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Excitatory glutamatergic inputs from limbic regions such as the hippocampus and the basolateral amygdala (BLA), and dopaminergic inputs from the ventral tegmental area converge in the nucleus accumbens (NAc). It has been proposed that interactions between these glutamatergic and dopaminergic pathways play an important role in adaptive behaviors. The present thesis employed a multidisciplinary approach to study these interactions, with a specific emphasis on the importance of mesoaccumbens dopamine (DA) transmission, in order to obtain a better understanding of the neural mechanisms by which the NAc transforms signals from the temporal lobes into behavior. The experiments of Chapter 2 utilized extracellular single-unit recordings of individual NAc neurons in combination with electrochemical measures of DA efflux in the NAc. Recordings from NAc neurons which received input from the hippocampus but not the BLA revealed that increased efflux of mesoaccumbens DA, evoked by tetanic stimulation of the fimbria, potentiated hippocampal-evoked neural activity in these cells. These effects were mediated by both DA and NMDA receptors. Similar recordings from neurons which received converging input from both the hippocampus and the BLA revealed tetanic stimulation of the fimbria again potentiated hippocampal evoked spiking activity, while concurrently suppressing BLA-evoked spiking activity in the same neurons. The suppression of BLA-evoked spiking activity was activity-dependent, and was mediated by both D, and adenosine A, receptors. Chapter 3 showed that random foraging on a radial-arm maze, which is dependent on a neural circuit linking the hippocampus to the NAc, was correlated with an increase in mesoaccumbens DA extracellular levels, as measured with microdialysis. In Chapter 4, pharmacological blockade of DA or NMDA receptors in the NAc, or selective disruption of dopaminergic modulation of ventral subicular inputs to the NAc (using an asymmetrical infusion procedure) significantly disrupted random foraging. These effects were mediated by the Dl receptor. In Chapter 5, the present data are integrated with previous research to formulate a model of ventral striatal function. It is proposed that the NAc mediates behavior through distinct patterns of activity and inactivity driven by excitatory limbic input projecting to different groups of neural ensembles. Mesoaccumbens DA transmission plays an essential role in regulating the synchrony ensemble activity, augmenting activity in one ensemble while suppressing activity in another. It is argued that the modulatory effects of DA appears to be essential when an organism must switch from one form of adaptive behavior to another in response to a constantly changing environment.

Controversy exists concerning the role that dopamine plays in analgesia. In the present studies, dopamine agonists produced analgesia, and D-amphetamine potentiated morphine analgesia, while treatment with 6-hydroxydopamine or mixed or selective D1 and D2 dopamine receptor antagonists attenuated or abolished morphine and D-amphetamine-induced analgesia, in the formalin test. Furthermore, microinjection of morphine into the ventral tegmental area (VTA) and ventral striatum produced analgesia, while intra-VTA microinjection of naloxone methylbromide antagonized the analgesia produced by systemic morphine, in the formalin test. In contrast, similar manipulations of dopamine had little or no effect in the tail flick test. Thus, dopamine appears to play a facilitatory role in formalin test analgesia, and there appear to be fundamental differences between the formalin and tail flick tests and parallels between the role of dopamine in the formalin test and in clinical pain, the vocalization after-discharge test and reward.

