This proposal describes a series of experiments designed to investigate the effects of phencyclidine (PCP) on associative learning and its substrates in the central nervous system. Behavioral, neurochemical, and biophysical methods will be used to examine potential cellular mechanisms for PCP-induced learning deficits. PCP, a common street drug of abuse, is a noncompetitive antagonist of the ionophore of the NMDA receptor. The NMDA channel has received considerable attention recently because of its involvement in the induction of neural plasticity. We will assess the effects of PCP on learning, memory, and its underlying neural mechanisms. The eyeblink conditioning task we will use in rabbits has direct behavioral, and presumably neural, parallels in humans. The PCP dose regimens to be used attempt to simulate the consumption patterns of PCP abusers. We hypothesize that activation of the NMDA receptor-complex is critical for associative learning, based on our finding that chronic PCP treatment blocks acquisition. Retention of previously learned tasks will also be tested. PCP binds with high affinity within the NMDA receptor's ionophore, with particularly dense binding concentrated in the hippocampus. We propose to test whether the hippocampus is a substrate for PCP's observed deleterious effects on learning, using two hippocampally-dependent tasks, trace and tone discrimination reversal eyeblink conditioning in rabbits. MK-801 binds to the PCP receptor site within the NMDA ionophore with higher affinity and greater specificity than PCP itself. We have preliminary evidence that eyeblink conditioning causes enhanced [3H]MK-801 binding (an increase in Bmax) in whole hippocampal membrane preparations from trained compared to pseudoconditioned or handled control rabbits. We will repeat and extend these experiments by examining the effects of PCP on [3H]MK-801 binding, and the time course enhanced binding related to specific stages of learning and specific schedules of PCP treatment. Quantitative autoradiographic techniques will be used to determine whether there is cellular specificity of altered binding within hippocampus following conditioning and/or PCP treatment. The slow afterhyperpolarization (AHP), a Ca2+-dependent kappa+ conductance(s), that follows a burst of action potentials in hippocampal CA1 pyramidal cells is reduced after learning. PCP also apparently affects specific kappa+ conductances. Changes in the AHP, in spike accommodation and in specific kappa+ conductances induced by learning and affected by PCP will be evaluated in CA1 pyramidal cells with current-and voltage-clamp recordings in the slice/patch preparation. Effects of PCP and/or learning on NMDA-mediated transmission will also be examined. Our experimental program is designed to characterize the behavioral deficits which PCP abuse causes, as well as to begin to investigate causative factors at the cellular level with biophysical and neurochemical techniques. Since PCP is a major drug of abuse, it is likely that this research program could make a rather direct contribution to understanding and possibly ameliorating the learning deficits which may be a major consequence of PCP abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA007633-01
Application #
3214323
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1991-12-15
Project End
1995-11-30
Budget Start
1991-12-15
Budget End
1992-11-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Moyer Jr, J R; Power, J M; Thompson, L T et al. (2000) Increased excitability of aged rabbit CA1 neurons after trace eyeblink conditioning. J Neurosci 20:5476-82
Power, J M; Thompson, L T; Moyer Jr, J R et al. (1997) Enhanced synaptic transmission in CA1 hippocampus after eyeblink conditioning. J Neurophysiol 78:1184-7
Najavits, L M; Gastfriend, D R; Nakayama, E Y et al. (1997) A measure of readiness for substance abuse treatment. Psychometric properties of the RAATE-R interview. Am J Addict 6:74-82
Thompson, L T; Disterhoft, J F (1997) Age- and dose-dependent facilitation of associative eyeblink conditioning by D-cycloserine in rabbits. Behav Neurosci 111:1303-12
Thompson, L T; Disterhoft, J F (1997) N-methyl-D-aspartate receptors in associative eyeblink conditioning: both MK-801 and phencyclidine produce task- and dose-dependent impairments. J Pharmacol Exp Ther 281:928-40
Blaxton, T A; Zeffiro, T A; Gabrieli, J D et al. (1996) Functional mapping of human learning: a positron emission tomography activation study of eyeblink conditioning. J Neurosci 16:4032-40
Thompson, L T; Moyer Jr, J R; Disterhoft, J F (1996) Trace eyeblink conditioning in rabbits demonstrates heterogeneity of learning ability both between and within age groups. Neurobiol Aging 17:619-29
Thompson, L T; Moyer Jr, J R; Disterhoft, J F (1996) Transient changes in excitability of rabbit CA3 neurons with a time course appropriate to support memory consolidation. J Neurophysiol 76:1836-49
Moyer Jr, J R; Thompson, L T; Disterhoft, J F (1996) Trace eyeblink conditioning increases CA1 excitability in a transient and learning-specific manner. J Neurosci 16:5536-46
Akase, E; Thompson, L T; Disterhoft, J F (1994) A system for quantitative analysis of associative learning. Part 2. Real-time software for MS-DOS microcomputers. J Neurosci Methods 54:119-30

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