Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been previously suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Investigating the underlying mechanisms, we identified a novel postsynaptic current during neurotransmission mediated by ASIC1A and ASIC2 and thus well-positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity in AMPA-to-NMDA ratio, all resembling changes previously associated with cocaine-induced behavior. Together, these data suggest ASIC1A inhibits plasticity underlying addiction-related behavior, and raise the possibility of therapies for drug addiction by targeting ASIC-dependent neurotransmission. The amygdala plays critical roles in the learning and expression of fear-related behavior. Previous studies have implicated the amygdala in CO2-evoked fear-like behavior in mice; however, a more recent study demonstrated that humans lacking the amygdala bilaterally experience fear and panic with CO2-inhalation. Because all subjects lacking the amygdala had panic attacks after inhaling CO2 compared to only 25% of controls, this data suggests the amygdala may play an inhibitory role in CO2-evoked panic. To assess the role of the amygdala in CO2-evoked behaviors in mice, we lesioned the amygdala and optogenetically stimulated different amygdalar nuclei. We found that large unilateral and bilateral amygdala lesions caused the emergence of escape-like jumping behavior in mice exposed to CO2 and a relative deficit in CO2-evoked freezing. This jumping behavior depended on the dorsal periaqueductal gray, a brain area previously associated with panic attacks. Additionally, the putative CO2 chemosensor ASIC1A and ASIC2 are not necessary for CO2-evoked jumping, and may even play an inhibitory role in this behavior. Optogenetic manipulation of the amygdala revealed that stimulation of the basolateral amygdala enhanced jumping behavior and inhibited freezing behavior. This may be due to the basolateral amygdala's ability to inhibit the main output center of the amygdala, the central nucleus. Together, these results suggest that different amygdalar nuclei differentially modulate CO2-evoked behavior by regulating the switch between mobile and immobile defense responses. Additionally, they provide additional evidence that amygdalar dysfunction may contribute to panic disorder.

Drug addiction is a complex behavioral disorder that has been extensively studied in an attempt to uncover its underlying biological mechanisms. This paper contributes to the literature on addiction by demonstrating that addiction is a result of an improperly functioning decision making process. The areas of the brain that are most implicated in decision making demonstrate significant overlap with those areas most affected by addiction. Specifically, the limbic structures of the brain (amygdala, basal ganglia, and mesolimbic reward pathway) and the prefrontal cortices (orbitofrontal cortex, dorsolateral prefrontal cortex, and ventromedial prefrontal cortex) are discussed in relation to their involvement in prominent theories of decision making such as Prospect Theory and the Somatic Marker Hypothesis. This paper will then use the above knowledge regarding the specific brain mechanisms that control decision making and apply it to neurobiological theories of addiction. The view that addiction is a behavioral disorder that results primarily from a degradation of the brain mechanisms involved in decision making processes is important to consider because it can help provide a concrete approach to developing more individualized and effective treatment programs in the future.

Studying protein-protein interactions has been vital for understanding how proteins function within the cell, how biological processes are strictly regulated by these interactions, and what molecular mechanisms underlie cellular functions and diseases. Recent biochemical and biophysical studies have provided evidence supporting that G protein-coupled receptors (GPCRs) can and do interact with one another to form dimers or larger oligomeric complexes, which may determine the structure and function of GPCRs, including receptor trafficking, scaffolding and signaling. This may help to understand the physiological roles of GPCRs and mechanisms underlying certain disease pathologies and to provide an alternative approach for drug intervention.<p>Cannabinoid CB1 and dopamine D2 receptors are the most common GPCRs in the brain and exert a mutual regulation in brain functions involved in learning, memory and drug addiction. There is structural and functional evidence supporting the idea that CB1 and D2 receptors physically interact with each other in hippocampal and striatal neurons to modulate their functions. Direct evidence supporting a physical interaction between the CB1 and D2 receptors was obtained from cultured HEK293 cells stably coexpressed with both receptors.<p> This research project was designed to critically test the hypothesis that a specific protein sequence (i.e. motif) in the D2 receptor is responsible for in vitro protein-protein interactions between the CB1 and D2 receptors. To reach this goal, fusion proteins containing various domains and motifs of the CB1 and D2 receptors were prepared and then used first to determine the domains of the CB1 and D2 receptors responsible for in vitro protein-protein interactions between CB1 and D2 receptors, and then to identify the specific motifs in the D2 receptor responsible for in vitro CB1 coupling with the D2 receptors. The major method used in this study is in vitro pull-down assay, which uses a purified and tagged bait protein to generate a specific affinity support that is able to bind and purify a prey protein from a lysate sample. The present study provides the first evidence that CB1 intracellular C-terminal (CB1-CT) and D2 intracellular loop 3 (D2-IL3) can directly interact with each other, and that the specific motifs D2-IL3(Ⅳ1) and D2-IL3(Ⅳ3) in the D2 receptor are likely responsible for their in vitro coupling with the CB1 receptors. <p>The results of the present study are invaluable for future research exploring in vivo protein-protein interaction between the CB1 and D2 receptors in the rat striatum by co-immunoprecipitation. Specifically, future studies will determine whether the identified specific motifs D2-IL3(Ⅳ1) and D2-IL3(Ⅳ3) in the D2 receptor are indeed critical for their in vivo coupling with the CB1 receptors.

