Cholinergic, M1 Receptors in the Nucleus Accumbens Mediate Behavioral Depression: A Possible Downstream Target for Fluoxetine

Autor: Rebecca A. Kosloff, Pedro Rada, Bartley G. Hoebel, David T. Chau
Rok vydání: 1999
Předmět:
Zdroj: Annals of the New York Academy of Sciences. 877:769-774
ISSN: 1749-6632
0077-8923
Popis: Antidepressants alleviate behavioral depression via monoamines, notably serotonin,1,2 but the next step in the mechanism is not established. A possible role of acetylcholine in mood disorders has been widely discussed,3,4 although it is not clear which cholinergic system is involved nor where in the brain it might act. Brainstem serotonergic neurons innervate much of the brain, including the nucleus accumbens, a mesolimbic region important for reward, aversion and incentive motivation.5 Local infusion into the posterior-medial nucleus accumbens (NAc) of serotonin, a serotonin 1-A receptor agonist (5-OH-DPAT) or a serotonin reuptake inhibitor (fluoxetine, Prozac) decreased extracellular acetylcholine (ACh).6 This suggests that serotonin inhibits ACh interneurons in the NAc via 5-HT1A receptors. Given that depression is associated with low serotonergic transmission in the brain,2 it is possible that during depression ACh interneurons in the NAc are disinhibited. According to this theory, high synaptic ACh in NAc may be involved in depression. If so, extracellular ACh should rise as a correlate of behavioral depression. This was tested using microdialysis in the Porsolt swim test. The swim test is an animal model of depression that can effectively screen wide classes of antidepressants.7 In this model, rodents placed in a swim tank vigorously try to escape for several minutes, then give up and just tread water displaying reduced motivation to escape. Antidepressants prolong the animal’s escape behaviors. If antidepressants act in the nucleus accumbens (NAc), then serotonergic drugs such as 8-OH-DPAT might reduce depression (i.e., increase swimming time) when injected locally in the NAc. Further, if ACh plays a causal role in depression, then appropriate cholinergic receptor agonists injected in the NAc should increase immobility, and cholinergic antagonists should increase swimming. If successful, this series of results would suggest that fluoxetine alleviates some behavioral manifestations of depression via inhibition of ACh release in the NAc.
Databáze: OpenAIRE
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