Since the Bretton Woods System collapsed, the volatility of the exchange rate return has been an important and concerned issue in financial domain. The purpose of this paper is to investigate the empirical relevance of stricture breaks for the volatility of the exchange rate return, and we use both in-sample and out-of-sample tests. GARCH(1,1) Model is considered to be the representative quantitative method for analyzing the volatility of asset returns, as a result, we picked GARCH(1,1) as natural benchmarks in this article. In addition, we cogitated the structure breaks in this paper, and used ICSS(Iterated Cumulative Sums of Squares) algorithm to test the points of structural breaks. The results of empirical analysis show that there are significant evidences of structural breaks in the unconditional variance for six of eight US exchange rate return series, which implying unstable GARCH processes for these exchange rates. We also find those competing models that accommodating structural breaks will have higher predictive ability. Pooling forecasts from different models that allow for structural breaks in volatility appears to offer a reliable method for improving volatility forecast accuracy given the uncertainty surrounding the timing and size of the structural breaks.

Although it is well-established that animals will self-stimulate electric current to various diverse brain structures, the neural substrate of brain stimulation reward (BSR) has eluded identification since its discovery more than a half-century ago. We show that GABA neurons in the midbrain, hypothalamus and thalamus express connexin-36 (Cx36) gap junctions and couple electrically with dopamine application or by stimulation of the internal capsule (IC), which also supports self-stimulation. The threshold for responding for self-stimulation of the IC is the threshold for coupling between these GABA neurons, the degree of responding for IC ICSS is proportional to the magnitude of electrical coupling between these GABA neurons, and GJ blockers, including the Cx36 blocker mefloquine, increase the threshold for IC self-stimulation without affecting performance. Thus, electrical coupling between this network of GABA neurons fits the prevailing model for the elusive integrator of BSR.

The noncompetitive NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in patients suffering from major depressive disorder. However, abuse liability is a concern. To further evaluate the relationship between antidepressant-like and abuse-related effects of NMDA receptor antagonists, this study evaluated the effects of ketamine, MK-801, and phencyclidine in male Sprague-Dawley rats responding under two procedures that have been used to assess antidepressant-like effects [differential-reinforcement-of-low-rate (DRL) 72 s schedule of food reinforcement] and abuse-related drug effects [intracranial self-stimulation (ICSS)]. Under DRL 72 s, ketamine produced an antidepressant-like effect by increasing reinforcers, decreasing responses, and producing a rightward shift in the peak location of the interresponse time (IRT) distributions. Phencyclidine produced a modest antidepressant-like effect by increasing reinforcers and decreasing responses, but did not shift the IRT distributions. In contrast, MK-801 produced a psychostimulant-like effect by decreasing reinforcers, increasing responses, and producing a leftward shift in the peak location of the IRT distributions. The antidepressant-like effects of ketamine on the DRL 72 s procedure do not appear to be mediated by inhibiting the reuptake of serotonin via serotonin transporters or antagonism of 5-HT2 receptors. Additionally, the dissociable effects of ketamine and MK-801 in the DRL 72 s procedure may be mediated by 5-HT2 receptors. Following acute administration, ketamine produced only dose- and time-dependent depression of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. In contrast, MK-801 and phencyclidine effects produced dose- and time-dependent facilitation of ICSS by MK-801. Taken together, our findings provide further evidence that expression of these antidepressant-like and abuse-related effects of ketamine, phencyclidine, and MK-801 may be related to NMDA receptor affinity.

Methcathinone (MCAT) is the β-ketone analog of methamphetamine, and like its amphetamine analog, MCAT functions as a monoamine releaser that selectively promotes the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). MCAT produces amphetamine-like psychostimulant effects and is classified as a Schedule I drug of abuse by the United States Drug Enforcement Administration (DEA). Recently, synthetic MCAT analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like “bath salts” in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse display varying selectivity to promote release of DA/NE vs. 5-HT, and selectivity for DA neurotransmission is believed to correlate with abuse liability. The goal of this dissertation was to conduct preclinical research to examine structural determinants of abuse-related behavioral and neurochemical effects produced by a series of synthetic MCAT analogs. Specifically, this project focused on one feature of the methcathinone scaffold: the para substituent of the benzene ring. A series of six novel MCAT analogs will be examined to evaluate how physicochemical parameters (steric, Es; electronic, σp; lipophilic, πp) of the para substituent influence in vitro monoamine transporter selectivity as well as in vivo neurochemical and behavioral effects. Results from this body of work implicate steric factors as being particularly important in determining a compound’s abuse-related neurochemical and behavioral effects. Thus, these data not only offer an improved understanding of the mechanism of abuse-related drug effects produced by synthetic MCAT analogs, but also help in the generation of homology models of the human DA and 5-HT transporters (DAT and SERT, respectively).

