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Procholinergic and Memory Enhancing Properties of The Molecular Psychiatry (2006) 11, 187–195 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp ORIGINAL ARTICLE Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine ET Tzavara, FP Bymaster, CD Overshiner, RJ Davis, KW Perry, M Wolff, DL McKinzie, JM Witkin, and GG Nomikos Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN, USA Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treat- ment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3–3 mg/kg, i.p.), – increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine a-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.) – currently the most commonly prescribed medication for the treatment of ADHD – and with the norepinephrine uptake inhibitor reboxetine (3–30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1–3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test. Molecular Psychiatry (2006) 11, 187–195. doi:10.1038/sj.mp.4001763; published online 18 October 2005 Keywords: ADHD; atomoxetine; acetylcholine; microdialysis; reboxetine; methylphenidate Introduction attention and working memory depend upon the integral function of cortical and hippocampal The norepinephrine (NE) uptake inhibitor cholinergic afferents (reviewed in Everitt and Rob- atomoxetine constitutes today the only first-line bins3). Procholinergic drugs such as cholinesterase alternative to the psychostimulant drugs, methylphe- inhibitors are used in the therapeutics of Alzheimer’s nidate and D-amphetamine for pharmacotherapy disease and other neurodegenerative diseases with of attention deficit/hyperactivity disorder (ADHD). cognitive impairment. Recently, the ability of atypical The psychostimulants are currently classified as antipsychotics to reduce negative symptoms and to schedule II drugs of the Controlled Substance improve performance in cognitive tasks has been Act and have been used for half a century in associated with the stimulatory effects of these agents the treatment of ADHD, the most common psychiatric on neocortical and hippocampal acetylcholine (ACh) disorder in children (3–10% prevalence) that release.4,5 often (60% of the cases) persists into adulthood. Although the effects of atomoxetine on DA and ADHD is characterized by attention deficits, hyper- NE efflux in the brain have been reported,6 its effects activity and impulsivity, and atomoxetine signifi- on cholinergic neurotransmission have not been cantly improves these symptoms in children and studied. Therefore, we assessed the ability adults with ADHD.1,2 of the compound to enhance ACh efflux in cortical In the central nervous system, cholinergic (medial prefrontal cortex and hippocampus) neurons modulate information flow in cortical and subcortical (nucleus accumbens) regions by and subcortical regions implicated in vigilance and in vivo microdialysis in rats. We also investigated cognition. In particular, sustained and selective in this species the procognitive potential of the drug in two animal cognition models, the radial-arm Correspondence: Dr GG Nomikos, Eli Lilly and Company, Lilly maze and the object-recognition tests. We report Corporate Center-DC0510, Indianapolis, 46285, IN, USA. E-mail: [email protected] increases in cortical ACh efflux engendered by Received 29 March 2005; revised 19 August 2005; accepted 10 atomoxetine and parallel enhancement in memory September 2005; published online 18 October 2005 performance. Atomoxetine increases cortical acetylcholine ET Tzavara et al 188 Materials and methods were used were based on those previously used in in vivo microdialysis studies and are relevant to clini- Animals cally used doses.6 All studies were performed according to the guide- Data (n ¼ 4–7 rats per group) were expressed as lines set forth by the National Institutes of Health and multifold change from baseline, which is the average implemented by the Animal Care and Use Committee of the five basal values before any manipulation and of Eli Lilly and Company. Male Wistar or Sprague– were analyzed either with one-way, that is, treatment Dawley rats (250–300 g, purchased from Harlan (between subjects variable), two-way, that is, treat- Sprague–Dawley, Indianapolis, IN, USA) were used ment (between subjects variable) Â time (within sub- for experiments. jects variable) or three-way (treatment 1 Â treatment In vivo microdialysis 2 Â time) ANOVA followed by Duncan’s test. The effects of each of the drugs are