No description available.

The activity of neurons in the prefrontal cortex (PFC) may underlie working memory processes in the brain. Both the performance of working memory tasks and the activity of PFC neurons are modulated by dopamine. The goal of the present thesis was to gain insight into the neural basis of working memory by studying the PFC, and the DA system in the PFC, from both a behavioral and cellular perspective. The functional contribution of the PFC to working memory processes in the rat was assessed in Chapter 2 of the present thesis using memory-based foraging tasks on an 8-arm radial maze. The results of these studies indicated that lidocaine-induced inactivations of the PFC selectively disrupted the ability to use mnemonic information to guide foraging, but not the ability to acquire or retain such information. The ability to use mnemonic information to guide foraging was also disrupted by microinjection of a D1 but not D2 receptor antagonist into the PFC. Chapters 3-5 investigated how PFC neurons process synaptic inputs to their dendrites to produce spike output. The intrinsic membrane properties and synaptic responses at the soma and dendrites of deep layer PFC pyramidal neurons were recorded using sharp intracellular or whole-cell patch-clamp techniques in a brain-slice preparation. Different passive and active membrane properties of the soma and dendrites of PFC neurons were observed. The distal dendrites of PFC neurons responded most effectively to strong, highly coincident synaptic inputs. Ca²⁺currents near the soma both amplified the effects of these inputs and modulated the spike output pattern. Spike output at the soma was also controlled by the interplay of slowly-inactivating Na⁺ and K⁺ currents. Chapter 6 investigated the modulation of PFC neurons by DA. DA or a D1 but not D2 receptor agonist increased the evoked firing of PFC neurons via a D1- mediated modulation of slowly-inactivating Na⁺ and K⁺ currents. Concurrently, D1 receptor activation reduced burst firing in PFC neurons, due to a attenuation of Ca²⁺ currents. D1 receptor activation also increased both GABA[sub A] IPSPs and NMDA EPSPs. The final chapter of this thesis integrated these data into a cellular model of PFC function and its modulation by DA. It is proposed that DA may tune PFC neurons such that they respond selectively to strong synchronized inputs from other cortical areas. In the presence of DA, working memory processes mediated by the PFC may be influenced selectively by stimuli of behavioral significance.

A procedure was developed to determine the effect of a dopamine (DA) antagonist (haloperidol) and a DA agonist (d-amphetamine) on rats' perceptions of the hedonic value of food. Eighteen rats were trained to discriminate between two quantities of sweet food pellets (1 and 4), in a forced-choice two-lever successive discrimination procedure. To control for non-specific perceptual effects of the treatments, the rats were also trained to discriminate between 1 and 4 tones. It was established that rats attended to the value of food, as well as the proportional differences in quantity, when discriminating food quantities. This was accomplished by altering the value of the food in two ways. Firstly, "hunger" was altered by changing the degree of food deprivation during testing. Secondly, unsweetened food pellets were introduced as probe cues. These two methods of altering the value of food pellets were utilized while quantity generalization gradients were determined, by presenting animals with 1,2, 3 and 4 numbers of stimuli as probe cues. Two measures were derived from these generalization gradients: the point of subjective equality (PSE), which is the calculated number of stimuli that would maintain responses equally distributed between the two levers, and the slope of the gradient. The PSE primarily reflects perceptual processes, while the slopes of the gradients provide an index of performance impairment. It was observed that decreasing the value of food by either decreasing food deprivation or reducing the sweetness of the food pellets resulted in the rats perceiving a given quantity of food as larger than before these treatments (decreased the food PSE). Neither altering food deprivation nor introducing novel tone probes had an effect on the numerical attributes of tones, as reflected by the tone PSE. Haloperidol (0.030, 0.50 and 0.083 mg/kg, i.p.) produced a statistically significant, but slight dose-dependent performance deficit, as reflected by the slope of the generalization gradients. It did not affect the perception of food pellet quantities at any dose, as reflected by the food PSE. Haloperidol decreased the number of tones a given quantity was perceived as by rats (increased the tone PSE). Amphetamine (0.25, 0.50 and 1.0 mg/kg, i.p.) decreased the perception of a given quantity of food (increased the food PSE) in a dose-dependent manner, without a significant effect on performance. Thus, amphetamine enhanced the hedonic value of food. Amphetamine also increased rats' perceptions of a given number of tones (decreased the tone PSE). It therefore appears that while d-amphetamine can enhance the perceived hedonic value of food, haloperidol has no effect on rats' perceptions of the hedonic value of food. Furthermore, evidence that DA systems are involved in the mechanism of an "internal clock" or "counter" was obtained. / Medicine, Faculty of / Graduate

