期刊
NEUROPHARMACOLOGY
卷 53, 期 3, 页码 455-463出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2007.06.006
关键词
ACh; D2 receptors; NMDA receptons; Accumbens; prefrontal cortex; basal forebrain; schizophrenia
资金
- NIMH NIH HHS [K02 MH001072-09, MH60011024, R01 MH057436, R01 MH063114-04, R01 MH057436-08, MH063114, R01 MH063114, K02 MH001072, MH057436, K02 MH01072] Funding Source: Medline
- NINDS NIH HHS [R01 NS037026-09, R01 NS037026, NS37026] Funding Source: Medline
Glutamatergic and dopaminergic inputs converge on medium spiny neurons in nucleus accumbens and regulate the excitability of these projections to target areas including the cholinergic basal forebrain. NMDA receptors situated on these projections are locally modulated by D1- and D2-like receptors. We previously reported that the D1-like positive modulation of NMDA receptor activity is expressed trans-synaptically in the control of basal forebrain cholinergic projections to prefrontal cortex. The present experiments tested the hypothesis that D2-like receptors in accumbens negatively modulate cortical ACh release. Perfusion of NMDA (150 mu M) into the shell region of the accumbens produced a sustained increase (150-200%) in ACh release in prefrontal cortex. This increase was completely blocked by co-perfusion with the D2-like agonist quin-pirole (100 mu M). Perfusion of quinpirole also reduced basal ACh release (similar to 50%) in prefrontal cortex. The contribution of D2 receptors to the quinpirole effect was assessed in two additional studies. The first study revealed that co-perfusion of the D2 antagonist haloperidol (100 mu M) blocked the quinpirole-induced attenuation of NMDA mediated ACh release. The second experiment demonstrated that intra-accumbens perfusion of quinelorane (100 M), a more selective D2 agonist than quinpirole, also attenuated the NMDA mediated ACh release. Collectively, these studies demonstrate that D2 receptors in accumbens negatively modulate basal and NMDA mediated increases in ACh release in prefrontal cortex. This negative modulation may contribute to the integration of normal attentional processing and goal directed behavior and to the therapeutic effects of antipsychotic medication on cognition in psychopathologies such as schizophrenia, (C) 2007 Elsevier Ltd. All rights reserved.
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