published_or_final_version / abstract / Zoology / Doctoral / Doctor of Philosophy

To test the hypothesis that the hypothalamic tuberoinfundibular dopaminergic neuronal system plays a role in the dynamic regulation of pituitary prolactin secretion, its activity was correlated with experimentally-induced prolactin secretory episodes in the male rat. Direct estimates of tuberoinfundibular neuronal activity were made by measuring its rates of dopamine and norepinephrine synthesis or release. Prolactin secretion was assessed in vivo by measuring radioimmunoassayable prolactin levels in peripheral blood and the pituitary and in vitro by measuring prolactin concentrations released into incubation media. The anesthetic urethane and a substance isolated from the pineal gland were both demonstrated to inhibit prolactin secretion. Significant elevations of newly synthesized tuberoinfundibular dopamine were observed concomitant with this decreased prolactin secretion suggesting that acute increases in tuberoinfundibular dopaminergic neuronal activity were perhaps causally related to acute decreases in prolactin secretion since these substances were without a direct effect on the pituitary in vitro. Conversely, acute decreases in tuberoinfundibular neuronal activity induced by dopamine biosynthesis inhibition or mimicked by pituitary receptor blockade induced acute increases in prolactin secretion. As another prerequisite for its involvement in the dynamic regulation of prolactin secretion, the tuberoinfundibular neuronal system was demonstrated to be involved in the negative feedback control of prolactin over its own secretion. Elevated circulating prolactin levels produced by pituitary homografts transplanted beneath the kidney capsule accelerated tuberoinfundibular dopaminergic neuronal activity. In two unrelated experimental conditions, rats rendered blind and anosmic or hyperprolactinemic, the chronic inhibition of prolactin secretion was not associated with the maintenance of an increased tuberoinfundibular neuronal activity, but rather with a supersensitivity of the anterior pituitary to the prolactin-release-inhibitory action of dopamine. Long-lasting alterations in tuberoinfundibular dopaminergic neuronal activity appeared to induce this pituitary supersensitivity to dopamine. The tuberoinfundibular neuronal system appears to have the capacity to modulate prolactin secretory episodes via the alteration of its dopaminergic activity. Long-lasting alterations in this activity may induce changes in anterior pituitary sensitivity to dopamine essential for the chronic inhibition of pituitary prolactin secretion.

Stroke is a widespread condition, which often leaves survivors with lasting deficits in motor function, however, physical rehabilitation is the only treatment available after the acute period. A large body of preclinical literature suggests dopamine-augmenting drugs, could enhance motor recovery following stroke. Unfortunately, mixed clinical results have prevented the implementation of such treatments, possibly due to the wide variety of G protein-coupled receptors these drugs can activate. Using a mouse photothrombosis stroke model and a battery of motor and sensorimotor behavioural tests, the current study aims to demonstrate proof of principle for the use of D1-class dopamine receptor agonists to enhance poststroke motor recovery and to evaluate the role of aerobic exercise rehabilitation in an asynchronous study design. The effect of light-dark cycle on behavioural outcome (horizontal ladder test, adhesive removal test, cylinder test) and histological outcome (infarct size) in photothrombotic stroke was evaluated in order to optimize the stroke model, but no there was no evidence of differences between strokes occurring during the light or dark period of a mouse’s circadian rhythm. A bioactive, suboptimal dose of D1-agonist dihydrexidine, was determined by evaluating its effect on locomotor activity and its ability to increase expression of immediate early gene c-fos. Using the determined dose, studies evaluating the efficacy of 7-days and 2-days of dihydrexidine administration on poststroke motor recovery, were performed, indicating efficacy of a 7-days, but not of a 2-days, course of treatment. The 7-days dihydrexidine treatment resulted in accelerated recovery as compared to a control group receiving saline. This work demonstrates, for the first time, proof of principle for the use of specific activation of D1-class dopamine receptors to enhance motor recovery following stroke.

Motivation has been defined as a set of processes which enables organisms to overcome obstacles by energizing behavior in the pursuit of a goal. There are several important observations about motivated behavior which provide insight into the neural mechanisms underlying goal-directed motivation. First, motivation serves two important functions, as it both energizes behavior and also directs it toward or away from specific stimuli. Many of the behavioral tasks used to assay motivation in laboratory rodents do not specifically aim to measure these two distinct aspects of motivation. A second feature of goal-directed motivation is that it is sensitive to both costs and benefits of a given situation, enabling animals to make cost-benefit decisions. Again, many of the behavioral tasks which study cost-benefit decision making do not specifically aim to independently measure the impact of cost manipulations and benefit manipulations in an isolated manner. Here, I first develop behavioral measures which aim to specifically dissociate activational and directional effects of motivation. By characterizing a novel behavioral measure known as a Progressive Hold Down (Ph.D.) task, and using this task in parallel with a more traditionally used Progressive Ratio (PR) task, I show that methamphetamine robustly enhances activational effects of motivation, leading to increased response rates in both the Ph.D. and PR task, but mice are not more goal-directed in the Ph.D. task. I next develop and characterize two novel behavioral assays which are specifically used to examine effort and value contributions to cost-benefit decision making. The Concurrent Effort Choice (CEC) task measures how changes in effort levels impact decision making whereas the Concurrent Value Choice (CVC) task measure how changes in reward value impact decision making. Using these novel assays to examine specific processes important for goal-directed motivation, I carefully examine the role of manipulation of the Dopamine D2 receptor (D2R) in a mouse model which over-expresses the D2R within the striatum (D2R-OE), and the role of pharmacological manipulation of the Serotonin 2C receptor (5-HT2CR) with the functionally selective ligand SB242084. Whereas D2R-OE specifically impacts sensitivity to changes in effort levels which decrease overall levels of goal-directed motivation, selective modulation of the 5-HT2CR via treatment with SB242084 increases response vigor through enhanced dopamine release in the dorsomedial striatum, but this increase in response vigor does not alter sensitivity to effort or value changes when working for rewards. Together, these studies demonstrate the benefits of developing a more nuanced understanding of how specific manipulations impact motivated behavior by examining the specific underlying processes being altered.

