Increased Levels of 5-HT 1A Receptor Binding in Ventral Visual Pathways in Parkinson’s Disease Philippe Huot, MD, PhD, FRCPC, DABPN, 1,2 Tom H. Johnston, PhD, 1 Naomi P. Visanji, PhD, 3 Tayyeba Darr, BSc, 1 Donna Pires, RVT, 1 Lili-Naz Hazrati, MD, PhD, FRCPC, 3 Jonathan M. Brotchie, PhD, 1 and Susan H. Fox, MB ChB, MRCP(UK), PhD 1,2 * 1 Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada 2 Division of Neurology, University of Toronto, Movement Disorder Clinic, Toronto, Ontario, Canada 3 Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Ontario, Canada ABSTRACT: Visual hallucinations are common in advanced Parkinson’s disease (PD). The pathophysiol- ogy of visual hallucinations may involve enhanced sero- tonergic neurotransmission. The atypical antipsychotics clozapine and quetiapine, which have affinity for 5-HT 2A and 5-HT 1A receptors, are effective against visual hallu- cinations in PD. 5-HT 2A receptors are increased in ven- tral visual pathways in PD patients with visual hallucinations, and we hypothesized that 5-HT 1A recep- tors were also involved in visual hallucinations in PD. Autoradiographic binding using [ 3 H]-WAY-100,635 and NAN-190 was performed in brain sections from 6 PD patients with visual hallucinations, 6 PD patients without visual hallucinations, and 5 age-matched controls. All PD subjects had been treated with L-dopa. Brain areas studied were the orbitofrontal, inferolateral temporal, and motor cortices, as well as the striatum, globus pal- lidus, substantia nigra, and thalamus. 5-HT 1A -binding levels were dramatically increased in the ventral visual pathways of all PD patients compared with controls (0 vs 11 and 0 vs 100 nmol/mg, respectively; both P < .05). There was no significant difference in 5-HT 1A -bind- ing levels in PD patients with visual hallucinations com- pared with PD patients without visual hallucinations or with controls in any of the brain areas studied (P > .05). Gross abnormalities in 5-HT 1A levels in ventral visual areas occurred in all PD patients exposed to L-dopa. However, as there was no difference in 5-HT 1A -binding levels between hallucinators and nonhallucinators, alter- ations in 5-HT 1A receptor levels may not contribute spe- cifically to visual hallucinations in PD. However, the discrete anatomical distribution of rises to the ventral visual areas suggests some role in predisposing to vis- ual hallucinations. V C 2012 Movement Disorder Society Key Words: Parkinson’s disease; serotonin; 5-HT 1A receptors; L-dopa; visual hallucinations Parkinson’s disease (PD) is classically regarded as a disease caused by low dopamine levels in the striatum secondary to degeneration of dopaminergic neurons of the substantia nigra (SN). 1,2 However, the degenera- tive processes in PD extend beyond the dopaminergic system and, with disease progression, Lewy body pa- thology is present in virtually all brain areas. 3,4 The serotonergic system is one such system also affected in PD, 5,6 with degeneration of neurons from the raphe complex 7 and reduced serotonin (5-HT) levels in the basal ganglia and cortex. 8–10 Psychiatric, nonmotor symptoms of PD are a signifi- cant cause of morbidity in advanced disease. 11 Visual hallucinations (VH) are one such important nonmotor manifestation, affecting up to 60% of PD patients. 12,13 The presence of VH in PD is a strong predictor of nursing home placement, 14 and VH have been identified as a marker of advanced disease and precedes death by about 5 years. 15 VH cannot be viewed as a simple complication of chronic L-3,4- ------------------------------------------------------------ *Correspondence to: Susan H. Fox, Movement Disorder Clinic, McL 7-421, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8; sfox@uhnresearch.ca Funding agencies: This study was supported by the Dean’s New Staff Award (to S.H.F.) and Krembil Neuroscience Fund (to J.M.B. and S.H.F.). Philippe Huot held a fellowship from the Edmond J. Safra Philanthropic Foundation, the Parkinson Society Canada, and the Canadian Institutes of Health Research. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 3 November 2011; Revised: 27 January 2012; Accepted: 9 February 2012 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.24964 RESEARCH ARTICLE Movement Disorders, Vol. 000, No. 000, 2012 1