Midbrain dopamine neurons express inhibitory D2 dopamine autoreceptors. Therefore, D2 receptor antagonists such as the antipsychotic drug haloperidol act acutely to excite these cells. However, chronic haloperidol acts after a delay to decrease dopamine release and dopamine dependent behavior. The long-term regulation of dopamine neuron activity, which might contribute to the therapeutic action of antipsychotic drugs, has been a source of controversy because of the confounding effects of general anesthetics present during in vivo recording. We have used an experimental approach that bypasses the need for anesthetics to demonstrate that chronic haloperidol dampens the intrinsic excitability of young rat midbrain dopamine neurons. This is caused by upregulation of Kv4.3 A-type K+ channels. Furthermore, we find that this effect can be recapitulated in cell culture with chronic exposure to the D2 receptor antagonist sulpiride. In this proposal, we will determine: (i) whether Kv4.3 auxiliary subunit expression is also regulated by the antipsychotic drug, (ii) the ionic basis for irregular pacemaker activity induced by chronic haloperidol, (iii) whether an atypical antipsychotic drug acts similarly to remodel dopamine neuron excitability, (iv) the role of D2 receptors and second messengers in the long-term effect in vitro, and (v) how remodeling of dopamine neuron excitability depends on age and duration of antipsychotic drug treatment. These experiments will determine how D2 receptors and clinically used antipsychotic drugs remodel dopamine neuron intrinsic pacemaker activity. This long-term regulation may operate during normal development and in response to changes in D2 receptor activity induced by addictive and antipsychotic drugs. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053050-02
Application #
7028920
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Stewart, Randall R
Project Start
2005-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$301,420
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Colgan, Lesley A; Putzier, Ilva; Levitan, Edwin S (2009) Activity-dependent vesicular monoamine transporter-mediated depletion of the nucleus supports somatic release by serotonin neurons. J Neurosci 29:15878-87
Putzier, Ilva; Kullmann, Paul H M; Horn, John P et al. (2009) Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons. J Neurosci 29:15414-9
Putzier, Ilva; Kullmann, Paul H M; Horn, John P et al. (2009) Dopamine neuron responses depend exponentially on pacemaker interval. J Neurophysiol 101:926-33
Hahn, Junghyun; Kullmann, Paul H M; Horn, John P et al. (2006) D2 autoreceptors chronically enhance dopamine neuron pacemaker activity. J Neurosci 26:5240-7
Redman, P T; Jefferson, B S; Ziegler, C B et al. (2006) A vital role for voltage-dependent potassium channels in dopamine transporter-mediated 6-hydroxydopamine neurotoxicity. Neuroscience 143:1-6