ORIGINAL INVESTIGATION Guanfacine produces differential effects in frontal cortex compared with striatum: assessed by phMRI BOLD contrast Neil Easton & Yasmene B. Shah & Fiona H.Marshall & Kevin C.Fone & Charles A.Marsden Received: 7 June 2006 / Accepted: 2 August 2006 / Published online: 3 October 2006 # Springer-Verlag 2006 Abstract Rationale Guanfacine (an alpha- 2A adrenoreceptor agonist) is a drug ofbenefitin the treatment of attention deficit hyperactivity disorder (ADHD) (Taylor FB, Russo J, J Clin Psychopharmacol 21:223–228, 2001).Assessment of this drug using neuroimaging will provide information about the brain regions involved in its effects. Objectives The pharmacological magnetic resonance imag- ing blood oxygenation level dependent (BOLD) response was determined in rat brain regions following administration of guanfacine. Methods Male rats were individually placed into a 2.35 T Brukermagnet for 60 min to achieve basal recording of changes in signal intensity. Either saline (n = 9) or guanfa- cine (0.3 mg/kg, i.p.; n=9)was then administered and recording was continued for a further90 min.Data were analysed forBOLD effectsusing statistical parametric maps.Respiration rate, blood pressure and blood gases were monitored and remained constant throughout scanning. Results The main changes observed were negative BOLD effects in the caudate putamen and nucleus accumbens with positive BOLD effects in frontal association, prelimbic and motor cortex areas. Conclusions These data suggest thatguanfacine can de- crease neuronal activity in the caudate while increasing frontalcortex activity. This ability to changeneuronal activity in specific areas of rat brain that are known to be impaired in ADHD (Solanto MV, Behav Brain Res 130:65– 71, 2002) may contribute to guanfacine’s beneficial effect Keywords ADHD . Guanfacine . Frontal cortex . phMRI . BOLD . PFC . Striatum . Tenex Introduction The alpha- 2A adrenergic receptor subtype appears to be the site ofaction ofthe beneficial clinicaleffects ofalpha-2 agonists on prefrontal cortex (PFC) function (reviewed in Arnsten et al. 1996, 1998). Alpha- 2A receptors are localised both pre- and post-synaptically, but severallines of evidence suggest that the site of action of alpha- 2A agonists (includingnoradrenaline) is post-synaptic in the PFC (Arnsten et al. 1988;Cai et al. 1993).Alpha-2-adrenergic agonists such as clonidine, guanfacine and medetomidine can improvespatialworking memory performance in monkeys (Arnsten et al. 1988),rats (Carlson et al. 1992) and humans (Coull et al. 1995; Jakala et al. 1999) but have little effectin impairing tasksdependent on posterior corticesor hippocampus (Arnstenet al. 1998). The cognitive enhancing effects of guanfacine have not been replicated in healthy male volunteers (Muller et al. 2005); however, guanfacine may show different effects in attentio deficithyperactivity disorder (ADHD) patients. Further- more,guanfacinedose-dependently prevents deficitsof spatial working memory performance produced by phen- cyclidine (PCP) in rats,suggesting an important role for Psychopharmacology (2006) 189:369–385 DOI 10.1007/s00213-006-0558-1 N. Easton (*) : K. C. Fone : C. A. Marsden School of Biomedical Sciences, Medical School, Institute of Neuroscience, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK e-mail: neil.easton@nottingham.ac.uk Y. B. Shah Institute of Neuroscience, Sir Peter Mansfield Magnetic Resonance Centre, University of Nottingham, University Park, Nottingham, UK F. H. Marshall Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB1 2QJ, UK