Objective: To investigate whether there is an association between use of cocaine, amphetamines, or psychedelics and psychotic symptoms. Method: Cumulated data from a prospective, longitudinal community study of 2588 adolescents and young adults in Munich, Germany were used. Substance use was assessed at baseline, 4-year and 10-year follow-up using the Munich Composite International Diagnostic Interview; psychotic symptoms were assessed at 4-year and 10-year follow-up. Multinomial logistic regression analyses, adjusted for sociodemographic factors, common mental disorders, other substance use, and childhood adversity (adjusted odds ratios, AOR), revealed associations between cocaine, amphetamine or psychedelic use and psychotic symptoms. Results: Lifetime experience of psychotic symptoms was associated with lifetime use of cocaine (AOR 1.94; 95%CI 1.10-3.45), amphetamines (AOR 1.69; 95%CI 0.98-2.93), psychedelics (AOR 2.37; 95%CI 1.20-4.66) and all three substances (AOR 1.95; 95%CI 1.19-3.18). Conclusion: Associations between psychotic symptoms and use of cocaine, amphetamines, and/or psychedelics in adolescents and young adults call for further studies to elucidate risk factors and developmental pathways.

Attention deficit hyperactivity disorder (ADHD) affects up to 10% of school-aged children and half as many adults. The core features of impulsivity, hyperactivity, and inattentiveness commonly give rise to academic underachievement, poor social relationships, and increased risk for mood and anxiety disorders. Although the relevant neurobiological mechanisms remain poorly understood, altered mesocorticolimbic dopamine (DA) transmission has been proposed. The aim of the present study was to compare striatal DA function in treatment-naive adults with ADHD vs. age- and IQ-matched controls. Two PET/[11C]raclopride scans, one with placebo and one with d-amphetamine (d-AMP; 0.3 mg/kg, p.o.), were administered to five men with ADHD and five healthy male volunteers. The ADHD group differed from controls in demonstrating significant d-AMP-induced reductions in posterior caudate (p<0.05). These results may support a proposed model of reduced DA tone leading to increased phasic signaling in ADHD.

No description available.

Doctor of Philosophy / Department of Psychology / Mary E. Cain / Glutamate contributes to the neurological and behavioral changes that occur during differential rearing, and those that occur during conditioned hyperactivity and sensitization. Metabotropic glutamate receptor 5 (mGluR5) in particular contributes to the psychostimulant reward pathway, plasticity, and differential rearing. The present study examined the role of mGluR5 in conditioning and sensitization in differentially reared rats. Rats were reared in an enriched (EC), impoverished (IC), or social (SC) condition for 30 days, after which they received repeated amphetamine (0.3 mg/kg) or saline injections. Following training, rats received an injection of the mGluR5 antagonist MTEP or saline prior to undergoing conditioned hyperactivity and sensitization tests. Results showed that MTEP attenuated conditioned hyperactivity and sensitization in IC but not EC and SC rats, suggesting that glutamatergic changes occur during differential rearing that alter the effects of MTEP on amphetamine conditioning and sensitization. Additionally, results demonstrated that enrichment rearing has a protective effect against conditioned hyperactivity at low doses of amphetamine.

Master of Science / Department of Psychology / Mary E. Cain / Previous research has shown that both the environment and psychostimulant use influence dopamine levels via the mesolimbic dopamine pathway. C-fos expression has also been observed following exposure to novel environments and psychostimulants. The present study looked to determine the effects of acute amphetamine exposure on locomotor activity and c-fos expression in the basolateral and central nucleus of the amygdala, for rats raised in either an enriched condition (EC), impoverished condition (IC), or social condition (SC). Rats were reared in either the EC, IC, or SC for 30 days, after which they received an acute amphetamine injection (1.0 mg/kg) and locomotor activity was measured. Following the locomotor test rats were perfused and immunohistochemistry was used to measure c-fos levels in the basolateral and central nucleus of the amygdala. Results showed that EC amphetamine rats had significantly greater locomotor activity compared to EC saline rats. There were no significant group or treatment differences in c-fos expression in the ACe. In the BLA SC amphetamine rats had significantly greater c-fos expression than EC amphetamine rats. Overall, the current study revealed that environmental enrichment and amphetamine do significantly alter locomotor activity and c-fos expression in the BLA.

