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Bregman T.,Neuroimaging Research Section | Diwan M.,Neuroimaging Research Section | Nobrega J.N.,Neuroimaging Research Section | Hamani C.,Neuroimaging Research Section | Hamani C.,University of Toronto
Brain Stimulation | Year: 2014

Background Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve. Objective To show that supraorbital stimulation is effective in preclinical models. Methods Rats were given supraorbital stimulation at different settings in the forced swim test (FST) and open field. Results Supraorbital stimulation did not induce an antidepressant-like response in rats undergoing the FST. This is in contrast to other neuromodulation treatments, such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy, which are all effective in this paradigm. Conclusions Supraorbital stimulation was ineffective in rats undergoing the FST. Such findings do not invalidate results of recent clinical trials. © 2014 Elsevier Inc.

Hamani C.,Neuroimaging Research Section | Hamani C.,University Federal Of So Paulo | MacHado D.C.,University Federal Of So Paulo | Hipolide D.C.,University Federal Of So Paulo | And 7 more authors.
Biological Psychiatry | Year: 2012

Background: Deep brain stimulation (DBS) is being investigated as a treatment for major depression, but its mechanisms of action are still unknown. We have studied the effects of ventromedial prefrontal cortex (vmPFC) stimulation in a chronic model of depression and assessed the involvement of the serotonergic system and brain derived neurotrophic factor (BDNF) in a DBS response. Methods: Rats were subjected to chronic unpredictable mild stress during 4 weeks. Decline in preference for sucrose solutions over water, an index suggested to reflect anhedonic-like behavior, was monitored on a weekly basis. The outcome of chronic vmPFC stimulation alone (8 hours/day for 2 weeks) or combined with serotonin-depleting lesions was characterized. BDNF levels were measured in the hippocampus. Results: Stress induced a significant decrease in sucrose preference as well as hippocampal BDNF levels as compared with those recorded in control subjects. vmPFC stimulation completely reversed this behavioral deficit and partially increased BDNF levels. In contrast, DBS did not improve stress-induced anhedonic-like behavior in animals bearing serotonin-depleting raphe lesions with associated normal hippocampal BDNF levels. Conclusions: vmPFC stimulation was effective in a chronic model of depression. Our results suggest that the integrity of the serotonergic system is important for the anti-anhedonic-like effects of DBS but question a direct role of hippocampal BDNF. © 2012 Society of Biological Psychiatry.

Araujo J.A.,University of Toronto | Araujo J.A.,CanCog Technologies Inc. | Nobrega J.N.,University of Toronto | Nobrega J.N.,Neuroimaging Research Section | And 4 more authors.
Pharmacology Biochemistry and Behavior | Year: 2011

Memory deficits associated with aging and Alzheimers disease have been linked to cholinergic dysfunction. The present study investigated this hypothesis by comparing the effects of the muscarinic cholinergic receptor antagonist scopolamine on recent memory performance and by examining muscarinic receptor density in aged and young dogs. Scopolamine (15 μg/kg; SC) was administered prior to testing young (M = 2.8 years) and aged (M = 13.0 years) dogs on a delayed-non-matching-to-position task (DNMP). Scopolamine significantly impaired performance of aged, but not young dogs. Muscarinic receptor density was assessed autoradiographically using the non-selective radioligand [3H]quinuclidinylbenzilate. Aged dogs (M = 14.1 years) showed significantly decreased density of muscarinic receptors in all brain regions examined except the cerebellum compared to young dogs (M = 3.7 years). The results are consistent with those seen in aged humans and Alzheimers patients and support the hypothesis of age-dependent cholinergic dysfunction in the dog, although this was not directly determined in the current study. These findings demonstrate that markers of cholinergic hypofunction, in addition to the natural cognitive decline and amyloid pathology previously noted, are seen in canine aging. Collectively, this supports the use of the aged dog as a model for examining early pathological events in the development of Alzheimers disease. © 2011 Elsevier Inc. All rights reserved.

Sander S.E.,Free University of Berlin | Raymond R.,Neuroimaging Research Section | Nobrega J.N.,Neuroimaging Research Section | Richter A.,Free University of Berlin
Pharmacology Biochemistry and Behavior | Year: 2010

Previous examinations demonstrated periodic increases in striatal extracellular dopamine levels during dystonic attacks and changes in dopamine D1 and D2 receptor binding in the dtsz mutant hamster, an animal model of paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. Since dopamine D3 receptors are involved in the regulation of striatal dopamine release, D3 receptor function was investigated by autoradiographic and pharmacological examinations in mutant hamsters in the present study. [125I]7-[[(E)-3-iodoprop-2-enyl]-propylamino]-5,6,7,8-tetrahydronaphthalen-2-ol ([125I]7-OH-PIPAT) binding was not significantly altered in the striatum, n. accumbens, ventral pallidum or cerebellum in dtsz hamsters in comparison to non-dystonic control hamsters. In line with the unaltered D3 receptor binding, the preferential dopamine D3 versus D2 receptor antagonist U-99194 (5,6-dimethoxy-N,N-dipropyl-2,3-dihydro-1H-inden-2-amine hydrochloride) did not exert significant effects on the severity of dystonia in dtsz hamsters at doses of 10 to 40mg/kg which induced hyperlocomotion. These results suggest that periodic elevations of dopamine levels in these animals are not related to D3 receptor dysfunctions. © 2010 Elsevier Inc.

Natesan S.,Kings College London | Reckless G.E.,Schizophrenia Program and the Center | Barlow K.B.L.,Neuroimaging Research Section | Nobrega J.N.,Neuroimaging Research Section | And 2 more authors.
International Journal of Neuropsychopharmacology | Year: 2011

While dopamine D2 receptor partial agonists (PAs) have been long considered for treating schizophrenia, only one, aripiprazole, is clinically available for therapeutic use. This raises critically important questions as to what is unique about aripiprazole and to what extent animal models can predict therapeutic success. A number of PAs whose clinical fate is known: aripiprazole, preclamol, terguride, OPC-4392 and bifeprunox were compared to haloperidol (a reference antipsychotic) in several convergent preclinical animal models; i.e. amphetamine-induced locomotion (AIL) and conditioned avoidance response (CAR), predictive of antipsychotic effects; unilateral nigrostriatal lesioned rats, a model of hypo-dopaminergia; striatal Fos induction, a molecular marker for antipsychotic activity; and side-effects common to this class of drugs: catalepsy (motor side-effects) and prolactaemia. The results were compared across drugs with reference to their measured striatal D2 receptor occupancy. All the PAs occupied striatal D2 receptors in a dose dependent manner, inhibited AIL and CAR, and lacked motor side-effects or prolactinaemia despite D 2 receptor occupancy exceeding 80%. At comparative doses, aripiprazole distinguished itself from the other PAs by causing the least rotation in the hypo-dopaminergic model (indicating the least intrinsic activity) and showed the highest Fos expression in the nucleus accumbens (indicating functional D 2 antagonism). Although a number of PAs are active in antipsychotic animal models, not all of them succeed. Given that only aripiprazole is clinically available, it can be inferred that low functional intrinsic activity coupled with sufficient functional antagonism as reflected in the animal models may be a marker of success. © 2011 CINP.

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