This application for a Mentored Research Scientist Development Award is intended to provide me with the background knowledge, research experience and management skills that will prepare me for an independent research career. Training will take place in the Department of Neuropharmacology (Dr. Floyd E. Bloom, Chair) of The Scripps Research Institute in La lolla. under the mentorship of Dr. George R. Siggins. The objective of this proposal is to study the cellular mechanisms of action of cannabinoid substances in the brain. Our studies will explore the role of compounds that bind to the recently characterized cannabinoid receptor. This goal will be accomplished by combining state of the art intracellular electrophysiological and imaging techniques to assess the modulation of ionic conductances that govern neuronal excitability. The effect of the psychoactive constituent in marijuana. 9-tetra-hydrocannabinol (THC), as well as the newly described endogenous agonists, the anandamides (AEAs). and various synthetic agonists and an antagonist will be explored. as well as potential interactions among such active substances occurring at the receptor level. Our studies will be mainly done in the hippocampus, a region involved in cognition and memory, processes impaired by marijuana consumption. This brain region also presents one of the highest densities of cannabinoid receptors in the brain. We will determine the cannabinoid modulation of non-inactivating conductances found in hippocampal neurons, such as the M-, AHP-, and Q-currents. as well as resting ('leak') currents. Ca++ conductances, such as the high (HVA) and low (LVA) voltage activated currents, will also be studied. We also intend to investigate the likely involvement of intracellular 'second' messenger systems in the cellular signaling of the cannabinoids. We will then extend our ohservations in the hippocampal us to the ventral striatum (nucleus accumbens). a brain region implicated in reward phenomena and drug dependence. The last part of this project will examine whether the effects observed in naive animals are altered in animals chronically treated with cannahinoid substances. Thus, this project will investigate the hypothesis that active substances contained in marijuana alter the normal functioning of the brain by acting on intrinsic properties of single central neurons. Up to now, cannabinoid studies involving intracellular recordings have been performed on cell lines, cultured neurons, or expression systems. We propose to evaluate cannabinoid effects in a native and mature system. using brain slice preparations. The evaluation of the neurobiological substrates and their interaction with agonists of exogenous origin may provide valuable insights into the physiological phenomenon associated with the consumption of marijuana, and will also provide critical data on a newly discovered endogenous system of signaling molecules. These studies also promise to yield new understanding of the physiological role and brain mechanisms implicated in the consumption of cannahinoid related compounds, and have implications for the etiology and treatment of drug ahuse.
| Schweitzer, P (2000) Cannabinoids decrease the K(+) M-current in hippocampal CA1 neurons. J Neurosci 20:51-8 |
| Schweitzer, P; Siggins, G R; Madamba, S G (1999) Cannabinoid modulation of neuronal activity in adult rat hippocampus. Adv Exp Med Biol 469:547-52 |
| Madamba, S G; Schweitzer, P; Siggins, G R (1999) Dynorphin selectively augments the M-current in hippocampal CA1 neurons by an opiate receptor mechanism. J Neurophysiol 82:1768-75 |
| Madamba, S G; Schweitzer, P; Siggins, G R (1999) Nociceptin augments K(+) currents in hippocampal CA1 neurons by both ORL-1 and opiate receptor mechanisms. J Neurophysiol 82:1776-85 |
| Schweitzer, P; Madamba, S G; Siggins, G R (1998) Somatostatin increases a voltage-insensitive K+ conductance in rat CA1 hippocampal neurons. J Neurophysiol 79:1230-8 |
