In the present study, we have coupled the chronic mild stress (CMS) protocol with Affymetrix microarray technology to screen the rat genome for gene changes in the frontal cortex. The aim of our work was to assess whether the CMS protocol could be a useful experimental model to provide insights into the molecular basis of depression. Under our experimental conditions, 59 transcripts changed by more than +/-1.5-fold between naïve and anhedonic rats and showed significantly altered expression levels (P < 0.05). Among these, 18 were upregulated (fold change range +1.509 to +3.161) and 41 were downregulated (fold change range -1.505 to -2.659). To confirm the data obtained with microarrays, we used real-time reverse transcription polymerase chain reaction (RT-PCR). The results confirmed the downregulation of Itga6, Camk2a, Plcb1, Cart, Gad1, Homer1 and Th and the upregulation of Egr2 and Ptgs2 observed in the DNA microarray analysis. Moreover, the fold change data of the nine validated transcripts from microarray analysis and real-time polymerase chain reaction showed a good correlation (r = 0.863, 7 d.f., P < 0.01; slope = 0.976). It is of great interest that prostaglandin-endoperoxide synthase 2, tyrosine hydroxylase, Cart, Homer1 and glutamate decarboxylase have already been implicated in affective disorders by different approaches in previous reports. In conclusion, our findings indicate that the CMS paradigm is a useful preclinical model with which to investigate the molecular basis of anhedonia and to help in the discovery of novel targets for antidepressant drugs.

We have shown that chronic QTP treatment prevented anhedonia and reversed, at least in part, the changes of gene expression induced by CMS in the rat frontal cortex. We have also identified and confirmed by two different methods that 11 genes, representing molecular targets of QTP, are presumably the effectors of its clinical efficacy.

The role of atypical antipsychotics as add-on treatments and as primary mood stabilizers in different phases of bipolar disorder is an important current research area. Although in bipolar patients the main therapeutic indication of quetiapine (QTP) is the management of acute mania, several observations suggest that this agent may exert antidepressant as well as antimanic effects. However, in our knowledge, there are no preclinical studies supporting this hypothesis. Thus, the main goal of the present work was to evaluate the putative antidepressant effect of QTP (0.4, 2.0, or 10 mg/kg/day), in comparison to amitriptyline (AMI) (2 or 5 mg/kg/day), in rats exposed to acute or chronic stress. The administration of QTP, 2 mg/kg/day, prevents the onset of anhedonia in rats exposed to a 6-week chronic mild stress (CMS) protocol. The effect of QTP has a slow onset, beginning at week 5, and causes a complete recovery from anhedonia. In this respect, the effect of QTP is similar to that obtained after chronic administration of AMI 2 or 5 mg/kg/day. Our findings also indicate that a 6-week administration of QTP, 2 or 10 mg/kg/day, has protective effects against the onset of anhedonia caused by the exposure to an acute subthreshold stressful event in rats that have previously experienced the CMS procedure. The results suggest that QTP is able to prevent both the transient mood depression caused by acute stress and the long-lasting anhedonic state induced by exposure, over a period of weeks, to a variety of unpredictable mild stressors.

No abstract

INTRODUCTIONThe term canine cognitive dysfunction syndrome (CCDS) is used in veterinary literature to describe the progressive neurodegenerative disorder of senior dogs that is characterized by a gradual decline in cognitive function [1,2]. Currently a diagnosis of cognitive impairment is based on identifying the clinical symptoms by collecting owner's opinions and observations. Although neuropsychological testing is certainly a better measure of cognitive impairment than owner assessment, most of the pet dogs are periodically controlled by veterinary practitioners that are not specialists of behaviour. Since this condition does not allow the use of complex procedures, availability to practitioners of a battery of easy and short protocols to measure the cognitive impairment is advisable. In the present work we have developed a battery of tests (open field, curiosity test and reversal learning) for assessment of cognitive decline in pet dogs.

