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Ghrelin is a 28 amino acid peptide that interacts with ghrelin receptors (GHS-Rs) to modulate brain reinforcement circuits. Systemic ghrelin infusions augment cocaine (COC) stimulated locomotion and conditioned place preference (CPP) in rats, whereas genetic or pharmacological ablation of GHS-Rs has been shown to attenuate the acute locomotor-enhancing effects of nicotine (NIC) and COC, and to blunt the CPP induced by food, alcohol, amphetamine and COC in mice. The stimulant NIC can induce CPP and like COC, repeated administration of NIC induces locomotor sensitization in rats. In experiment 1, we examined the effects of GHS-R antagonism with JMV 2959 on COC-induced locomotion and found that JMV 2959 suppresses COC-induced locomotor sensitization. In experiment 2, we examined the effects of GHS-R antagonism with JMV 2959 on NIC-induced locomotion and found that JMV 2959 suppresses NIC-induced locomotor sensitization. In experiment 3, we examined the effects of GHS-R knockout on COC-induced locomotion and found that animals sustaining GHS-R knockout display a suppression of COC-induced locomotor sensitization. In experiment 4, we examined the effects of GHS-R knockout on COC-induced locomotion and found that animals sustaining GHS-R knockout display a suppression of COC-induced locomotor sensitization. In experiment 5, we examined the effects of JMV 2959 on NIC-enhanced intracranial self-stimulation (ICSS) responding and found that JMV 2959 alone had no effect, but when combined with NIC,JMV 2959 pretreatment reversed the enhancement of responding produced by NIC. In experiment 6, we examined the effects of GHS-R knockout on ICSS responding and found that animals sustaining GHS-R knockout were unable to acquire ICSS at current intensity levels that would support responding by WT animals. It was not until the intensity was ramped up four fold that these knockout rats were able to acquire responding. These results show that antagonism of GHS-Rs diminishes the reinforcing effects of NIC and COC. This provides evidence that antagonists of GHS-Rs could be useful in the treatment of drug addiction, particularly that involving nicotine.

Thesis (M.A. in Security Studies (Western Hemisphere))--Naval Postgraduate School, June 2008. / Thesis Advisor(s): Giraldo, Jeanne ; Berger, Marcos. "June 2008." Description based on title screen as viewed on August 27, 2008. Includes bibliographical references (p. 67-72). Also available in print.

Thesis (M.S.)--University of Alabama at Birmingham, 2010. / Title from PDF t.p. (viewed July 19, 2010). Includes bibliographical references (p. 35-36).

Thesis (Ph. D.)--Washington State University, August 2007. / Includes bibliographical references.

Thesis (M.A.)--Boston University / Cocaine use among opioid dependent persons is common, with an estimated 40 to 70% of those seeking treatment for opioid dependence, also using cocaine (Sullivan et al., 2011 ). The effects of cocaine use on treatment outcomes for those seeking medication assisted treatment (MAT) for opioid dependence are not well understood. Buprenorphine, prescribed under the brand name Suboxone, has recently emerged as a convenient, effective method of MAT. The Facilitated Access to Substance Abuse Treatment with Prevention And Treatment of HIV (FAST PATH) program at Boston Medical Center, is a research study to provide substance abuse treatment along with primary care and HIV risk-reduction counseling to those afflicted with these epidemics. The objective of this study was to determine the association of cocaine use with treatment retention and opioid abstinence at six months for patients receiving buprenorphine in the FAST PATH program. A prospective cohort study was conducted on 116 patients enrolled in the FAST PATH program through 02/01/2012. Assessments were conducted at baseline and six months to evaluate the association between baseline cocaine use and treatment retention as well as opioid abstinence at six months. Baseline cocaine use was measured by either any urine toxicology screen positive for cocaine prior to study enrollment or 30 day self-reported cocaine use on the initial assessment. Of the 116 participants, 39% were positive for cocaine use at baseline and 52% were HIV positive. Baseline cocaine use had no effect significant on treatment retention or opioid abstinence at six months. Among all the participant characteristics measured, there were no significant differences between the cocaine positive (n=45) and cocaine negative (n=71) groups. In adjusted analysis, age was the only covariate which was significant at predicting the odds of treatment retention or opioid abstinence with a 1.11 (p-value = 0.0003) and 1.08 (p-value = 0.02) greater odds of each, respectively. Although cocaine use did not affect the dependent variables, integrated substance abuse and primary care clinics utilizing buprenorphine are a rich area of future research. Specifically, subsequent studies should determine how varied groups of opioid dependent persons perform within this framework, and the underlying characteristics moderating their outcomes.