This dissertation work investigated the effect of acute and repeated in vivo administration of lobeline on dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. The effects of lobeline were then compared to the effects of acute and repeated in vivo administration of methylphenidate and amphetamine to determine if lobeline produced similar effects compared to these Attention Deficit Hyperactivity Disorder (ADHD) medications. These medications are considered the first line of pharmacotherapy for ADHD, although there is a growing concern associated with their potential for abuse and other side effects. This merits the need for novel ADHD treatments that have a safer side effect profile. If lobeline alters DAT and VMAT2 function in the same way as methylphenidate or amphetamine, further investigation may be necessary to evaluate lobeline as a potential treatment for ADHD. Kinetic analysis of [3H]dopamine (DA) was utilized to determine the effect on DAT and VMAT2 function in rat striatum. Results from the DAT experiments, revealed that lobeline as well as amphetamine had no effect on DAT function. However, methylphenidate increased DAT function after acute and 7-day treatment. None of the drug treatment regimens altered Km. To determine if the methylphenidateinduced increase in DAT function was due to DAT trafficking, biotinylation and Western blot analyses were performed. Acute administration of methylphenidate did not alter surface DAT, however repeated administration of methylphenidate for 7 days decreased intracellular DAT, suggesting that methylphenidate redistributes DAT in a time-dependent manner. Similar results were found in the VMAT2 experiments. Lobeline and amphetamine had no effect on VMAT2 function after acute or repeated administration. Amphetamine decreased the Km after repeated administration for 7 days. Methylphenidate increased VMAT2 function after acute and repeated administration for 7 days. The overall results of these experiments suggest that methylphenidate interacts with DAT and VMAT2 in a different manner than amphetamine and lobeline. In addition, since lobeline and amphetamine had no effect on DAT and VMAT2 function, further investigation is warranted to elucidate the underlying mechanisms of the therapeutic actions of these agents. This additional information will aid in the development of novel treatments for ADHD.

Primary polydipsia, excessive drinking without known medical cause, continues to occur with a significant prevalence in psychiatric populations. While the etiology of polydipsia remains unknown, the fact that it is significantly associated with a diagnosis of schizophrenia has led some to postulate that the two may share common neurological pathophysiologies. Animal models of schizophrenia-like symptoms have focused on modeling the core behavioral and neurochemical features of the illness, like cognitive deficits and enhanced dopamine transmission. Here, we used three well-established models, including repeated amphetamine treatment, subchronic MK-801 (an N-methyl-D-aspartate [NMDA]-receptor antagonist), and post-weaning social isolation. We also examined a “double-hit” model, combining NMDA-receptor antagonism and social isolation. We paired these models to test the hypothesis that drinking will be enhanced in a paradigm of excessive drinking in the rat. In rodents, non-physiologic drinking can be induced by intermittent presentation of food (e.g., one sugar-pellet a minute) in the presence of a drinking spout to a hungry animal, termed schedule-induced polydipsia (SIP). Animals pretreated with pharmacological or non-pharmacological models of schizophrenia-like symptoms showed significantly increased SIP, The “double hit” model did not further increase drinking above that of either social isolation or MK-801 treatment alone. A moderate amount of spontaneous polydipsia in the homecage of MK-801-treated rats was also observed and resulted in one death secondary to excessive drinking, a phenomenon also found in inpatients with schizophrenia. Following repeated treatment with AMPH, there was some evidence that over time, animals learned to drink increased amounts independently of the scheduled food presentation. This evidence suggests that the excessive drinking behavior observed in polydipsia associated with schizophrenia may have a learned component. In summary, animal models of schizophrenia-like symptoms augmented SIP behavior, showing that polydipsia associated with schizophrenia may be modeled in rodents. As each model has been shown to modify dopamine transmission to some degree, the evidence suggests augmented SIP may reflect changes in dopamine transmission and dopamine may be the common link between polydipsia and schizophrenia. Further research is necessary to fully elucidate the mechanisms underlying SIP, polydipsia and schizophrenia. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-10-31 17:43:18.34

