The present experiments investigated the effects of different antidepressant treatments on dopamine (DA) transmission by employing in vivo microdialysis in the nucleus accumbens (NAC) and the striatum of freely moving rats. The treatments were: a) the tricyclic antidepressant desipramine (DMI), b) the novel antidepressant drug bupropion, and c) electrically induced seizures (ECS). The following results were obtained: 1) Neither acute (5 mg/kg), nor chronic (5 mg/kg, b.i.d. X 21) DMI influenced basal interstitial concentrations of DA in the NAC or the striatum. Chronic DMI did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. In contrast, d-amphetamine (1.5 mg/kg, s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC (not in striatum) of the chronic DMI group. d-Amphetamine-induced hypermotility was also enhanced in the chronic DMI group. 2) Bupropion (10, 25 and 100 mg/kg, i.p.) increased extracellular striatal DA concentrations in a dose-, time-, and action potential-dependent manner. Bupropion produced similar responses in the NAC. The in vivo neurochemical effects of bupropion were compared with the effects of other DA uptake inhibitors such as d-amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, and benztropine by direct administration of the drugs to the striatum via the perfusion fluid in increasing concentrations (1 to 1000 μM). The rank order of potency of these drugs as determined by the increases in extracellular DA produced by 10 or 100 μM (following correction for dialysis efficiency of the test compounds in vitro) was: GBR 12909> benztropine> amphetamine= nomifensine= methylphenidate> cocaine> bupropion. Simultaneous in vivo microdialysis in the NAC and striatum was employed to investigate the effects of chronic (10 mg/kg, b.i.d. X 21) bupropion treatment on bupropion (25 mg/kg, i.p.)-induced increases in extracellular DA concentrations. The effect of the challenge bupropion injection was significantly enhanced in the NAC (not in striatum) of the chronic bupropion group. Bupropion-induced hyperlocomotion was also enhanced in the chronic bupropion group. 3) Following a single ECS (150 V, 0.75 sec) interstitial concentrations of DA in the NAC and striatum increased sharply to 130% and 300%, respectively. The ECS-induced DA increase in the striatum was Ca⁺⁺-sensitive, partially TTX-independent, and was not influenced by barbiturate-induced anaesthesia. Seizure activity induced by flurothyl did not influence dialysate DA concentrations from the striatum, but increased dialysate DA from the NAC to 150%. These results suggest that the ECS-induced DA release in the striatum (not in the NAC) is related to the passage of current and not to the seizure activity. A course of ECS (8 treatments, one every second day) did not influence basal extracellular DA concentrations in the striatum or the NAC, while it significantly increased the DA metabolites in the striatum. Chronic ECS did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. d-Amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC of the chronic ECS group. d-Amphetamine-induced hypermotility was also enhanced in the chronic ECS group. These results provide in vivo neurochemical confirmation that chronically administered DMI or ECS do not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI- or chronic ECS-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a potentiation of its effects on interstitial DA concentrations in the NAC. Moreover, these results demonstrate that chronic bupropion-induced behavioral sensitization is accompanied by a selective potentiation of its effects on interstitial DA concentrations in the NAC. Taken together, the present data provide direct neurochemical evidence that these antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system. / Medicine, Faculty of / Graduate