Drug toxicity may cause liver injury, resulting in damage to cells and tissues. This damage can lead to cytotoxic events that may result in an activation of poly (ADP-ribose) polymerase (PARP). A study was conducted to determine if cocaine and acetaminophen toxicity lead to DNA damage and to the activation of the repair protein, PARP in the liver using the hepatotoxicants: cocaine and acetaminophen (APAP). A dose-response analysis for cocaine concluded that a dose as low as 20 mg/kg resulted in elevated ALT levels. A higher dose of 60 mg/kg was tested for analyses but resulted in severe hemorrhaging. The dose-response analyses for APAP resulted in no elevated liver enzyme levels for a 75 mg/kg and 150 mg/kg dose. A dose of 50 mg/kg for cocaine, and a dose of 300 mg/kg for APAP were used to analyze temporal trends for both toxicants. Both cocaine and APAP produced incremental increases in ALT at the 2 hour, 6 hour, 18 hour, and 24 hour time points, respectively. PARP activity analysis for cocaine measured the highest activity at the 2hr and 6hr time points. PARP analysis for acetaminophen measured gradual increases until the 18 hour time point where the highest level of PARP activity was measured. A PARP inhibition analysis was conducted with cocaine and (APAP) to understand the impact of a PARP inhibitor, 1,5-dihydroxyisoquinoline (DIQ), on PARP activity in the liver. A 50 mg/kg dose of cocaine or a 300 mg/kg dose of APAP was administered, followed by a 10 mg/kg dose of DIQ at 1) the time of initial toxicant dose (0 hour), or 2) 1 hour after initial toxicant dose (1hr). The PARP inhibition analysis for cocaine and APAP was conducted at 6 and 18 hours post initial dose, respectively, when the highest levels of PARP were observed. Inhibition analyses determined that ALT declined significantly when DIQ was administered immediately following the initial toxicant dose for both toxicants. DIQ administered 1 hr after initial toxicant dose resulted in slightly higher ALT than the 0 hr time point. Decreases in PARP activity were observed at the 0 hr time point, with slightly higher PARP levels observed at the 1 hr time point. Decreased PARP activity was observed following DIQ treatment with both, a concurrent drug treatment and treatment following drug administration. Cocaine and APAP treatment did not cause DNA fragmentation. A liver glutathione (GSH) analysis conducted for cocaine and APAP did not correlate with DIQ alteration of PARP activity. The mechanism of DIQ effects on drug-induced hepatotoxicity appears to be GSH independent. DIQ was effective in reducing drug-induced hepatotoxicity and preserving organ function.