The thesis examines Thomas De Quincey’s opium use as a product of social strain. De Quincey’s collection of work provides evidence that he felt alienated from society prior to his addiction and that his feelings of inadequacy contributed to his dependence on drugs. Utilizing Robert K. Merton’s strain theory, this thesis delineates De Quincey’s aspirational references and perceived failures through an examination of his imagery and interprets his perceptions of human life as a catalyst for his compulsions to cope with opium. De Quincey, strained by the aspirations of an industrial and imperialistic society, looked for several avenues of escape. The Romanticism of William Wordsworth presented De Quincey with a method for alleviating social strain; however, when De Quincey failed to discover the transcendence evident in Lyrical Ballads he turned to the intoxicating effects of opium and retreated from English society.

Studying protein-protein interactions has been vital for understanding how proteins function within the cell, how biological processes are strictly regulated by these interactions, and what molecular mechanisms underlie cellular functions and diseases. Recent biochemical and biophysical studies have provided evidence supporting that G protein-coupled receptors (GPCRs) can and do interact with one another to form dimers or larger oligomeric complexes, which may determine the structure and function of GPCRs, including receptor trafficking, scaffolding and signaling. This may help to understand the physiological roles of GPCRs and mechanisms underlying certain disease pathologies and to provide an alternative approach for drug intervention.<p>Cannabinoid CB1 and dopamine D2 receptors are the most common GPCRs in the brain and exert a mutual regulation in brain functions involved in learning, memory and drug addiction. There is structural and functional evidence supporting the idea that CB1 and D2 receptors physically interact with each other in hippocampal and striatal neurons to modulate their functions. Direct evidence supporting a physical interaction between the CB1 and D2 receptors was obtained from cultured HEK293 cells stably coexpressed with both receptors.<p> This research project was designed to critically test the hypothesis that a specific protein sequence (i.e. motif) in the D2 receptor is responsible for in vitro protein-protein interactions between the CB1 and D2 receptors. To reach this goal, fusion proteins containing various domains and motifs of the CB1 and D2 receptors were prepared and then used first to determine the domains of the CB1 and D2 receptors responsible for in vitro protein-protein interactions between CB1 and D2 receptors, and then to identify the specific motifs in the D2 receptor responsible for in vitro CB1 coupling with the D2 receptors. The major method used in this study is in vitro pull-down assay, which uses a purified and tagged bait protein to generate a specific affinity support that is able to bind and purify a prey protein from a lysate sample. The present study provides the first evidence that CB1 intracellular C-terminal (CB1-CT) and D2 intracellular loop 3 (D2-IL3) can directly interact with each other, and that the specific motifs D2-IL3(Ⅳ1) and D2-IL3(Ⅳ3) in the D2 receptor are likely responsible for their in vitro coupling with the CB1 receptors. <p>The results of the present study are invaluable for future research exploring in vivo protein-protein interaction between the CB1 and D2 receptors in the rat striatum by co-immunoprecipitation. Specifically, future studies will determine whether the identified specific motifs D2-IL3(Ⅳ1) and D2-IL3(Ⅳ3) in the D2 receptor are indeed critical for their in vivo coupling with the CB1 receptors.