INTRODUCTIONThe term canine cognitive dysfunction syndrome (CCDS) is used in veterinary literature to describe the progressive neurodegenerative disorder of senior dogs that is characterized by a gradual decline in cognitive function [1,2]. Currently a diagnosis of cognitive impairment is based on identifying the clinical symptoms by collecting owner's opinions and observations. Although neuropsychological testing is certainly a better measure of cognitive impairment than owner assessment, most of the pet dogs are periodically controlled by veterinary practitioners that are not specialists of behaviour. Since this condition does not allow the use of complex procedures, availability to practitioners of a battery of easy and short protocols to measure the cognitive impairment is advisable. In the present work we have developed a battery of tests (open field, curiosity test and reversal learning) for assessment of cognitive decline in pet dogs. MATERIALS AND METHODSIn the open field test, various locomotion indices were recorded in a 3 · 3 m testing room for a fixed time (3 min). The curiosity test allows the dog to examine and play with a variety of toys to assess the animal's reaction to novel objects or exploratory behaviour. In the reversal learning test, the animal must discriminate between two positions to obtain a food reward: once the dog learns which position is correct, the food reward is switched to the previously unrewarded position and the animal must then inhibit its learned behaviour. RESULTSThe results of the open field test indicate no significant difference in locomotor activity (P < 0.05, Student t-test for unpaired data) between a group of young-middle aged pet dogs (2-9 years) and a group of aged pet dogs (over 10 years). Similar results were obtained in the curiosity test. Conversely, the performance of the two groups was significantly different both during the acquisition and the reversal session of the reversal learning test. Aged dogs took more time than young-middle aged dogs to discriminate between two positions to obtain a food reward (267 ± 9.4 s versus 227 ± 14 s; P < 0.05, Student t-test for unpaired data) or to inhibit their previous learned behaviour (255 ± 13 s versus 135 ± 15 s; P < 0.05, Student t-test for unpaired data). Finally, from our data, a linear relationship and a significant correlation between chronological age (independent variable) and the progressive impairment of cognitive performance (dependent variable) in both sessions of the reversal learning have been obtained (acquisition: y = 8.02x + 178; r = 0.732, P < 0.05) (reversal: y = 17x + 51.5; r = 0.856, P < 0.05). DISCUSSIONOur protocols, together with the accurate anamnesis and the specific geriatric examination, could be valuable and effective tools to formulate a diagnosis of cognitive impairment in aged pet dogs. REFERENCES 1.

Clinical Management Issues 25principalmente legate alla compromissione dell'abilità motoria. L'elevata incidenza di disturbi extrapiramidali causata dall'uso cronico degli antipsicotici tipici ha dato grande impulso alla ricerca di nuove molecole che, pur mantenendo la stessa efficacia dei composti già in uso, fossero dotate di un migliore profilo di sicurezza. I risultati scaturiti dallo sforzo congiunto della ricerca industriale e accademica hanno condotto, verso la fine del secolo scorso, alla "rivalutazione" di clozapina e alla scoperta di altri antipsicotici atipici. Le peculiari caratteristiche farmacocinetiche e farmacodinamiche di questi ultimi hanno fatto di questi farmaci degli strumenti terapeutici di indubbia efficacia, con un profilo di effetti avversi decisamente favorevole e una tossicità comportamentale inferiore rispetto ai composti tipici, in particolare nell'impiego a lungo termine. IntroduzIoneLa commercializzazione dei primi farmaci antidepressivi (triciclici e inibitori delle monoaminoossidasi) e antipsicotici (fenotiazine e butirrofenoni) ha senza dubbio fornito un contribuito decisivo all'intenso sviluppo della psicofarmacologia avvenuto nella seconda metà del secolo scorso. In particolare gli antipsicotici tipici, utilizzati con successo per oltre 50 anni nel trattamento di pazienti schizofrenici, bipolari psicotici o in stato di agitazione psicomotoria, sono risultati essenziali nella risoluzione dei casi più gravi, a elevato rischio di mortalità, e hanno consentito un miglioramento di quadri clinici un tempo ritenuti intrattabili. Tuttavia l'impiego terapeutico di antipsicotici a intensa azione antidopaminergica D 2 genera sindromi neurologiche più o meno gravi,