Excitatory glutamatergic inputs from limbic regions such as the hippocampus and the basolateral amygdala (BLA), and dopaminergic inputs from the ventral tegmental area converge in the nucleus accumbens (NAc). It has been proposed that interactions between these glutamatergic and dopaminergic pathways play an important role in adaptive behaviors. The present thesis employed a multidisciplinary approach to study these interactions, with a specific emphasis on the importance of mesoaccumbens dopamine (DA) transmission, in order to obtain a better understanding of the neural mechanisms by which the NAc transforms signals from the temporal lobes into behavior. The experiments of Chapter 2 utilized extracellular single-unit recordings of individual NAc neurons in combination with electrochemical measures of DA efflux in the NAc. Recordings from NAc neurons which received input from the hippocampus but not the BLA revealed that increased efflux of mesoaccumbens DA, evoked by tetanic stimulation of the fimbria, potentiated hippocampal-evoked neural activity in these cells. These effects were mediated by both DA and NMDA receptors. Similar recordings from neurons which received converging input from both the hippocampus and the BLA revealed tetanic stimulation of the fimbria again potentiated hippocampal evoked spiking activity, while concurrently suppressing BLA-evoked spiking activity in the same neurons. The suppression of BLA-evoked spiking activity was activity-dependent, and was mediated by both D, and adenosine A, receptors. Chapter 3 showed that random foraging on a radial-arm maze, which is dependent on a neural circuit linking the hippocampus to the NAc, was correlated with an increase in mesoaccumbens DA extracellular levels, as measured with microdialysis. In Chapter 4, pharmacological blockade of DA or NMDA receptors in the NAc, or selective disruption of dopaminergic modulation of ventral subicular inputs to the NAc (using an asymmetrical infusion procedure) significantly disrupted random foraging. These effects were mediated by the Dl receptor. In Chapter 5, the present data are integrated with previous research to formulate a model of ventral striatal function. It is proposed that the NAc mediates behavior through distinct patterns of activity and inactivity driven by excitatory limbic input projecting to different groups of neural ensembles. Mesoaccumbens DA transmission plays an essential role in regulating the synchrony ensemble activity, augmenting activity in one ensemble while suppressing activity in another. It is argued that the modulatory effects of DA appears to be essential when an organism must switch from one form of adaptive behavior to another in response to a constantly changing environment. / Arts, Faculty of / Psychology, Department of / Graduate

Goldfish (Carassius auratus) (40-80g) were injected with dopamine into the forebrain to study the possible involvement of this amine in central temperature regulation in these fish. Dopamine caused a decrease in selected temperature after injection into the rostral nucleus preopticus periventricularis (NPP). This effect was dependent on the dose of dopamine administered. Doses of 25, 50, 100 and 250 ng were used, injected in a volume of 0.2μ1. Injections in regions adjacent to the NPP elicited hypothermic effects only at the higher dosages. These effects were not consistent. Injections in caudal regions of the NPP elicited no effect. The effects of dopamine were blocked by haloperidol, a selective antagonist of dopamine. It is suggested that dopamine acts on central thermoregulatory neurons, present in the rostral NPP, in the mediation of thermoregulatory behavior. Further, it is suggested that this action is mediated via dopaminergic receptors.