The mesolimbic dopamine system, including dopaminergic projections from the ventral tegmental area (VTA) to nucleus accumbens (NAc), is critically involved in the development of addiction to many drugs of abuse, including cocaine (CA). Although there is an attractive hypothesis that the modifications of mesolimbic reward circuit following repeated drug exposure are responsible for cocaine-addicted causes behaviors change, however, our understanding in the underlying molecular mechanisms at the neural circuit level is still in its infancy. It has been suggested PKMzeta, a constitutively active atypical isoform of PKC, plays a critical role in spatial memory formation and long-term synaptic potentiation in hippocampus. To define the relationship among PKMzeta, CA-induced synaptic long-term potentiation and CA addiction, we examined the regulation of PKMzeta after CA administration in Sprague-Dawley rat. We found single CA injection elicits an increase in PKMzeta protein expression in the VTA region. The increase was first observed 10 min after CA administration and lasted for 7 days, the longest sampling time point of our experimental design. The PKMzeta protein expression can also be induced in 10 minutes while incubating the acute isolated brain slice with CA, the expression within 1 hr can be eliminated at the present of Chelerythrine (PKC inhibitor) and ZIP (PKMzeta inhibitor) suggests a positive feedback loop. The PKMzeta mRNA expression can be induced within 1 hr, and Actinomycin d (transcription inhibitor) had no effect on the PKMzeta protein expression indicating CA increases PKM£a translation from preexisting PKM£a mRNA. Furthermore,real time PCR-based analysis showed resembling increase profile ofPKM£a mRNA after single CA injection, suggesting a co-upregulation of transcription and translation of PKM£a after CA administration in VTA. Eticlopride (dopamine receptor D2-subtype antagonist) ¡BSCH-23390(dopamine receptor D1-subtype antagonist)¡BH-89 (PKA inhibitor)¡B Wortmannin (PI3K inhibitor)¡BPD98059 (MEK1 inhibitor) decreasedcocaine-induced PKM£a expression within 1 hr in VTA. On the contrary, KN-62 (CaMK II inhibitor) has no obvious effect on PKM£a expression. CA challenge not only induces the PKM£a expression in the VTA region but also in the NAc and hippocampus region. The CA-induced PKM£a expression is more obvious in elder group (>45 days in age) than younger group (18~30 days in age), similar results also showed in the locomotor activity assay. Prenatal CA exposure decreased the postnatal CA-induced PKM£a expression and the locomotor sensitivity in younger group. Overall, results from our current experiments have raised the possibility of PKM£a involvement in CA addiction. How CA regulates PKM£a expression and the context dependence between PKM£a and CA-induced behavior change and synaptic long-term potentiation remains further elucidation.

The abuse of stimulant drugs, such as methamphetamine (METH), has become a major source of public concern in New Zealand. Specific medications for treating METH addiction are not available at present. The newly discovered trace amine- associated receptor 1 (TAAR1) constitutes a novel receptor target for medication development in neuropsychiatry. TAAR1 regulates monoamine systems in the brain, especially dopamine, and is activated directly by psychomotor stimulants, including METH. This study examined the effects of the newly developed TAAR1 partial agonist, RO5203648, in rat models of METH abuse. In experiment 1 rats were administered different doses of RO5203648 (0, 1.67, 5mg/kg i.p.) followed by METH (0, 0.75, 2mg/kg i.p.). Locomotor activity was monitored via automated video tracking system in an open field. The results revealed that RO5203648 dose- dependently reduced acute METH-induced stimulation and prevented long-term sensitization following chronic exposure. Paradoxically, in experiment 2, RO5203648 and METH treatment increased c-Fos protein expression in the nucleus accumbens and dorsal striatum. In experiment 3 rats were trained to consistently self-administer METH (0.5mg/kg/infusion) and were then pre-treated with RO5203648 (0, 3, 10mg/kg i.p.). The data showed that RO5203648 drastically reduced METH intake. Next, RO5203648 was substituted (0.25, 0.5, 1.0 mg/kg/infusion) for METH in the same paradigm. Remarkably, RO5203648 exhibited no reinforcing efficacy compared with METH. Taken together, these observations showed that RO5203648 is able to attenuate METH-related behaviours, including locomotor stimulation, sensitization and self-administration, and highlight the great potential of TAAR1-based medications for the treatment of METH addiction.

