Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.

Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.

Synthesis and Pharmacology of Potential Site-Directed Therapeutic Agents for Cocaine Abuse Susanna Moore 235 Pages Directed by Dr. David M. Collard and Dr. Howard M. Deutsch Stimulants such as cocaine continue to dominate the nations illicit drug problem. An effective medication for any aspect of cocaine addiction has not been developed. Cocaine binds, although not selectively, to the dopamine transporter (DAT) and disrupts normal dopamine (DA) neurotransmission between neurons. While the dopamine hypothesis for the mechanism of action of cocaine has been widely accepted, cocaine also possesses the ability to block the uptake of serotonin at the serotonin transporter (5-HTT) and norepinephrine at the norepinephrine transporter (NET). The purpose of the work described herein is directed towards synthesizing and testing compounds selective for the DAT, leading to the identification of candidates as potential pharmacotherapies for cocaine dependence. A series of disubstituted and trisubstituted [2.2.2] and [2.2.1]bicycles were synthesized and tested for inhibitor potency in [3H]WIN 35,428 (WIN) binding at the DAT and for inhibition of [3H]DA uptake. Based on results from some of the pharmacology data new regio- and stereochemical isomers of bicyclic [2.2.1]heptanes and [2.2.2]octanes were synthesized. This will lead to further structure-activity-relationships, which will provide a better understanding of the structural requirements needed to bind at the DAT.

Thèse de doctorat : Neurosciences : Paris 12 : 2006. / Titre provenant de l'écran-titre. Pagination : 218 f. Bibliogr. f. 203-218.

Thèse de doctorat : Neurosciences : Paris 12 : 2004. / Version électronique uniquement consultable au sein de l'Université Paris 12 (Intranet). Titre provenant de l'écran-titre. Bibliogr. f. 133-146.

Thesis (M.S.)--State University of New York at Binghamton, Department of Psychology, 2007. / Includes bibliographical references (leaves 38-49).

The ability to switch between different forms of locomotion is critical to many aspects of survival, whether it is switching from walking to running to evade predators, or switching to a slower gait to obtain food. Uncovering the mechanisms behind gait transitions has implications for many fields, from treating Parkinson Disease to understanding the impact of drugs of abuse on movement. However, the mechanisms of gait transitions are not well understood. The experiments outlined in this thesis sought to understand the neuronal basis for gait switching. This work employed the nematode Caenorhabditis elegans, a unique model organism chosen for its genetic tractability and fully characterized nervous system. C. elegans displays different forms of motion: crawling on land and swimming in liquid. First, I sought to determine the mechanisms for switching between these forms of motion in collaboration with Dr. Andres Vidal-Gadea. In the process, we discovered that crawling and swimming actually represent distinct gaits in contrast to recent reports that suggested they were merely a single gait. We further elucidated mechanisms for gait transition in C. elegans. For instance, we found that the transition to crawling required viii the D1-like dopamine receptors DOP-1 and DOP-4; and activation of dopamine neurons via the light-activated cation channel Channelrhodopsin2 was sufficient to induce crawling behavior in worms immersed in liquid. Conversely, photoactivation of serotonergic neurons expressing Channelrhodopsin2 induced swim-like behavior on land. Finally, laser microablation of dopaminergic or serotonergic neurons was sufficient to impair the transition to crawl or swim, respectively. Together these results show that transitions to crawling and swimming are controlled by dopamine and serotonin respectively. Next I wanted to better understand how gait transitions are impaired by a drug of abuse, alcohol. I found that, as in other organisms, ethanol disrupts gait transitions, causing worms in water to inappropriately transition from swim to crawl and to display other land-specific behaviors. Animals lacking the D1-like dopamine receptor DOP-1 were resistant to the ethanol-induced transition to crawl. Finally, I found that several interneurons required for the transition to crawl. Specifically, laser microablation of the DOP-4 receptor-expressing neuron RID or the DOP-1-expressing neurons PQR or RIS resulted in a significant impairment in the time to crawl onset. Overall, the findings presented in this thesis represent the first evidence that C. elegans uses an evolutionarily conserved mechanism to transition between gaits and provides the beginning of a molecular description of gait transitions. / text

Functional asymmetries, most commonly associated in humans with population-level hand preference and lateralization in language processing, are complex, heterogeneous traits with poorly understood biological and genetic bases. Notably, functional asymmetries are also associated with familial non-right handedness suggesting that common genetic factors influence both handedness and functional lateralization. This dissertation has two aims. The first is the development of a specific biological hypothesis that may partially account for the consistent co-lateralization of hand preference and prefrontal language function. I argue that asymmetries in local neural properties that affect the excitability and signal-to-noise ratio of neural assemblies can produce a bias in the direction and, to some extent, the degree of functional lateralization for complex functions. At a high level of representation, this hypothesis is similar to long-standing theories of hemispheric differences, but differs from these by providing a single biological difference between hemispheres that influences both motor and prefrontal asymmetries. Specifically, I propose that a hemispheric asymmetry in the ratio of activity at D1 and D2 dopamine receptors can account for both forms of asymmetry. The second aim is to identify novel electrophysiological and behavioral correlates of genetic effects linked to handedness. By applying a standard genetic model to familial handedness data, I obtain an estimate of these genetic effects for individual research participants that may improve sensitivity over previous studies that have primarily used categorical classifications to study familial handedness effects. Two EEG studies of executive function provide evidence for computational changes associated with familial handedness. The first, an auditory oddball paradigm, suggests that cortical noise is increased in conjunction with estimated genetic effects associated with left handedness. In the second study, a go-nogo task, a dissociation between response inhibition and response conflict processing was found with respect to estimated genetic effects associated with left handedness. In addition to bearing on current theories of conflict processing, these results may provide indirect evidence for dopaminergic contributions to neurological and behavioral differences associated with familial sinistrality. Additional studies of resting EEG and behavioral responses to Necker cube viewing provide additional evidence for broad effects of familial sinistrality.

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