Dysfunction of central dopaminergic systems has been implicated in neuroendocrine, neurodegenerative and psychiatric disorders. Monoamine oxidase and catechol-Omethyltransferase represent the key catabolic enzymes of dopamine, terminating neurotransmission following synaptic release of this catecholamine. Thus, both enzymes have been associated with the pathology of dopaminergic systems and represent therapeutic targets elf enormous clinical importance. Some neuroendocrine and circadian effects of melatonin have been attributed to an antidopamimetic effect of this pineal hormone in the hypothalamus and pituitary. Furthermore, both melatonin and dopamine modulate the behavioural output of the mesencephalic dopaminergic pathways of the basal ganglia, including movement disorders. However, the biochemical basis for the tonic inhibitory effect of melatonin in the nigro-striatal pathway has been poorly delineated. Thus, this study determined whether melatonin influences dopaminergic function in the corpus striatum of the Wistar rat by modulating monoamine oxidase and catecholO- methyltransferase activity. Reciprocally, the putative existence of an intrapineal dopaminergic system was investigated by determining the effect of selective dopaminergic agents, R-( -)apomorphine, haloperidol and dopamine, on indole metabolism of the pineal gland. The akinetic state of drug-induced catalepsy was employed as an animal model of Parkinson's disease to probe the neurotransmitter systems involved in the behavioural effects of melatonin. Indole metabolism was a reliable indicator of state-dependent metabolic fluxes in pineal gland function. These included a robust diurnal and seasonal variation in N-acetylserotonin and melatonin biosynthesis, and photoperiod- and drug-induced alterations of Inftabolism. The predominant changes could be attributed to an effect on serotonin N-acetyltransferase activity and/or the melatoninl5-methoxytryptophol ratio. Pineal 5-methoxyindole biosynthesis was determined primarily by the bioavailability of the corresponding 5-hydroxyindole and its affinity for hydroxyindole-O-methyltransferase. Evidence was found for the negative feedback or paracrine control of pineal indole metabolism by melatonin. A high inter-individual variability was observed in the biosynthesis of N-acetylserotonin and melatonin biosynthesis, and the weight of the pineal glands. Accordingly, the rats could be classified as either high or low capacity producers of these two indoles. R-(-)-apomorphine and dopamine in vitro, but not acute haloperidol in vivo, had dose- and phase-dependent effects on pineal indole metabolism. The predominant effect was a suppression of the scotophase-dependent induction ofN-acetylserotonin and melatonin biosynthesis by dopamine and R-( -)-apomorphine. It is postulated that these agonists inhibited nocturnal N-acetyltransferase activity via postsynaptic pineal D2 or D2-like receptors. The observed modulatory nature of the intrapineal dopaminergic system suggests that dopamine may be involved in the long-term regulation of pineal indole biosynthesis. Several lines of evidence are presented that the activity of striatal monoamine oxidase A and catechol-O-methyltransferase, represented predominantly by the soluble isoform, is statedependent and regulated in vivo by endogenous melatonin. Firstly, both enzymes showed a daynight variation in activity. Secondly, acute and subchronic administration and photoperiod manipulation studies indicated that both exogenous and endogenous melatonin inhibited each enzyme in a chronotypic fashion, with a more robust effect against catechol- -methyltransferase. The intensity of the in vivo effects was critically dependent on the dose, duration, route and the phase-timing of administration during the light dark cycle, and the length of the exposure to constant light. Melatonin in vitro had no effect on basal or Mg2+ -induced catechol-Omethyltransferase activity. Thus, it is proposed that the in vivo effects of the hormone can be attributed to a time-dependent change in the amount of active molecules of this enzyme. In contrast, melatonin and numerous other endogenous indolic compounds were found to be reversible inhibitors of striatal monoamine oxidase A in vitro. Structure-activity modeling revealed that the 5-methoxy moiety on the indole nucleus and substitution of the free primary amine of these compounds were the principal determinants of the potency and time-dependency of inhibition. Thus melatonin most likely has a direct inhibitory effect in vivo at the level of the active site of monoamine oxidase A. Exogenous melatonin alone had no cataleptogenic potential whereas a variety of behavioural responses were observed following intraperitoneal administration of y-hydroxybutyrate. The latter responses were state-dependent with day-night variations in intensity. Furthermore, yhydroxybutyrate stimulated melatonin biosynthesis during the photophase both in vitro and in vivo. These results point to a possible involvement of melatonin in the behavioural and neurochemical effects of y-hydroxybutyrate. Thus the general conclusion is that dopamine and melatonin display functional antagonism at the level of the pineal gland and corpus striatum of the Wistar rats. Therefore melatonin may be an important homeostatic modulator of dopaminergic neurotransmission throu~out the central nervous system. Furthermore, the putative existence of a functional pineal-striatal axis would greatly strengthen the argument for a holistic concept of brain homeostasis. The ability of endogenous melatonin to regulate monoamine oxidase A and catechol-O-methyltransferase may represent an alternative strategy for the treatment of disorders associated with these enzymes.

Abstract not available

The involvement of dopamine in anticipatory and consummatory aspects of feeding behaviors was investigated in the present thesis. All measurements of dopaminergic activity were taken by in vivo electrochemical techniques. In Experiment 1, dopamine efflux in the nucleus accumbens and caudate of male rats was monitored during sessions in which a small, unsignalled liquid meal was consumed. Increases in the electrochemical measure of dopamine activity, which were of similar temporal pattern and magnitude, were observed in both the nucleus accumbens and striatum following meal consumption. These data suggest a possible postingestional role of dopamine in these two brain structures. In Experiment 2, a conditioned feeding paradigm was utilized to study the role of dopamine during a discrete anticipatory phase of feeding. Rats were conditioned to discriminate between a positive conditioned stimulus (CS+) predictive of meal delivery, and a negative conditioned stimulus (CS-) that was not associated with food. Increases in dopamine activity, as determined by changes in electrochemical oxidation currents, were found to be greater during the CS+ than during the CS- in both the nucleus accumbens and caudate. In addition, the magnitude of increase was greater in the nucleus accumbens than the caudate, suggesting that the accumbens may be preferentially involved in the processing of external incentive stimuli. The results support a role for dopamine in both the nucleus accumbens and caudate during appetitive or anticipatory responding for food in the male rat. / Medicine, Faculty of / Graduate