Journal Article

Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus

Temel, Yasin, Steinbusch, Harry W.M, Blokland, Arjan, Magill, Peter J, Sharp, Trevor, Visser-Vandewalle, Veerle, Boothman, Laura J

2007

Overview

Bilateral, high-frequency stimulation (HFS) of the subthalamic nucleus (STN) is the surgical therapy of choice for movement disability in advanced Parkinson's disease (PD), but this procedure evokes debilitating psychiatric effects, including depressed mood, of unknown neural origin. Here, we report the unexpected finding that HFS of the STN inhibits midbrain 5-hydroxytryptamine (5-HT) neurons to evoke depression-related behavioral changes. We found that bilateral HFS of the STN consistently inhibited (40-50%) the firing rate of 5-HT neurons in the dorsal raphe nucleus of the rat, but not neighboring non-5-HT neurons. This effect was apparent at clinically relevant stimulation parameters (>=100 Hz, >=30 μA), was not elicited by HFS of either neighboring or remote structures to the STN, and was still present in rat models of PD. We also found that bilateral HFS of the STN evoked clear-cut, depressive-like behavior in a widely used experimental paradigm of depression (forced swim test), and this effect was also observed in a PD model. Importantly, the depressive-like behavior elicited by HFS of the STN was reversed by a selective 5-HT-enhancing antidepressant, thereby linking the behavioral change to decreased 5-HT neuronal activity. Overall, these findings link reduced 5-HT function to the psychiatric effects of HFS of the STN observed in PD patients and provide a rational basis for their clinical management. More generally, the powerful interaction between the STN and 5-HT system uncovered here offers insights into the high level of comorbidity of basal ganglia disease and mood disorder.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Action Potentials - drug effects / Animal behavior / Animal models / Animals / antidepressants / behavior change / Behavior, Animal / Behavioral neuroscience / Biological Sciences / brain / comorbidity / Deep Brain Stimulation - adverse effects / Depression - etiology / Depressive disorders / Disease Models, Animal / Electrodes / Electrophysiology / ganglia / Lesions / Male / Mental depression / Mental stimulation / Muscimol - pharmacology / Neurons / Neurons - cytology / Neurons - drug effects / Neurons - metabolism / Organ Specificity - drug effects / Parkinson disease / Parkinson's disease / Parkinsonian Disorders - pathology / patients / Raphe Nuclei - cytology / Raphe Nuclei - drug effects / Raphe Nuclei - metabolism / Rats / Rats, Sprague-Dawley / Rodents / serotonin / Serotonin - metabolism / Serotonin receptors / Subthalamic Nucleus - cytology / Subthalamic Nucleus - drug effects / Subthalamic Nucleus - metabolism / Subthalamus / therapeutics