema attenuate but do not prevent the anorectic action of peripheral serotonin (5-HT) in rats, Amer. J. Physiol., 269:R1314-R1320, 1995.
Simansky, K. J. 5-HT receptor subtypes influencing feeding and drinking: focus on the periphery. In Cooper, S. J. and Clifton, P. G. (Eds.), Drug Receptor Subtypes and Ingestive Behaviour, Academic Press, London, 1996, pp. 59-97.
Lee, M. and Simansky, K. J. CP-94,253: A selective serotonin1B (5-HT1B) agonist that promotes satiety. Psychopharmacology, 1997,131:264-270.
Lee, M. D., Aloyo, V. J., Fluharty, S. J., and Simansky, K. J. Infusion of the serotonin1B (5-HT1B) agonist CP-93,129 into the parabrachial nucleus potently and selectively reduces food intake in rats. Psychopharmacology, 1998, 136:304-307.
Yi, D. K., Adipudi, V., Shibayama, M., Giszter, S., Tessler, A., Murray, M. and Simansky, K. J. Direct agonists for serotonin receptors enhance locomotor function in rats that received neural transplants after neonatal spinal transection. J. Neuroscience, 1999, 19:6213-6224.
Kim, D., Murray, M. and Simansky, K. J. The serotonergic 5-HT2C agonist m-chlorophenylpiperazine increases weight-supported locomotion without development of tolerance in rats with spinal transactions.Experimental Neurology, in press.
Simansky, K. J. and Nicklous, D. M. Parabrachial infusion of d-fenfluramine reduces food intake: Blockade by the 5-HT1B antagonist SB-216641. Submitted. |