Cocaine is a powerfully active psychostimulant which exerts its effects through blockade of dopamine, serotonin and norepinephrine transporters and resultant increases in extracellular levels of these neurotransmitters. Much of the focus on cocaine abuse in the literature has been directed towards study of the dopamine system; however, several studies have identified a role for the serotonin system in regulating the rewarding effects of cocaine as well. Specifically, the serotonin 2C (5-HT2C) receptor regulates cocaine-induced alterations in serotonin and dopamine levels in an inhibitory manner, and 5-HT2C receptor agonist treatment attenuates cocaine-induced behaviors like self-administration. In the first aspect of the current thesis study, the effects of activation of 5-HT2C receptors on cocaine-induced conditioned place preference and behavioral sensitization were assessed. It was found that pretreatment with a 5-HT2C receptor agonist, Ro 60-0175, on cocaine (10 mg/kg) conditioning days of the conditioned place preference paradigm, attenuated the development of conditioned place preference in a dose-dependent manner. These results suggest that activation of 5-HT2C receptors inhibits the euphoric effects elicited by cocaine. Behavioral sensitization studies demonstrated that pretreatment with Ro 60-0175 prior to cocaine (10 mg/kg) over a 5 day period attenuated cocaine-induced hyperactivity. When injected with a cocaine challenge injection 10 days after the last cocaine injection, mice pretreated with Ro 60-0175 demonstrated lower levels of locomotor activity as compared to saline pretreated, cocaine-injected mice. This portion of the first study demonstrated that 5-HT2C receptor activity attenuated acute cocaine-induced conditioned reward, hyperactivity and the development of long-term alterations of cocaine exposure, as measured by behavioral sensitization. The second aspect of the current study focused on the regulation of anxiety produced by withdrawal from chronic cocaine administration. Anxiety during cocaine withdrawal is a component of the negative affective state often experienced by cocaine-dependent individuals during abstinence from drug use. Anxiety during cocaine withdrawal is likely to increase an individual's susceptibility to relapse to drug use in alleviation of this negative symptom. Studies have shown a downregulation of the serotonin and dopamine systems during withdrawal that potentially contributes to anxiety symptoms. As the 5-HT2C receptor exerts inhibitory control over both the serotonin and dopamine systems, it was hypothesized that blockade of 5-HT2C receptors would attenuate anxiety-like behavior during cocaine withdrawal. Previous studies have identified co-localization of 5-HT2C receptors on inhibitory gamma-aminobutyric acid (GABA) neurons, thus it was hypothesized that a 5-HT2C receptor-GABA mediated mechanism would be involved in the regulation of anxiety during withdrawal. The dorsal raphe brain region was targeted in these studies, as this region is the primary source of serotonin for forebrain structures. The actions of cocaine on the serotonin system likely originate with influence of cocaine on the dorsal raphe neurocircuitry, with implications for dysregulation in downstream projection areas of the dorsal raphe. In this portion of the current thesis study, electrophysiology techniques were used to measure GABA activity in subregions of the dorsal raphe either 30 minutes, 25 hours, or 7 days following a 10-day chronic binge cocaine paradigm (15 mg/kg, 3 injections per day at 1 hour intervals). Controls received saline injections. Mice were tested for anxiety-like behavior on the elevated plus maze and then brain slices were collected for electrophysiology recordings. It was found that at 25 hours of withdrawal, cocaine-treated mice demonstrated heightened anxiety-like behavior on the elevated plus maze, as compared to saline controls. Mice tested during an active cocaine stage 30 minutes after the last injection, or at 7 days of withdrawal did not demonstrate increased anxiety-like behavior. Heightened GABA activity was exhibited in serotonin cells from cocaine-withdrawn mice at 25 hours of withdrawal, an effect that was normalized upon 5-HT2C receptor blockade. No differences were observed at 30 minutes after the last cocaine injection; however, there was an anatomical shift observed at 7 days of withdrawal, in that heightened GABA activity exhibited in two subregions of the dorsal raphe (dorsomedial and ventromedial aspects) at 25 hours of withdrawal shifted to the lateral wing areas at 7 days of withdrawal. The differential regulation of the three subregions has implications on serotonin output to projection areas and contribution to anxiety mechanisms. It was found that systemic administration and local intra-dorsal raphe administration of the 5-HT2C receptor antagonist, SB 242084, prior to elevated plus maze testing attenuated anxiety-like behavior in cocaine-withdrawn mice at 25 hours of withdrawal. Taken together, this portion of the thesis study demonstrated that 5-HT2C receptor activity, specifically within the dorsal raphe, regulates anxiety during cocaine withdrawal, through influence on the GABA inhibitory feedback system. A final aspect of the current thesis study addressed the link between dorsal raphe 5-HT2C receptor activity and activity at downstream structures in the context of cocaine withdrawal-induced anxiety, particularly the nucleus accumbens. Since the dorsal raphe is important in providing serotonin input for brain regions largely involved in regulating the effects elicited by cocaine, it is likely that dysregulation of dorsal raphe signaling during withdrawal has influence on the regulation of downstream structures in the contribution of anxiety mechanisms produced by cocaine withdrawal. It was found that dorsal raphe 5-HT2C receptor blockade attenuated cocaine withdrawal-induced reductions in cFos immunoreactivity in the nucleus accumbens. Further work is needed to investigate these interactions in the context of cocaine withdrawal-induced anxiety. Lastly, autoradiography experiments assessed the effects of cocaine withdrawal-induced anxiety on 5-HT2C receptor expression in various brain regions including the dorsal raphe, medial prefrontal cortex, nucleus accumbens, caudate putamen, and ventral tegmental area. A significant decrease in 5-HT2C receptor binding was found in the dmDR region of cocaine-withdrawn mice as compared to saline controls; however, no differences were found between groups in other regions. Future studies testing 5-HT2C receptor signaling are needed to fully understand the impact of cocaine withdrawal-induced anxiety on receptor function in these structures. In conclusion, the first portion of the current study showed that activation of 5-HT2C receptors attenuated the rewarding and locomotor sensitizing effects of cocaine, as evidenced by conditioned place preference and behavioral sensitization studies. In the second aspect of the current thesis study, we have established a role for the 5-HT2C receptor in the regulation of anxiety during cocaine withdrawal. During withdrawal, blockade of 5-HT2C receptor activity, both global as well as local dorsal raphe blockade, attenuated anxiety at 25 hours of withdrawal. This attenuation of cocaine withdrawal-induced anxiety resultant of 5-HT2C receptor blockade was likely due to a suppression of increased GABA activity evident in serotonin cells from cocaine-withdrawn mice. / Pharmacology