Qu'est ce qui nous pousse à agir? Les théories neuroéconomiques suggèrent que nos comportements sont déterminés par des mécanismes d'optimisation entre les coûts et les bénéfices attendus de nos actions. Dans ce travail, nous avons étudié les mécanismes de la motivation à l'effort grâce à des paradigmes de motivation incitative, et développé un modèle computationnel reposant sur une optimisation cout-bénéfice. Nous avons d'abord étudié les effets motivationnels d'interactions sociales, comme la coopération et la compétition, et montré que l'activité du complexe striatopallidal ventral corrélait avec les comportements utilitaires, tandis que l'activité et le volume de la jonction temporopariétale, prédisaient les biais altruistes, suggérant son rôle clé dans la détermination des efforts prosociaux. L'étude de patients parkinsoniens a ensuite permis, au niveau comportemental et computationnel, de dissocier les effets moteur et motivationnel de la dopamine. Ces effets prédisaient respectivement les variations des scores cliniques moteurs et d'apathie. Nous avons également montré que des traitements sérotoninergiques atténuaient les mécanismes de motivation incitative, pouvant ainsi rendre compte de l'existence de syndromes apathiques sous ces traitements. Enfin, nous avons pu identifier plusieurs profils d'atteinte motivationnelle au sein de pathologies neurologiques focales, dégénératives, ou psychiatriques. Ce travail propose ainsi un cadre normatif pour rendre compte des mécanismes déterminant la direction et l'intensité du comportement, et vise à progresser dans la compréhension des mécanismes de la motivation et de ses déficits dans les pathologies neuropsychiatriques. / Why do we do what we do? Recent neuroeconomic theories suggest that our behaviour is determined by optimizing the difference between the benefit and the cost of our actions. In this work, we studied the neural basis of motivation by using incentive motivation tasks, and we developed a computational model of goal-directed effort production that gathers theories of motor control with decision-making principles of cost/benefit optimization. We first studied the motivational effects of social interactions, such as cooperation and competition, and showed that the activity in the ventral striato-pallidal complex correlated with utilitarian behaviours, whereas the activity and the cortical volume in the temporoparietal junction predicted altruistic biases, suggesting a key role for this region in prosocial motivation.Next, we studied Parkinson’s disease patients, and showed a dissociation, at the behavioural and the computational level, between the motor and the motivational effects of dopamine. These effects predicted respectively the clinical change in motor dysfunction and apathy. We also showed that serotoninergic treatments in healthy subjects affected incentive motivation. This effect could account for the occurrence of apathetic syndromes with these treatments.Finally, we identified different profiles of motivational deficits in psychiatric, focal or degenerative neurological conditions.This work thus suggest a normative framework to account for the mechanisms that determine the direction and the intensity of the behaviour, and aims at better understanding the neural basis of motivation and its deficits among neuropsychiatric disorders.

The research presented in this thesis focuses on the study of the reaction between boronic acids and diols and its evaluation as a possible "click" reaction, possibly applicable in bioconjugation and drug delivery. A key feature of this reaction is its reversibility at acidic pH, which could allow the release of a diol-containing drug from a bioconjugate in the acidic environment of late endosome/lysosome, possibly after undergoing receptor mediated endocytosis. Over the last two decades various studies have focused on the study of the conjugation of boronic acids to diols using Alizarin Red S as a fluorescence reporter. In this research we have presented an alternative method based on the batochromic shifts of Alizarin Red S absorbance; this method is particularly advantageous in complex systems with an elevated scattering, such as colloidal dispersions or for binding to complexed active compounds. We have therefore demonstrated that this method allows the determination of equilibrium constants between diols (e.g. catecholamines) and boronic acids. We have also demonstrated that the method allows to follow the kinetics of enzymatic reactions involving catechols; in particular, we have focused on cytochrome P450-mediated reactions such as the conversion of estradiol to 2-hydroxyestradiol using CYP1A2, or the demethylation of 3-methoxytyramine to dopamine using CYP2D6. Once we have established a reliable method for following this reaction on low molecular weight compounds, we have applied it to polymeric bioconjugates. Specifically, we have selected hyaluronic acid (HA) as a biocompatible and biodegradable polymeric backbone and produced derivatives containing boronic acids, catechols and dimethylated catechols (as negative controls). The resulting polymers where characterised via UV-Vis, 1H NMR and SLS, also qualitatively evaluating their cytotoxicity and enzymatic degradability. The conjugates with boronic acids showed the lowest cytotoxicity, and the highest degradability. The complexation of HA-boronic derivatives was then studied; using the same library of diols previously used with low molecular weight compounds, evaluating the effect of the presence of the polysaccharidic macromolecular chain.