Psychomotor stimulant abuse is a significant public health problem. While many individuals experiment with stimulants, there is marked variability in individuals' behavioral and subjective response to these drugs and these differences may be associated with their risk for abuse. One characteristic shown to be associated with drug abuse is sensation seeking, defined as the seeking of novel sensations and experiences and the willingness to take risks for the sake of such experiences. While observational studies have shown that individuals with elevated sensation seeking are more likely to report stimulant use and abuse, less clear is whether subjective and behavioral response to acute stimulant administration may vary as a function of sensation seeking status. We recently completed an outpatient laboratory study in which 37 healthy adults received repeated opportunities to sample and choose between d-amphetamine (d-AMPH; 5, 10, 20 mg/70kg) or placebo. That study provided an opportunity to examine associations between sensation seeking and d-AMPH choice and subjective response under rigorous double-blind experimental conditions. The Zuckerman Sensation Seeking Scale V was administered at intake, providing a Total sensation seeking score as well as four subscales (i.e., Experience Seeking, Disinhibition, Thrill and Adventure Seeking, Boredom Susceptibility). We hypothesized that elevated sensation seeking at intake would be associated with increased preference for d-AMPH over placebo in subsequent choice sessions, as well as greater positive d-AMPH subjective effects. Among males, increased baseline sensation seeking was associated with increased d-AMPH choice and positive subjective effects at the 5 and 10 mg/70 kg doses. Among females we found no significant associations between sensation seeking and d-AMPH choice or subjective effects. Finally, when the association between sensation seeking and other baseline characteristics was examined, there was a significant positive association with lifetime drug use as well as impulsivity. Taken together, our data suggest that elevated sensation seeking in males may be associated with increased sensitivity to d-AMPH reinforcement and positive subjective effects, suggesting increased vulnerability for stimulant use and abuse.

Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation of many of these compounds (i.e. amphetamine, methamphetamine, phenmetrazine) is their propensity for abuse; however, not all monoamine releasers are abused (i.e. fenfluramine). The goal of this dissertation was to examine pharmacological determinants of abuse-related effects produced by monoamine releasers in two preclinical assays in rats: intracranial self-stimulation (ICSS) and drug discrimination. First, this work confirmed and expanded upon previous findings that selectivity for promoting release of dopamine versus serotonin is one determinant of abuse-related effects produced by monoamine releasers. This was accomplished by determining the behavioral effects of 11 different compounds that ranged in their selectivity for dopamine versus serotonin, and a correlation was found between the ability of a compound to facilitate ICSS and the selectivity of that compound for releasing dopamine versus serotonin. These data were then submitted to a rate-dependency analysis. Here, we found that all compounds produced rate-dependent effects, but that the profile of these effects varied with a compound’s selectivity for dopamine versus serotonin. Next, the mechanism by which serotonin exerts it response rate-decreasing effects was investigated - specifically, the hypothesis that the 5HT2C receptor mediates serotonin’s abuse-limiting effects of monoamine releasers was tested. The data collected suggest that the 5HT2C receptor contributes to, but is not exclusively responsible for, the abuse-limiting effects produced by serotonin release. Finally, selectivity for norepinephrine versus dopamine was examined as a potential determinant of monoamine releaser abuse liability; results from these studies suggest that release of both dopamine and norepinephrine are required for expression of abuse-related effects in assays of ICSS and drug discrimination. These data provide a systematic examination of the determinants of the abuse-related effects produced by monoamine releasers and may contribute to development of medications with reduced abuse potentials.

Doctor of Philosophy / Psychological Sciences / Mary E. Cain / Gene-environment interactions play a significant role in drug abuse and addiction. Epigenetics (the study of how environmental stimuli alter gene expression) has gained attention in recent years as a significant contributor to many behavioral phenotypes of drug addiction. The current study sought to determine if differential rearing conditions can alter a specific epigenetic mechanism, histone deacetylase (HDAC), and how HDAC inhibition can affect drug-taking and drug-seeking behaviors differently among enriched, isolated, or standard-housed rats. Ninety male Sprague-Dawley rats were reared for 30 days in enriched (EC), isolated (IC), or standard (SC) conditions prior to amphetamine (0.03, 0.05, 0.1 mg/kg/infusion, i.v.) self-administration, extinction, or reinstatement sessions. Trichostatin A (TsA; 0.3 mg/kg, i.v.), an HDAC inhibitor, was injected 30 min prior to drug-taking or drug-seeking sessions. Results indicated that EC rats self-administered less amphetamine (0.03 mg/kg/infusion) than IC rats. No significant effects of TsA administration were found on general self-administration for any of the three amphetamine doses. While enrichment facilitated the extinction of active lever pressing, there was also a mild facilitation of extinction in IC-TsA rats compared to IC-vehicle counterparts. Lastly, TsA administration decreased cue-, but not drug-induced reinstatement, with IC-TsA rats exhibiting significantly attenuated cue-induced reinstatement compared to IC-vehicle rats. These findings suggest that differential rearing can alter HDAC mechanisms that can change drug-seeking behaviors, particularly in rats reared in isolated conditions. While TsA-induced HDAC inhibition may be less protective against general amphetamine self-administration, it may decrease drug-seeking tendencies during relapse that are induced by the reintroduction of contextual environmental cues heavily associated with drug reward.