Previous reports have indicated that prenatal, but not postnatal, haloperidol impairs the ontogenic development of striatal dopamine D-2 receptors. In the present study a specific D-2 receptor antagonist, spiroperidol (1.0 mg/kg i.p.) and/or a specific D-1 receptor antagonist, SCH 23390 (0.30 mg/kg i.p.), was administered to rats for 32 successive days from birth. Postnatal spiroperidol and SCH 23390 treaments markedly impaired the development of striatal dopamine D-2 and D-1 receptors, respectively, at 12 weeks after birth. Spiroperidol did not affect D-1 receptor development and did not modify the effect of SCH 23390 treatment. Also, SCH 23390 did not affect D-2 receptor development and did not modify the effect of spiroperidol treatment. When rats with impaired development of striatal D-2 receptors were challenged at 12 weeks with spiroperidol (1.0 mg/kg per day i.p. × 17 days) D-2 receptors did not up-regulate. However, when rats with impaired development of striatal D-1 receptors were challenged at 12 weeks with SCH 23390 (0.30 mg/kg per day i.p. × 17 days) D-1 receptors did up-regulate. These findings demonstrate that postnatal treatment with D-1 and D-2 receptor antagonists can permanently impair the development of striatal D-1 and D-2 receptors. Moreover, the ability of developmentally impaired striatal D-1 receptors to up-regulate in adulthood appears to be greater than that for the developmentally impaired striatal D-2 receptors.

No description available.

The mesoaccumbens dopamine system has been implicated in many basic psychological processes (e.g. "wanting" and "liking") and illnesses (e.g. addiction, depression, schizophrenia). However, the precise computational functions of nucleus accumbens and dopamine neurons within the system remain unknown. In this thesis, we test some of the current hypotheses regarding the function of this system using a behavioural neurophysiology approach in the rat. The first question we wanted to answer was whether nucleus accumbens neurons process reward-predictive stimuli (e.g. conditioned reinforcers) and reward delivery differently, since previous studies report equivocal findings. To do so, we trained thirsty rats to bar-press on a second-order schedule of saccharin reinforcement, within which the temporal pattern of rats' bar-pressing was reinforced by presentations of a conditioned reinforcer and primary reinforcer (reward). We found that nucleus accumbens neurons typically responded to these conditioned and primary reinforcers with opposite sign, which suggests they were processed differently. We were not sure whether responses to conditioned reinforcers encoded reward-prediction or facilitated a behavioural switch in the rat's behaviour. Indeed, since studies using a variety of experimental techniques have implicated the mesoaccumbens dopamine system in both reward prediction and behavioural switching, we sought to test whether neurons in the nucleus accumbens and dopamine-rich areas of the midbrain respond to outcome-associated stimuli to predict reward or switch behaviour. We found both sets of neurons predominantly did the former. Finally, to understand more about reward consummatory responses from both sets of neurons, we developed a rat behavioural task providing measures of reward "wanting" and "liking". In conclusion, on the basis of our data, the most parsimonious explanation for the function of the mesoaccumbens dopamine system is that it acts to modulate goal-seeking behaviour. Further research is required to identify the function of the interactions between nucleus accumbens and dopamine neurons during goal-seeking and goal consumption.

published_or_final_version / Zoology / Master / Master of Philosophy

This dissertation is composed of five major chapters. The first is a comprehensiveliterature review, followed by three chapters of research findings, and a final concludingchapter. Major Depressive Disorder (MDD) is a phenotypically complex andheterogeneous syndrome. This challenge and others faced when investigating the geneticbasis for the susceptibility to MDD are discussed, as are tools used to address andovercome these challenges. Included in this review of the literature is a discussion onfindings of genome-wide analyses of MDD, as well as candidate genes that may play arole in the susceptibility to major depression. Following the literature review, threechapters of studies are presented. The first one demonstrates that in humans, the actualnumber of risk genotypes in the serotonin system accounts for over half of the variance inmood response to tryptophan depletion. There was no association between the dopaminesystem and mood response. The main conclusion from that study is that using a pathwayanalysis, rather than a single gene approach, may lead to more informative results whenstudying the genetics of a complex behavior. The next study demonstrates a similarconclusion, however, is not pathway specific. It is shown that in a group of de pressedsubjects not capable of treatment response, the mean number of risk genotypes is greaterthan in a group without depression. This supports the thought that treatment resistancemay be a more severe form of MDD. This study also presents data on single gene resultswhich demonstrate that the genetic basis for susceptibility to major depression may bedifferent and independent from the genetic basis for the capacity to respond to treatment.Several individual polymorphisms are implicated in each case. The final investigation is apublished manuscript refuting the findings of a previously published article onpolymorphisms in the TPH2 gene and association with treatment resistance. Many otherresearch groups have also been able to replicate the results demonstrated here. A finalchapter discusses the overall conclusions about the three research studies, as well as thefield of psychiatric genetics with a focus on the continuing search for the genetic basis ofsusceptibility to major depressive disorder.