Cannabinoid agonists, including marijuana containing delta-9-tetrahydrocannabinol (THC), are found rewarding by humans. In addition to human self-reports and experimental studies that show marijuana is rewarding, contributions from preclinical studies also have implicated cannabinoid receptors in reward-motivated behavior. One way to assess these preclinical effects of cannabinoids is intracranial self-stimulation (ICSS), where an animal performs a response to receive electrical stimulation of a specific brain area or circuit known to be involved in reward. Drugs of abuse, such as psychomotor stimulants, facilitate responding for ICSS. While a few studies have shown facilitating effects of cannabinoids in rats, several have shown the opposite effect, and no studies so far have evaluated cannabinoids in mouse ICSS. Furthermore there are no studies evaluating specific inhibitors of endocannabinoid catabolic enzymes in ICSS in any species. In these studies we assessed the cannabinoid agonist THC, as well as the fatty acid amide hydrolase (FAAH) inhibitor, PF-3845, the monoacylglycerol lipase (MAGL) inhibitor JZL184, and the combined FAAH/MAGL inhibitor SA-57 in ICSS of the medial forebrain bundle in C57BL/6 mice. Additionally, we assessed the psychomotor stimulant cocaine as a positive control to facilitate ICSS. These studies were complimented with spontaneous locomotor activity and food-maintained operant experiments to assess the sensitivity of ICSS to cannabinoids. Additionally, brain endocannabinoid levels were measured in brain regions associated with the mesolimbic system after enzyme inhibitor treatments. THC, JZL184, and SA-57 all produced time-dependent reductions in ICSS that were mediated through CB1 receptors, as they were blocked by pre-treatment with the CB1 antagonist rimonabant, but not with the CB2 antagonist SR144528. PF-3845 also reduced ICSS, but did so independent of CB1 and CB2 receptors, and only with one dose (30.0 mg/kg) that has not been assessed previously in vivo. We showed that ICSS was more sensitive to the rate-reducing effects of cannabinoids than other measures of behavior with motor components including spontaneous locomotor activity and operant nose-poking for food, and that the reduction of ICSS produced by both JZL184 and SA-57 is accompanied by increases in 2-AG in mesolimbic brain areas. Thus, cannabinoids do not facilitate ICSS in C57BL/6 mice over a range of doses and pre-treatment times, similar to most studies with rats. These data suggest that cannabinoids may produce rewarding effects through non-mesolimbic areas of the brain.

No description available.

Inhalants are a loosely defined diverse group of volatile substances which people abuse. Despite widespread misuse of inhalants, there are limited preclinical methods available to study the reinforcement-like properties of inhalants. One procedure which has demonstrated substantial promise as a tool to investigate inhalant pharmacology is the intracranial self-stimulation (ICSS) procedure. ICSS utilizes pulses of electrical stimulation to the mesolimbic reward pathway to serve as a temporally defined and controlled operant reinforcer with a highly adjustable efficacy. The first aim of the project was to characterize the effects of commonly abused inhalants: including toluene, trichloroethane, nitrous oxide, isoflurane and R134a in ICSS. The second aim was to attenuate inhalant-facilitated ICSS by utilization of compounds which would attenuate the pharmacological actions of toluene on GABAA receptors. The low efficacy benzodiazepine negative modulator Ro15-4513 significantly attenuated the ability of toluene to facilitate ICSS without itself significantly altering baseline ICSS responding. Pretreatment with Ro15-4513 also attenuated methamphetamine ICSS even though there is no evidence of methamphetamine interacting with GABAA receptors. Given these unexpected results, I employed a microdialysis procedure to examine the effect of Ro15-4513 on methamphetamine stimulated dopamine release in the nucleus accumbens. Pretreatment with Ro15-4513 significantly attenuated methamphetamine stimulated dopamine release while having a negligible effect on dopamine release when administered alone. These results suggest that a modest level of benzodiazepine-site negative modulation can reduce the reinforcement enhancing effects of abused drugs regardless of their primary mechanism of action through allosteric modulation of GABAergic neurons within the mesolimbic pathway. Further, these results may have implications for expanding the examination of GABAA negative modulator medications beyond those trials currently being conducted with alcohol. Finally, the effects of chronic intermittent toluene exposure on ICSS and nesting behaviors were examined. Subjects were systemically exposed to air, chronic intermittent toluene (CIT), or escalating chronic intermittent (ECIT) toluene for 15 min at 3300 PPM toluene vapor per exposure. The results show that ECIT resulted in decreased overall responding in ICSS relative to air control and showed a tolerance-like effect to facilitatory effects of 3300 ppm toluene during ICSS compared to CIT group. These results indicate that escalating use of toluene produces reductions in its reward-like effects and may contribute to escalation to other drugs of abuse.