The activity of neurons in the prefrontal cortex (PFC) may underlie working memory processes in the brain. Both the performance of working memory tasks and the activity of PFC neurons are modulated by dopamine. The goal of the present thesis was to gain insight into the neural basis of working memory by studying the PFC, and the DA system in the PFC, from both a behavioral and cellular perspective. The functional contribution of the PFC to working memory processes in the rat was assessed in Chapter 2 of the present thesis using memory-based foraging tasks on an 8-arm radial maze. The results of these studies indicated that lidocaine-induced inactivations of the PFC selectively disrupted the ability to use mnemonic information to guide foraging, but not the ability to acquire or retain such information. The ability to use mnemonic information to guide foraging was also disrupted by microinjection of a D1 but not D2 receptor antagonist into the PFC. Chapters 3-5 investigated how PFC neurons process synaptic inputs to their dendrites to produce spike output. The intrinsic membrane properties and synaptic responses at the soma and dendrites of deep layer PFC pyramidal neurons were recorded using sharp intracellular or whole-cell patch-clamp techniques in a brain-slice preparation. Different passive and active membrane properties of the soma and dendrites of PFC neurons were observed. The distal dendrites of PFC neurons responded most effectively to strong, highly coincident synaptic inputs. Ca²⁺currents near the soma both amplified the effects of these inputs and modulated the spike output pattern. Spike output at the soma was also controlled by the interplay of slowly-inactivating Na⁺ and K⁺ currents. Chapter 6 investigated the modulation of PFC neurons by DA. DA or a D1 but not D2 receptor agonist increased the evoked firing of PFC neurons via a D1- mediated modulation of slowly-inactivating Na⁺ and K⁺ currents. Concurrently, D1 receptor activation reduced burst firing in PFC neurons, due to a attenuation of Ca²⁺ currents. D1 receptor activation also increased both GABA[sub A] IPSPs and NMDA EPSPs. The final chapter of this thesis integrated these data into a cellular model of PFC function and its modulation by DA. It is proposed that DA may tune PFC neurons such that they respond selectively to strong synchronized inputs from other cortical areas. In the presence of DA, working memory processes mediated by the PFC may be influenced selectively by stimuli of behavioral significance. / Arts, Faculty of / Psychology, Department of / Graduate

The neurochemical effects of partial D2-like agonists (i.e., terguride) to alter striatal DOPA accumulation under high and low dopaminergic tone was examined in preweanling rats. The results indicate that terguride has agonist-like (quinpirole-like) effects under a low dopaminergic tone and antagonist-like (haloperidol-like) effects under a high dopaminergic tone during the preweanling period.

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Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 138-142).

No description available.

The extended striatum is a large, dopamine-innervated forebrain structure comprising the caudate-putamen, nucleus accumbens and olfactory tubercle (OT). The OT remains largely unexplored, despite its potentially important role in behaviour and dopamine (DA)-mediated reward. One method of studying function is examining "supersensitive" behavioural responses to DA agonists in animals after striatal DA loss. We examined whether D1 or D2 receptor supersensitivity occurs in the OT and neighbouring islands of Calleja (ICj), after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle and medial OT (mOT). We also asked if the resulting DA receptor supersensitivity is anatomically heterogeneous. Our results showed D1-like receptor supersensitivity occurring in the OT with several DA agonists, and heterogeneously across the extended striatum. There is evidence of D2-like receptor supersensitivity in the ICj. Our focal mOT lesion failed to show DA receptor supersensitivity. Finally, there is little evidence for D2 supersensitivity as measured by [ 35S]GTPgammaS binding.

Background Past studies from this laboratory have shown that quinpirole administration from postnatal day (P) 1–21 produces persistent supersensitization of the dopamine D2 receptor that persists throughout the animal's lifetime. Methods In Experiment 1, both male and female rats were treated with quinpirole or saline from P1–21 and tested on the place and match-to-place versions of the Morris water task (MWT) from P22–28. In Experiment 2, both male and female rats were administered either acute or chronic injections of quinpirole (1 mg/kg) or saline beginning on P1 until analysis for corticosterone (CORT) on P7, 14, or 21. Results Neonatal quinpirole treatment produced deficits on both versions of the MWT compared with saline control. One day after behavioral testing, brain tissue was harvested, and the hippocampus was analyzed for nerve growth factor (NGF) and brain-derived nerve growth factor (BDNF); NGF was found to be significantly decreased by neonatal quinpirole treatment. Acute or chronic quinpirole treatment on P14 produced a larger increase in CORT than controls and produced larger increases in CORT than control rats on P21. Conclusions These results demonstrate that neonatal quinpirole treatment produces cognitive deficits that could be related to decreases in hippocampal NGF and increases in CORT, resulting in abnormalities in hippocampal development.