The neural mechanisms mediating one-trial and multi-trial behavioral sensitization during early ontogeny are poorly understood. The purpose of this thesis was to assess the importance of D2-like receptors for the induction of cocaine- and methamphetamine-induced one-trial and multi-trial behavioral sensitization during the middle and late preweanling period. In a series of four experiments, rats were injected with saline or the selective dopamine D2-like receptor antagonist raclopride 15 min prior to treatment with the indirect dopamine agonists cocaine or methamphetamine. Acute control groups received two injections of saline. The pretreatment regimens occurred on either PND 16 or PND 20 (one-trial behavioral sensitization) or PND 13-16 or PND 17-20 (multi-trial behavioral sensitization). On PND 17 or PND 21, rats were challenged with either cocaine or methamphetamine and sensitized responding was assessed. With only a single exception, both one -trial and multi-trial cocaine- and methamphetamine-induced sensitization was evident on PND 17 and PND 21. Importantly, the D2-like receptor antagonist raclopride did not prevent the induction of cocaine- or methamphetamine-induced one-trial behavioral sensitization. In regards to multi-trial behavioral sensitization, raclopride failed to inhibit cocaine -induced sensitized responding on PND 17 and PND 21. Interestingly, higher doses of raclopride (0.5 and 1 mg/kg) were able to prevent the induction of multi-trial methamphetamine-induced sensitization on PND 17. Therefore, D2-like receptor antagonism differentially affected methamphetamine -induced behavioral sensitization depending on whether a one-trial or multi-trial paradigm was employed. When considered together, these results suggest that the neural mechanisms underlying the methamphetamine -induced behavioral sensitization of preweanling rats differs depending on the type of experimental paradigm (one- vs multi-trial) being used. Other potential explanations (i.e., nonspecific antagonist effects, impact of contextual conditioning, etc.) for this interesting effect are presented in the Discussion.

Excessive risk-taking is a characteristic of several psychopathological disorders. In order to alleviate maladaptive risky behavior, a thorough understanding of the neurobiological and pharmacological substrates of risky choice must be developed. In this dissertation, the “risky decision-making task” was utilized to explore the mechanisms by which dopamine mediates risky choice. In experiment 1, we characterized rats in risky decision-making as well as a variety of other behavioral traits. This was performed to determine if the behavioral patterns obtained in the risky decision-making task represent an independent cognitive construct rather than a function of a separate behavioral trait. Risky decision-making performance was not correlated with measures of motivation, anxiety, pain tolerance, or other types of decision-making. In contrast, risky choice was correlated with impulsive action as assessed by the Differential Rates of Low Responding Task, suggesting that risky choice may be mechanistically similar to impulsive action. In experiment 2, the effects of various dopaminergic drugs on risky decision-making was investigated. Amphetamine administration attenuated risky choice, while the dopamine antagonist α-flupenthixol had no effect on risky choice. Agonists and antagonists specific to D1 dopamine receptors had no effects on risky choice; however, the D2 dopamine receptor agonist bromocriptine reduced risky choice in a manner similar to amphetamine. Furthermore, coadministration of amphetamine with a D2 antagonist abolished amphetamine’s effects on risky choice, and amphetamine’s effects were unaffected by coadministration of a D1 antagonist. These data suggest that D2 signaling at the receptor is particularly critical to risky decision-making behavior. In experiment 3, D2 dopamine receptor mRNA abundance was assessed in rats that had been previously characterized in risky decision-making using in situ hybridization. Levels of D2 cRNA hybridization in both orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) predicted risky decision-making behavior as assessed by nonlinear curve estimation analyses. Interestingly, opposite relationships between D2 mRNA abundance and risky choice were observed in these two cortical areas, with OFC D2 mRNA abundance showing a U-shaped relationship with risky choice, and mPFC D2 mRNA resembling an inverted U-curve. Additionally, increased levels of D2 mRNA in dorsal striatum were observed in risk-averse rats in comparison to risk-taking rats. In conclusion, these data suggest that signaling via D2 dopamine receptors is an important mediator of risky decision-making behavior, and that D2 signaling in frontostriatal circuitry may be particularly relevant toward these behaviors.

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published_or_final_version / Zoology / Master / Master of Philosophy

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 4 uppsatser.