Overdose and addiction are two medical complications of cocaine abuse. To date, there is no FDA approved pharmacotherapy specific for cocaine abuse. Cocaine hydrolases (CocHs) have been extensively investigated for its potential in anti-cocaine therapy. Previous studies have demonstrated that CocHs efficiently hydrolyze cocaine to generate biologically inactive metabolites both in vivo and in vitro. However, it has not been studied whether there is gender difference in the therapy using CocHs. In addition, the effectiveness of CocHs is unknown for treating cocaine toxicity when alcohol is co-administered. The main purpose of this dissertation is to characterize and evaluate efficient CocHs for cocaine overdose and cocaine addiction treatment. In the first set of studies, the effectiveness of human serum albumin-fused CocH1 were studied in male and female rats. The pharmacokinetic profiles, as well as the pharmacodynamic effects of CocH1-HSA were compared in male and female rats. The obtained data clearly demonstrated that CocH1-HSA was equally effective in both genders. The second set of studies investigated the efficiency of Fc-fused CocH5 in reversing cocaine toxicity in rats receiving simultaneous administration of cocaine and alcohol. Results showed that CocH5-Fc rapidly hydrolyzed cocaine and cocaine’s toxic metabolites in rats, and demonstrated that CocH5-Fc was efficient in treating cocaine toxicity when alcohol was simultaneously administered. In later studies to investigate the effects of CocH5-Fc for the treatment of cocaine addiction, a mathematical model was developed and validated to predict the effects of CocH5-Fc on the disposition of cocaine in rat blood and brain. This model adequately described the effects of CocH5-Fc in accelerating the elimination of cocaine and its toxic metabolites in both rat blood and brain. In conclusion, the studies within the current dissertation demonstrate the clinical potential of CocHs for the treatment of both cocaine overdose and cocaine addiction.

The main purpose of this research was to investigate the phenomenon of tolerance to cocaine. Tolerance is operationally defined as a decreased drug effect due to prior history of drug administration. The animal model that was chosen to investigate tolerance to cocaine was the drug discrimination model, which is an animal analogue of human subjective drug effects. In the drug discrimination procedure, animals are trained to emit one behavior when injected with saline. In the present experiments, rats were trained to press one lever when injected with cocaine, 10 mg/kg, and a different lever when injected with saline for food reinforcement. Once rats are trained, they can accurately detect the cocaine stimulus greater than 95% of the time.