published_or_final_version / Public Administration / Master / Master of Social Sciences

Darbo pavadinimas: 10 – 12 klasių mokinių gyvenančių namuose su tėvais ir globos namuose požiūris į narkotines medžiagas. Darbo objektas: Kauno rajono vidurinių mokyklų 10 – 12 klasių mokinių gyvenančių namuose su tėvais ir globos namuose nuomonės apie narkotines medžiagas ir jų vartojimą. Tyrimo tikslas: Išsiaiškinti 10 – 12 klasių mokinių gyvenančių namuose su tėvais ir globos namuose turimas žinias apie narkotines medžiagas bei atskleisti, kiek turimos žinios lemia narkotinių medžiagų vartojimą. Darbo uždaviniai: 1. Išsiaiškinti 10 – 12 klasių mokinių gyvenančių namuose su tėvais ir globos namuose turimas žinias apie narkotines medžiagas ir jų poveikį sveikatai. 2. Nustatyti 10 – 12 klasių mokinių gyvenančių namuose su tėvais ir globos namuose požiūrį į narkotinių medžiagų vartojimą. 3. Išsiaiškinti 10 – 12 klasių mokinių gyvenančių namuose su tėvais ir globos namuose asmeninę patirtį vartojant narkotines medžiagas. Darbo metodai: 1. Mokslinės literatūros analizė. 2. Anketinė apklausa. Respondentams buvo pateikta A. Zaborskio, L. Šumskio, N. Žemaitienės tyrime (2009) naudota anketa. 3. Statistinė analizė. Atsakymų pasiskirstymas pateiktas procentais. Naudotas Chi – kvadrato kriterijus, reikšmingumui tarp 10 – 12 klasių. mokinių atsakymų skirtumui nustatyti. Jei p<0,05 – skirtumas tarp atsakymų pasiskirstymų statistiškai reikšmingas, o jei p>0,05 – skirtumas tarp atsakymų pasiskirstymų statistiškai nereikšmingas Hipotezė: Kauno rajono 10 – 12 klasių mokinių... [toliau žr. visą tekstą] / The approach to drugs of 10th – 12th high schools students living at home with their parents and home care Object of a research: Approach to drugs and application of Kaunas area 10th -12th high schools students living at home with theirs parents and home care. Goal of a research: Figure 10th – 12th high school students living at home with his parents and home care available knowledge about drugs and to reveal the extent of available knowledge leads to drug use. Tasks of a research: 1. Figure 10th – 12th high schools students living at home with his parents and home care available knowledge about drugs and their effects on health. 2. Analyze the approach to drugs use of 10th – 12th high schools students living at home with his parents and home care. 3. Investigate personal experience with drugs of of 10th – 12th high schools students living at home with his parents and home care. Hypothesis: 10th – 12th high school students living at home with his parents and home care knowledge about drugs is associated with drugs use and distribution of Kaunas area schools. Methods of a research: 1. Analysis of scientific literature. 2. Questionnaire. Respondents were given A. Zaborskis, L. Šumskis, N. Žemaitienė investigation (2009) used questionnaire. 3. Statistical analysis. The distribution of responses by percentage. Used Chi – square criterion, the significance of between 10th – 12th high school students responses to determine the difference. If p<0,05 – the difference between... [to full text]

The Downtown Eastside of Vancouver is one of the city’s oldest neighbourhoods and one of Canada’s poorest. Once home to city hall and a bustling entertainment district, this neighbourhood has slowly been overtaken by an open drug market. With many individuals in this area without permanent residence, temporary shelters have become a refuge for the homeless. As a response to the need for permanent housing in this area, this thesis explores the role of architecture in housing the homeless, specifically those who suffer from drug addiction. Building on precedents of mixed use affordable housing programs in Canada and the U.S., this project focuses on ways of facilitating services and activities that seek to improve the quality of life for the disenfranchised.