Neuroimaging Research Section

Toronto, Canada

Neuroimaging Research Section

Toronto, Canada

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Hamani C.,Neuroimaging Research Section | Hamani C.,Toronto Western Hospital | Diwan M.,Neuroimaging Research Section | Macedo C.E.,Laboratorio Of Psicobiologia | And 7 more authors.
Biological Psychiatry | Year: 2010

Background: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). Methods: The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. Results: Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. Conclusions: Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS. © 2010 Society of Biological Psychiatry.

Natesan S.,King's 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.

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.

Hamani C.,Toronto Western Hospital | Hamani C.,Neuroimaging Research Section | Nobrega J.N.,Neuroimaging Research Section | Lozano A.M.,Toronto Western Hospital
Clinical Pharmacology and Therapeutics | Year: 2010

Deep brain stimulation (DBS) has dramatically changed the landscape of neurosurgery. Overall, the technique consists of the delivery of current into the brain parenchyma through implanted electrodes (Figure 1). It is estimated that 60,000 patients worldwide have received DBS, with the rate of accrual currently approaching 8,000 to 10,000 new patients a year. Although electrical stimulation has been used for more than 50 years to treat psychiatric disorders and pain, the technique as conducted today reemerged some 25 years ago, in the field of movement disorders. The striking clinical effects of DBS in these conditions and the similarities in outcome between stimulation and lesions soon prompted the investigation of the technique for various diseases previously treated by functional neurosurgeons. Equally important for the development of the therapy were imaging and electrophysiological studies. Because DBS modulates local neuronal activity and influences regions at a distance from the stimulated site, dysfunctional anatomic circuits and structures have been regarded as potential targets. Animal research has provided the rationale for the use of DBS in some applications of the therapy, although most experimental studies have been conducted to explore potential mechanisms for the effects of stimulation.

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.

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.

McCormick P.N.,University of Toronto | McCormick P.N.,PET Center | Kapur S.,PET Center | Kapur S.,University of Toronto | And 7 more authors.
Neuropsychopharmacology | Year: 2010

In a recent human [11C]-(+)-PHNO positron emission tomography study, olanzapine, clozapine, and risperidone occupied D2 receptors in striatum (STR), but, despite their similar in vitro D2 and D3 affinities, failed to occupy D3 receptors in globus pallidus. This study had two aims: (1) to characterize the regional D2/D3 pharmacology of in vitro and ex vivo [ 3H]-(+)-PHNO binding sites in rat brain and (2) to compare, using [3H]-(+)-PHNO autoradiography, the ex vivo and in vitro pharmacology of olanzapine, clozapine, risperidone, and haloperidol. Using the D3-selective drug SB277011, we found that ex vivo and in vitro [3H]-(+)-PHNO binding in STR is exclusively due to D2, whereas that in cerebellar lobes 9 and 10 is exclusively due to D3. Surprisingly, the D3 contribution to [ 3H]-(+)-PHNO binding in the islands of Calleja, ventral pallidum, substantia nigra, and nucleus accumbens was greater ex vivo than in vitro. Ex vivo, systemically administered olanzapine, risperidone, and haloperidol, at doses occupying 80% D2, did not occupy D3 receptors. Clozapine, which also occupied 80% of D2 receptors ex vivo, occupied a smaller percentage of D3 receptors than predicted by its in vitro pharmacology. Across brain regions, ex vivo occupancy by antipsychotics was inversely related to the D3 contribution to [3H]-(+)-PHNO binding. In contrast, in vitro occupancy was similar across brain regions, independent of the regional D3 contribution. These data indicate that at clinically relevant doses, olanzapine, clozapine, risperidone, and haloperidol are D2-selective ex vivo. This unforeseen finding suggests that their clinical effects cannot be attributed to D3 receptor blockade. © 2010 Nature Publishing Group All rights reserved.

Hamani C.,Neuroimaging Research Section | Hamani C.,Toronto Western Hospital | Diwan M.,Neuroimaging Research Section | Isabella S.,Neuroimaging Research Section | And 2 more authors.
Journal of Psychiatric Research | Year: 2010

Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is currently being investigated as a treatment for major depression. Despite the encouraging findings of the initial clinical series, several questions remain unanswered, including the most effective stimulation parameters (i.e., current intensity and frequency) and whether unilateral stimulation is also beneficial. We have recently found that some of the effects of SCG DBS could be modeled by stimulating the ventromedial prefrontal cortex (vmPFC) of rats undergoing the forced swim test (FST). Here we investigate whether changes in a number of DBS parameters, including electrode placement, influence outcome in this paradigm. Overall, we found that the antidepressant-like effects of DBS varied as a function of stimulation settings and target. The strongest response was observed with a current intensity of 200μA, followed by 100μA, and 300μA. In contrast, 400μA produced no effect. Using 200μA, a frequency of 130. Hz was more effective than 20. Hz. An intriguing finding was that left unilateral stimulation was as effective as bilateral DBS. When different targets within the vmPFC were considered, a significant antidepressant-like response was observed after PL DBS, whereas IL stimulation was associated with a non-significant reduction in immobility scores. In summary, vmPFC DBS at high frequency and moderate intensity led to a maximal response in the FST. © 2010 Elsevier Ltd.

Creed M.,University of Toronto | Hamani C.,Neuroimaging Research Section | Hamani C.,Toronto Western Hospital | Nobrega J.N.,University of Toronto | Nobrega J.N.,Neuroimaging Research Section
European Neuropsychopharmacology | Year: 2011

Deep brain stimulation (DBS) has recently emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists as yet regarding optimal stimulation parameters or neuroanatomical target for DBS in TD. Here we report the use of DBS in an animal model of TD. We applied DBS (100 μA) acutely to the entopeduncular nucleus (EPN) or subthalamic nucleus (STN) in rats with well established vacuous chewing movements (VCMs) induced by 12. weeks of haloperidol (HAL) treatment. Stimulation of the STN or EPN resulted in significant reductions in VCM counts at frequencies of 30, 60 or 130. Hz. In the STN DBS groups, effects were significantly more pronounced at 130. Hz than at lower frequencies, whereas at the EPN the three frequencies were equipotent. Unilateral stimulation at 130. Hz was also effective when applied to either nucleus. These results suggest that stimulation of either the EPN or STN significantly alleviates oral dyskinesias induced by chronic HAL. The chronic HAL VCM model preparation may be useful to explore mechanisms underlying DBS effects in drug-induced dyskinesias. © 2010 Elsevier B.V.

PubMed | Neuroimaging Research Section
Type: Journal Article | Journal: Behavioural brain research | Year: 2011

An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT(2)) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT(2A) antagonist M100,907, the 5-HT(2C) antagonist SB242,084 and the mixed 5-HT(2A/C) antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT(2) receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5 mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5 mg/kg) and ketanserin (1 mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT(2C) but not 5-HT(2A) mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2(2C) receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT(2C) antagonism could be targeted as a key property in the development of new antipsychotic medications.

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