Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.

In this field study, 103 individuals from two different music festivals, one in California and one in Michigan, were surveyed to observe current attitudes surrounding harm reduction strategies associated with psychedelic drug usage in the EDM scene. Topics from the survey included but were not limited to the chemical testing of substances, frequency of usage, spacing between usage, and adverse effects associated with usage. It was concluded that harm reduction education should become more integrated within the EDM scene in order to provide research-based evidence for ravers to make better decisions for their health. While authorities have pushed "just say no", the lack of education altogether in the community is life threatening. Education is the key to saving minds, bodies, and lives.

Abstract Cocaine is highly addictive because it exacerbates the action responsible for creating the feeling of "reward," which is controlled by the neurotransmitter dopamine. Dopamine receptors can be divided into five subtypes: D1, D2, D3, D4, and D5. The localization of D3 receptors is restricted to the mesolimbic pathway, which is often called the "reward pathway." This pathway is associated with emotions, motivation, and behavior. There is evidence that these receptors are upregulated in response to the repeated use of psychostimulants, such as cocaine, making these receptors a potential target for pharmaceutical therapeutics for drug addiction. In the present study, two compounds selective for D3 receptors, MC-250041 and LS-3-134, were examined for their effects on spontaneous and cocaine-primed locomotor activity. The present study also aimed to examine the effects of MC-250041 and LS-3-134 on the number of lever presses and infusions under a progressive ratio (PR) schedule when subjects are trained to self-administer cocaine within an operant conditioning chamber. Based on the present research on D3 receptor compounds and D3Rs, I hypothesized that pretreatment with MC-250041 or LS-3-134 decreases cocaine self-administration under a progressive ratio (PR) schedule of cocaine reinforcement at doses that would have no effect on locomotor activity. The results showed no significant effects on spontaneous or cocaine-primed locomotor activity following an injection of MC-250041 (1, 3, 5.6 mg/kg IP). Similarly, there was no change in the amount of lever presses or drug infusions within an operant conditioning chamber at any of the examined doses of MC-250041 (3, 5.6, 10 mg/kg IP) during self-administration. LS-3-134 decreased cocaine-primed locomotor activity, as well as lever presses and infusions during self-administration at the 5.6 mg/kg dose; however, there was no effect on spontaneous locomotor activity at any of the examined doses (1, 3.2, 5.6 mg/kg IP). In conclusion, the results of the study suggest that LS-3-134 effectively reduced motivation for cocaine at the 5.6 mg/kg dose; whereas, MC-250041 was unsuccessful at warranting any significant effect on motivation for cocaine at any of the examined doses.

In recent years the abuse of synthetic cathinones, "Bath Salts," has increased. The purpose of this study was to analyze two synthetic cathinones, methylone and α-pvp, for hedonic properties or the potential to be abused. This was tested using an intracranial self-stimulation paradigm, a robust measurement for reward. It was found methylone resulted in an abuse potential similar to MDMA, ecstasy, abuse. Moreover, the results for α-pvp showed a high liability for abuse.

This creative project explores the trend of designer/synthetic drug use in Arizona and nationwide. The project serves as "gap research" - bringing to light the problem of limited use statistics and constantly-changing drug chemical compounds. The project was thoroughly researched using media reports, psychology/drug addiction experts, community education organizers and available healthcare statistics. The results provided not definitive answer other than that more work needs to be done in the area of synthetic drug use. Parents and youth must educate themselves on the dangers of using these "legal" drugs.

Menopause is reproductive senescence characterized by a loss of ovarian estrogen and progesterone. Women can experience cognitive decline and other negative symptoms with the loss of ovarian hormones (Sherwin, 2006). While hormone therapies (HT) can treat symptoms of menopause and may have neuroprotective properties, such as the potential to decrease the risk of Alzheimer's Disease (Behl & Manthey, 2000), there are many effects of current HTs that are not ideal. Indeed, optimizing conventional HTs has proven complex, indicating a need for alternative therapies. Phytoestrogens are estrogenic compounds found naturally in plants such as soybeans, that could provide new treatment options. Dietary phytoestrogens can benefit memory in the rodent model (Luine, 2006), although the mechanism underlying these effects is unclear. Basal forebrain cholinergic projections have been shown to mediate the cognitive benefits of estrogen (Gibbs, 2010); we hypothesize that phytoestrogens act similarly, via the cholinergic system, to impact memory. We administered varying doses of phytoestrogen-containing diets to ovariectomized female rats, and used the place recognition task to evaluate spatial memory. Brains were then analyzed for choline acetyltransferase (ChAT), the synthesizing enzyme for acetylcholine, in the vertical-diagonal bands (VDB) and the medial septum (MS) of the basal forebrain. Results showed that ChAT cell counts in the VDB were marginally higher with dietary phytoestrogen treatment. Further, VDB ChAT cell counts positively correlated with place recognition performance, indicating that animals with more VDB ChAT neurons exhibited better spatial memory performance. These results suggest that phytoestrogens might act similarly to natural, endogenously circulating estrogens, and identify phytoestrogens as a direction for investigation as a HT.

ADHD is a childhood neurobehavioral disorder characterized by inordinate levels of hyperactivity, inattention and impulsivity. The inability to withhold a reinforced response, or response inhibition capacity (RIC), is one aspect of impulsivity associated with ADHD. The first goal of this dissertation was to evaluate the fixed minimum interval (FMI) schedule as a method for assessing RIC. Chapter 2 showed that latencies were substantially more sensitive than FMI-derived estimates of RIC to the effects of pre-feeding and changes in rate and magnitude of reinforcement. Chapter 3 examined the ability of the FMI to discriminate between spontaneously hypertensive rats (SHR), an animal model of ADHD, and Wistar Kyoto (WKY) controls. Results from Chapter 3 showed that RIC was not substantially different between SHR and WKY rats. However, latencies were significantly shorter for SHRs than for WKYs suggesting incentive motivation differed between strains. The second goal of this dissertation was to examine the sensitivity of the SHR to nicotine. ADHD is a risk factor for tobacco dependence. The goal of Chapters 4 and 5 was to determine whether the SHR provided a model of ADHD-related tobacco sensitivity. Chapter 4 examined nicotine's locomotor and rewarding effects in adolescent SHRs using the conditioned place preference (CPP) procedure. SHRs developed CPP to the highest nicotine dose tested and were sensitive to nicotine's locomotor-enhancing properties. WKY controls did not develop CPP to any nicotine dose tested and were not sensitive to nicotine's locomotor properties. However, it is likely that nicotine effects were obscured by a pseudo-conditioning to saline in WKYs. Chapter 5 demonstrated that SHRs were more active than WKYs in the open-field but not in the Rotorat apparatus. Results also showed that SHRs and WKYs were both sensitive to nicotine's locomotor sensitizing effects. However, WKYs were more sensitive than SHRs to nicotine's locomotor suppressing effects. Collectively, results from Chapters 4 and 5 show that SHRs are sensitive to the rewarding and locomotor-enhancing properties of nicotine. However, more research is necessary to confirm that SHRs are a suitable model for studying ADHD-related tobacco use.