Thèse de doctorat : Chimie organique : Strasbourg 1 : 2006. / Titre provenant de l'écran-titre. Bibliogr. p. 179-184.

Thesis (M.S.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains vii, 79 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 70-78).

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<p>The brain’s dopaminergic system is critical to adaptive behaviors, and is centrally implicated in various pathologies. For decades, research has aimed at better characterizing what drives the mesolimbic dopamine system and the resulting influence on brain physiology and behavior in both humans and animals. To date, the dominant modes of research have relied on extrinsic approaches: pharmacological manipulations, direct brain stimulation, or delivering behavioral incentives in laboratory tasks. A critical open question concerns whether individuals can modulate activation within this system volitionally. That is, can individuals use self-generated thoughts and imagery to invigorate this system on their own? This process can be referred to as “cognitive neurostimulation” -- a precise and non-invasive stimulation of neural systems via cognitive and behavioral strategies. And if not, can they be taught to do so? Recent technological advances make it feasible to present human participants with information about ongoing neural activations in a fast and spatially precise manner. Such feedback signals might enable individuals to eventually learn to control neural systems via fine-tuning of behavioral strategies. The studies described herein investigate whether individuals can learn to volitionally invigorate activation within the mesolimbic reward network. We demonstrate that under the right training context, individuals can successfully learn to generate cognitive states that elicit and sustain activation in the ventral tegmental area (VTA), the source of dopamine production within the mesolimbic network. Although participants were explicitly trained to increase VTA activation, multiple mesolimbic regions exhibited increased connectivity during and after training. Together, these findings suggest new frameworks for aligning psychological and biological perspectives, and for understanding and harnessing the power of neuromodulatory systems.</p> / Dissertation

Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug-related experiences are formed, resulting in persistent and uncontrollable drug-seeking behavior. However, it is well known that both acute and chronic alcohol (ethanol) exposures impair various types of learning and memory in both humans and animals. Consistent with these observations, both acute and chronic exposures to ethanol suppress synaptic plasticity, the major neural substrate for learning and memory, in multiple brain areas. Therefore, it remains unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. The mesolimbic dopaminergic system is critically involved in the learning of information related to rewards, including drugs of abuse. Both natural and drug rewards, such as ethanol, cause release of dopamine in the nucleus accumbens and other limbic structures, which is thought to drive learning by enhancing synaptic plasticity. Accumulating evidence indicates that plasticity of glutamatergic transmission onto dopamine neurons may play an important role in the development of addiction. Plasticity of NMDA receptor (NMDAR)-mediated transmission may be of particular interest, as NMDAR activation is necessary for dopamine neuron burst firing and phasic dopamine release in projection areas that occurs in response to rewards or reward-predicting stimuli. NMDAR plasticity may, therefore, drive the learning of stimuli associated with rewards, including drugs of abuse. This dissertation finds that repeated in vivo ethanol exposure induces a metaplasticity of NMDAR-mediated transmission in mesolimbic dopamine neurons, expressed as an increased susceptibility to the induction of NMDAR LTP. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5- trisphosphate (IP3) in producing the facilitation of action potential-evoked Ca2+ signals critical for LTP induction. Interestingly, amphetamine exposure produces a similar enhancement of IP3R function, suggesting this neuroadaptation may be a common response to exposure to multiple drugs of abuse. Additionally, ethanol-treated mice display enhanced learning of cues associated with cocaine exposure. These findings suggest that metaplasticity of NMDAR LTP may contribute to the formation of powerful memories related to drug experiences and provide an important insight into the learning component of addiction. / text

published_or_final_version / Zoology / Master / Master of Philosophy

published_or_final_version / Zoology / Master / Master of Philosophy