An extensive mapping of the caudate-putamen in the rat for intracranial self-stimulation (ICS) sites »as undertaken to provide additional support for the role of dopamine in brain stimulation reward. Eighty-seven percent of the placements in the neostriatum supported ICS, with self-stimulation rates greater than 250/15 min at 56% of the sites. In a second experiment, animals were prepared with electrodes aimed at the lateral caudate-putamen. Those subjects displaying ICS subsequently received 6-hydroxydopamine lesions to the dopamine cell bodies in the substantia nigra pars compacta either ipsilateral or contralateral to the electrode. The destruction of the dopamine cell bodies attenuated ICS in both groups during the first post-lesion test sessions. However, the rates in the ipsilateral group declined to between 2-9% of control scores, whereas the rates in the contralateral group improved over testing to 72% of control values, 28 days after the lesion. On the basis of these data, it was concluded that unilateral destruction of the dopaminergic nigro-neostriatal (NSB) has two effects on ICS behaviour. First, unilateral reduction of neostriatal dopamine is accompanied by a loss of brain stimulation reward at sites normally innervated by the NSB, specifically the caudate-putamen. Secondly, lesions of the NSB produce a general disruption in bar pressing behaviour, as evidenced by the attenuation of ICS following contralateral lesions. The possible role of the NSB in natural reward is discussed. / Arts, Faculty of / Psychology, Department of / Graduate

Excitatory glutamatergic inputs from limbic regions such as the hippocampus and the basolateral amygdala (BLA), and dopaminergic inputs from the ventral tegmental area converge in the nucleus accumbens (NAc). It has been proposed that interactions between these glutamatergic and dopaminergic pathways play an important role in adaptive behaviors. The present thesis employed a multidisciplinary approach to study these interactions, with a specific emphasis on the importance of mesoaccumbens dopamine (DA) transmission, in order to obtain a better understanding of the neural mechanisms by which the NAc transforms signals from the temporal lobes into behavior. The experiments of Chapter 2 utilized extracellular single-unit recordings of individual NAc neurons in combination with electrochemical measures of DA efflux in the NAc. Recordings from NAc neurons which received input from the hippocampus but not the BLA revealed that increased efflux of mesoaccumbens DA, evoked by tetanic stimulation of the fimbria, potentiated hippocampal-evoked neural activity in these cells. These effects were mediated by both DA and NMDA receptors. Similar recordings from neurons which received converging input from both the hippocampus and the BLA revealed tetanic stimulation of the fimbria again potentiated hippocampal evoked spiking activity, while concurrently suppressing BLA-evoked spiking activity in the same neurons. The suppression of BLA-evoked spiking activity was activity-dependent, and was mediated by both D, and adenosine A, receptors. Chapter 3 showed that random foraging on a radial-arm maze, which is dependent on a neural circuit linking the hippocampus to the NAc, was correlated with an increase in mesoaccumbens DA extracellular levels, as measured with microdialysis. In Chapter 4, pharmacological blockade of DA or NMDA receptors in the NAc, or selective disruption of dopaminergic modulation of ventral subicular inputs to the NAc (using an asymmetrical infusion procedure) significantly disrupted random foraging. These effects were mediated by the Dl receptor. In Chapter 5, the present data are integrated with previous research to formulate a model of ventral striatal function. It is proposed that the NAc mediates behavior through distinct patterns of activity and inactivity driven by excitatory limbic input projecting to different groups of neural ensembles. Mesoaccumbens DA transmission plays an essential role in regulating the synchrony ensemble activity, augmenting activity in one ensemble while suppressing activity in another. It is argued that the modulatory effects of DA appears to be essential when an organism must switch from one form of adaptive behavior to another in response to a constantly changing environment. / Arts, Faculty of / Psychology, Department of / Graduate