presented both over a Surgical procedures. At 2 weeks prior to the course of time every 15 min after the injection of the microdialysis experiments, the rats were drug as well as overall average effects during the 3-h anesthetized with a mixture of chloral hydrate and observation period after the injection of the drug pentobarbital (170 and 36 mg kgÀ1 in 30% propylene (index of area under curve). glycol and 14% ethanol), placed in a stereotaxic apparatus and implanted with a guide cannula Object recognition test (Bioanalytical Systems, West Lafayette, IN, USA Each rat was placed in a clear 25 Â 25 cm2 Plexiglas (BAS)) in the hippocampus (coordinates AP: À5.2, observation box with two identical objects, desig- ML: 5.2, DV: À3.8), medial prefrontal cortex (AP: 3.2, nated A. The rat was allowed to explore for 2 min and ML: 0.6, DV: À2.2) or nucleus accumbens (AP: 1.6, the time interacting with the objects (sniffing, gnaw- ML: 1.2, DV: À6.3) according to Paxinos and Watson.7 ing and behavior oriented to an object) was recorded. At 24 h before testing, a 4 mm (hippocampus, Behavior oriented to the object distinguishes between prefrontal cortex) or a 2 mm (nucleus accumbens) accidental sitting, standing on the object or touching concentric microdialysis probe (BAS, model BR-4 or the object when passing by, and active interaction/ BR-2) was inserted through the guide cannula. The exploration of the object. After a 3-h delay, the rat was actual location of the probes was verified returned to the observation box for the test trial. The histologically at the end of the experiment. test box contained a familiar object (object A) and a novel (object B) object. In the test trial, the objects ACh measurements. ACh determination in were placed at the exact same position as in dialysates from the different brain regions was the learning trial. The amount of time spent interact- performed as described8 with some modifications.9 ing with each object during the 2-min test was On the day of the experiment, a modified Ringer’s recorded. Atomoxetine was administered orally in solution (147.0 mM. NaCl, 3.0 mM KCl, 1.3 mM CaCl2, 5% acacia over a dose range of 0.3, 1, 3 and 10 mg/kg, 1.0 mM MgCl2, 1.0 mM Na2HPO4 Â 7H2O, 0.2 mM 1 h before the first trial. Results are expressed as NaH2PO4 Â H2OpH¼ 7.25) supplemented with percent time exploring the novel object during the 0.1 mM neostigmine was perfused at a rate of 2.4 ml/ retention test (i.e., tB Â 100/(tA þ tB), where tA and tB min in the hippocampus, prefrontal cortex or nucleus are the time spent during test trial with familiar object accumbens. Samples were collected every 15 min and A and novel object B, respectively), and were analyzed immediately, on-line, with HPLC coupled to analyzed with an one-way ANOVA followed by electrochemical detection, with a 150 Â 3 mm ACH-3 Dunnett’s test. column (Environmental Sciences Associates (ESA), Inc., MA, USA) maintained at 351C. The mobile phase Radial arm-maze (100 mM di-sodium hydrogen phosphate, 2 mM 1- The effects of atomoxetine on memory retention were octanesulfonic acid and 50 ml/l of a microbicide examined in a delayed nonmatch to sample task reagent (MB, ESA, Inc.); pH 8.0, adjusted with conducted in an eight-arm radial maze. Well-trained phosphoric acid) was delivered by an HPLC pump rats were required to recall, after a 7-h delay period, (ESA, Inc.) at 0.4 ml/min. The potentiostat used for where they received food during the information electrochemical detection (ESA, Inc.; model phase in order to obtain the remaining rewards during Coulochem II) was connected with a solid phase the retention phase conducted after a delay period. reactor for ACh (ESA, Inc.; model ACH-SPR) and with The apparatus, the training of the rats as well as an analytical cell with platinum target (ESA, Inc.; the information and retention sessions of the test were model 5041). as previously described.10 Atomoxetine (in 5% aca- Atomoxetine, reboxetine and methylphenidate cia) over a dose range of 1, 3 and 10 mg/kg or vehicle (synthesized at Eli Lilly and Company) were dis- was administered orally immediately after the infor- solved in saline (0.9% NaCl) and injected i.p. at a mation phase. During the retention phase, an entry volume of 1 ml/kg, at the doses indicated. Prazosin into a nonbaited arm or a re-entry into an and SCH 23390 (Sigma) (dissolved in saline) were arm previously visited during this phase of testing administered s.c.
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