The principal goal of this grant is to study the neural basis for phencyclidine (PCP) abuse and for its effects on behavior. The next project period will focus on comparing the effects of PCP to those of other types of N-methyl-D-aspartate (NMDA) antagonists. NMDA antagonists are being considered for development as medications for a number of neurological and behavioral disorders, including as possible treatments for drug tolerance and dependence. A significant goal of our work would be to provide information that could assist the development of medications that have diminished capacity for PCP-like psychological effects and abuse liability. Our strategy for doing this is to compare NMDA antagonists that act at various sites on the NMDA receptor complex, including PCPsite channel blockers, competitive antagonists, glycine-site antagonists, polyamine-site antagonists as well as NMDA receptor subtype selective agents which we anticipate will be developed over the next few years. In addition, the effects of NMDA antagonists will be compared to those of site-selective GABA agonists such as pentobarbital, diazepam and muscimol. PCP-like drugs and other site- selective NMDA antagonists will be compared in the following animal testing procedures: 1. Drug discrimination in rats and monkeys using the following training drugs: PCP, NPC 17742 (a competitive NMDA antagonist), a glycine-site antagonist, a potent NMDA agonist (D,L-(tetrazol-5-yl) glycine], pentobarbital, diazepam and muscimol 2. Intravenous drug self-administration in rhesus monkeys 3. Tests for anti-anxiety effects in mice and rats 4. Interactions with GABA agonists such as pentobarbital and diazepam in three animal models 5. Attenuation of physical dependence to morphine in rats 6. Attenuation of analgesic tolerance to morphine in rats The tolerance and dependence studies will also include an examination of the effects of a oligodeoxynucleotide directed against a specific subunit of the NMDA receptor. The proposed studies should help us learn more about the neural basis of PCP abuse, and perhaps that of other drugs whose pharmacologies overlap with those of PCP. This could lead to medications useful for treating PCP abuse or its psychological or neurological consequences. In addition, we will obtain basic scientific information about the role of glutamatergic neurotransmission in brain/behavior relationships, including its role in drug tolerance and dependence.
Showing the most recent 10 out of 63 publications