Spontaneously active frontal cortex and spinal cord networks grown on microelectrode arrays were used to study effects of D-methylphenidate. These central nervous system tissues have relatively low concentrations of dopaminergic and noradrenergic neurons compared to the richly populated loci, yet exhibit similar neurophysiological responses to methylphenidate. The spontaneous spike activity of both tissues was inhibited in a concentration-dependent manner by serial additions of 1-500 µM methylphenidate. Methylphenidate is non-toxic as spike inhibition was recovered following washes. The average concentrations for 50% spike rate inhibition (IC50 ± SD) were 118 ± 52 (n= 6) and 57 ± 43 (n = 11) for frontal cortex and spinal cord networks, respectively. A 3 hour exposure of a network to 1 mM methylphenidate was nontoxic. The effective concentrations described in this study are within the therapeutic dosage range. Therefore, the platform may be used for further investigations of drug mechanisms.

No description available.

TRPM7 (Transient Receptor Potential Melastatin-like 7) is an ion channel necessary for the proper development of many cell types. Insight into the precise role of the channel in different cells has been hampered by the lethality of knocking out the gene in model organisms such as the mouse. Here I examine a zebrafish that has a loss-of-function mutation in the gene encoding Trpm7. First, I show that trpm7 is important for the function of developing dopaminergic neurons in the zebrafish. Second, I examine the interaction between trpm7 and the related gene vmat2 in order to develop a cellular mechanism of trpm7 function in presynaptic dopaminergic neurons. Finally, I investigate the necessity of the kinase and ion channel domains of trpm7 in their ability to promote pigmentation in melanophores as a model cell type. Based on the results from these experiments and observations from other researchers, I form a new hypothesis for Trpm7 function in protein sorting. These studies provide a detailed and novel analysis of the function of an ion channel that is necessary for life.

Infusion of a dopamine D1-receptor antagonist into both the dorsolateral and dorsomedial striatum interfered with quinine-resistant alcohol drinking, but not unadulterated alcohol consumption. Dopamine in these two brain regions play a role in compulsive-like alcohol consumption.

Striatal oscillatory activity associated with movement, reward, and decision-making is observed in several interacting frequency bands. Rodent striatal local field potential recordings show dopamine- and reward-dependent transitions between a 'spontaneous' state involving beta (15-30 Hz) and low gamma (40-60 Hz) and a 'dopaminergic' state involving theta (4-8 Hz) and high gamma (60-100 Hz) activity. The mechanisms underlying these rhythmic dynamics and their functional consequences are not well understood. In this thesis, I construct a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of these rhythms as well as their modulation by dopamine and rhythmic inputs, and test its predictions using human electroencephalography (EEG) data. Chapter 1 describes the striatal model and its dopaminergic modulation. Building on previous work suggesting striatal projection neuron (SPN) networks can generate beta oscillations, I construct a model network of striatal fast-spiking interneurons (FSIs) capable of generating delta/theta (2-6 Hz) and gamma rhythms. This FSI network produces low gamma oscillations under low (simulated) dopaminergic tone, and high gamma activity nested within a delta/theta oscillation under high dopaminergic tone. In a combined model under high dopaminergic tone SPN network beta oscillations are interrupted by delta/theta-periodic bursts of gamma-frequency FSI inhibition. This high dopamine-induced periodic inhibition may enable switching between beta-rhythmic SPN cell assemblies representing motor programs, suggesting that dopamine facilitates movement in part by allowing for rapid, periodic changes in motor program execution. Chapter 2 describes the model's response to square-wave periodic cortical inputs. Comparing models with and without FSIs reveals that the FSI network: (i) prevents the SPN network's generation of phase-locked beta oscillations in response to beta's harmonic frequencies, ensuring fidelity of transmission of cortical beta rhythms; and (ii) limits or entrains SPN activity in response to certain gamma frequency inputs. Chapter 3 describes an analysis of phase-amplitude coupling at cortical electrodes in human EEG data during a reward task. The alternating rhythms predicted by the model appear in response to positive feedback. While the origins of these rhythms remain unclear, if they represent striatal signals, they provide a direct link between human behavior and striatal cellular function.