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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 A), 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 depressivelike 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.Parkinson's disease ͉ mood disorder ͉ deep brain stimulation T he use of stimulation electrodes implanted in the brain to control severely disabling neurological and psychiatric conditions is an exciting and fast emerging area of clinical neuroscience (1). As an example, bilateral, high-frequency stimulation (HFS) of the subthalamic nucleus (STN) has become the surgical therapy of choice for advanced Parkinson's disease (PD), and to date Ͼ30,000 PD patients worldwide have benefited from this procedure (2, 3). The relief of movement disability by HFS of the STN is predictable because this nucleus is a critical part of the basal ganglia motor circuitry that is dysfunctional in PD patients (4, 5) and in animal models of PD (6-8).Despite having important beneficial motor effects, in up to 40% of PD patients, bilateral STN HFS is associated with the occurrence of unpleasant and debilitating psychiatric effects, including cognitive alterations, low mood, aggression, and impulsive acts and thoughts that are linked to suicide (9-12). These psychiatric effects can be a major burden to patients and their families and often mitigate the positive effects on motor symptoms. In animals, HFS and other manipulations of the STN also produce a range of nonmotor behavioral changes, including increased impulsivity and altered cognitive responses that appear to correlate with the adverse effects experienced by PD patients (12). Collectively, these findi...

Background and purpose: Recent evidence suggests that 5-HT 2C receptor activation may inhibit midbrain 5-HT neurones by activating neighbouring GABA neurones. This hypothesis was tested using the putative selective 5-HT 2C receptor agonist, WAY 161503. Experimental approach: The effect of WAY 161503 on 5-HT cell firing in the dorsal raphe nucleus (DRN) was investigated in anaesthetised rats using single unit extracellular recordings. The effect of WAY 161503 on DRN GABA neurones was investigated using double label immunohistochemical measurements of Fos, glutamate decarboxylase (GAD) and 5-HT 2C receptors. Finally, drug occupancy at 5-HT 2A receptors was investigated using rat positron emission tomography and ex vivo binding studies with the 5-HT 2A receptor radioligand

1 Systemic administration of phenethylamine-derived, 5-hydroxytryptamine 2 (5-HT 2 ) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2 The 5-HT 2 receptor agonists DOI ((7)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ( (7)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10 -100 mg kg À1 i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by 480%. 3 Pretreatment with the 5-HT 2 receptor antagonist ritanserin (1 mg kg À1 i.v.) completely blocked the action of DOI. The 5-HT 2A receptor antagonist MDL 100,907 (0.2 mg kg À1 i.v.) blocked the action of both DOI and DOB. In comparison, the 5-HT 2B/C receptor antagonist SB 206553 (0.5 mg kg À1 i.v.) caused a small, but statistically significant, shift to the right in the dose response to DOI and DOB. 4 Pretreatment with the peripherally acting 5-HT 2 receptor antagonist BW 501C67 (0.1 mg kg À1 i.v.) had no effect on the DOI-induced inhibition of 5-HT cell firing, but completely blocked the DOIinduced rise in mean arterial blood pressure. 5 These data indicate that the inhibition of 5-HT cell firing induced by systemic administration of DOI and DOB is mediated predominantly by the 5-HT 2A receptor-subtype, but that 5-HT 2B/C receptors also play a minor role. Moreover, central and not peripheral mechanisms are involved. Given evidence that 5-HT 2 receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.

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