A better understanding of the neural mechanisms associated with Attention Deficit Hyperactivity Disorder (ADHD) and related cognitive deficits can potentially clarify the neural circuits involved in ADHD symptoms, help define neurobiologically informed subtypes and aid in developing more refined treatments. Two neurotransmitter (NT) systems have been implicated in ADHD: Dopamine (DA), and Norepinephrine (NE), and the primary cognitive deficits associated with ADHD are in working memory, response inhibition, reaction time variability, and reward processing. Frank et al. (2007a) proposes, based on computational models, that DA is associated with deficits in reward-based learning and updating of working memory, while NE is associated with deficits in response inhibition and greater response variability. Therefore, it might be possible to learn more about the NT systems' specific roles in ADHD by studying the associated cognitive deficits. The primary goal of this study was to assess performance in adolescents with and without ADHD on a number of cognitive tasks. We expected that the Attention Deficit Hyperactivity Disorder - Inattentive Subtype (ADHD-I) group would perform the worst on NE tasks and that the Attention Deficit Hyperactivity Disorder - Combined Subtype (ADHD-C) group would perform the worst on DA tasks, and that both groups would perform worse than controls on all tasks. Instead, we found that the ADHD-I group performed the most poorly on updating of working memory, while the ADHD-C group performed the best on this variable. However, the ADHD-C group performed worst on overall working memory. Dimensional analyses revealed that hyperactivity/impulsivity is positively correlated with updating of working memory, while inattention is negatively correlated with updating of working memory. In addition, hyperactivity/impulsivity was positively correlated with reaction time variability. In conclusion, it is likely that the roles of these NT systems are not as mutually exclusive as initially expected. It is also possible that our ADHD group was performing more like control groups in other studies, which might be due to a more 'pure' ADHD sample with less comorbid Oppositional Defiant Disorder (ODD) and Conduct disorder (CD), or could be due to a less symptomatic ADHD group.

Environmental stimuli associated with drug use are related to drug craving and relapse. The mechanism of cue-induced craving is thought to involve the release of dopamine (DA) in brain regions associated with reward and habit formation. The aim of the study was to investigate the role of DA in cue-induced craving in tobacco-dependent smokers using Positron Emission Tomography (PET) and a picture cue paradigm. Tobacco-associated cues were capable of eliciting significantly greater subjective reports of craving relative to neutral cues in tobacco smokers (n=6) in a neuroimaging environment. Using this cue paradigm and [11C]-(+)-PHNO PET (n=6), a non-significant trend towards a greater decrease in binding potential, indicative of dopamine release, was shown in selected brain regions of interest. These findings are similar to findings in cocaine-dependent individuals and suggest the involvement of dopamine in the response to smoking-associated cues in tobacco-dependent individuals.

No description available.

Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic neurons where its main function is to sequester DA from the extracellular space and to transport it back into the cell, a process that is electrogenic. AMPH and COC directly interact with DAT and alter its ionic currents. Not much is known about the effect of psychostimulant-induced DAT currents on neuronal excitability and neurotransmitter release. We use synthetic chemistry, molecular biology, and biophysics in heterologous expression systems to decipher the actions of drugs of abuse on DAT. Furthermore we demonstrate drug-induced DAT currents can activate Ca2+ channels associated with dopaminergic excitability. Lastly, we focused on investigating drug effects on excitability in a human midbrain dopaminergic cell line. Understanding how psychostimulants interact with DAT to produce the dysfunctional states of the transporter may facilitate the development of unique therapeutic strategies to treat psychostimulant dependence.

The high affinity, selective dopamine transporter ligand GBR 12909 has served as a template for the design of two novel classes of dopamine transporter ligands. A series of 3-[2- (diarylmethoxyethyidenyl)]-N-substituted tropane derivatives were synthesized and the binding affinities of these compounds were determined at the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in rat brain tissue preparations. The tropane derivatives were found to exhibit more potent affinity and selectivity for DAT than GBR 12909. From the SAR of the tropane analogues and GBR 12909, a novel series of 3-[2-(diarylmethoxyethylidenyl)]-Nsubstituted azetidine derivatives has been developed.