Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.

Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 54-60).

Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.

AN ABSTRACT OF THE THESIS OF Crystal Marie Welsh, for the Masters of Science degree in Equine Reproductive Physiology, presented on October 6, 2009, at Southern Illinois University Carbondale. TITLE: IMMUNOHISTOCHEMICAL IDENTIFICATION OF DOPAMINERGIC AND ADRENERGIC NERVES IN THE EQUINE OVARY MAJOR PROFESSOR: Dr. Sheryl S. King Dopamine (DA) appears to play a role in seasonal reproduction in the mare. We hypothesize that DA is delivered to the ovary by nerves. The objective of this study was to use immunohistochemical (IHC) localization to identify ovarian dopaminergic and adrenergic nerves. Ovaries were collected during anestrus (n=9) and cyclicity (n=11). Tissue was prepared for IHC using antibodies specific to tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DβH). Microscopic evaluation was performed, comparing the numbers and distribution of TH– versus DβH–specific immunoreactive (IR) neurons. Catecholaminergic neurons were present in all ovaries. The preponderance (P<0.0001) of IR neurons were dopaminergic. Neurons were moderately dispersed throughout the ovarian medulla and lightly in the cortex. Moderate to heavy neuron density was also noted around blood vessels. Neither dopaminergic nor adrenergic neuron type was consistently associated with specific reproductive structures. These results indicate that catecholaminergic innervation does exist in the equine ovary. The presence of ovarian DA nerves supports our hypothesis that DA has a direct role in ovarian function in the equine, although the mechanism of this function requires further study.

Despite substantial progress in the area of depression research, the current treatments for Major Depressive Disorder (MDD) remain suboptimal. Therefore, various medications are often used as augmenting agents in pharmacotherapy of treatment-resistant MDD. Despite the relative clinical success, little is known about the precise mechanisms of their antidepressant action. The present work was focused on describing the effects of three drugs with distinctive pharmacological properties (pramipexole, aripiprazole, and quetiapine) on function of the monoaminergic systems involved in the pathophysiology and treatment of MDD. Reciprocal interactions between the monoamines serotonin, norepinephrine, and dopamine systems allow the drugs targeting one neuronal entity to modify the function of the other two chemospecific entities. Electrophysiological experiments were carried out in anaesthetized rats after 2 and 14 days of drug administration to determine their immediate and the clinically-relevant long-term effects upon monoaminergic systems. Pramipexole is a selective D2-like agonist with no affinity for any other types of receptors. It is currently approved for use in Parkinson’s disorder and the restless leg syndrome. Long-term pramipexole administration resulted in a net increase in function of both dopamine and serotonin systems. Aripiprazole is a unique antipsychotic medication. Unlike all other representatives of this pharmacological class that antagonize D2 receptor, this drug acts as a partial agonist at this site. Chronic administration of aripiprazole elevated the discharge rate of the serotonin neurons, presumably increasing the overall serotonergic neurotransmission. Like aripiprazole, quetiapine is one of three atypical antypsicotic drugs approved for use in MDD. Prolonged administration of quetiapine led to a significant increase in both noradrenergic and serotonergic neurotransmission. Importantly, the clinically counter-productive decrease in the spontaneous firing of catecholaminergic neurons, induced by SSRIs, was overturned by the concomitant administration of both aripiprazole and quetiapine. The increase in serotonergic neurotransmission was a consistent finding between all three drugs studied herein. In every case this enhancement was attained in a distinctive manner. Understanding of the precise mechanisms leading to the amplification/normalization of function of monoamines enables potential construction of optimal treatment strategies thereby allowing clinicians greater pharmacological flexibility in the management of depressive symptoms.

Cariprazine is a novel dopamine (DA) and serotonin (5-HT) partial agonist with an in vitro receptor affinity profile that endows it with the potential to be used successfully in the treatment of both unipolar and bipolar disorders. The objective of this study was to determine whether in vitro findings with cariprazine lead to functional alterations of monoamine systems in the intact rat brain. In vivo electrophysiological recordings were carried out in male Sprague-Dawley rats under chloral hydrate anesthesia. Dorsal raphé nucleus (DRN), locus coeruleus (LC), and hippocampus cornu ammonis region 3 (CA3) pyramidal neurons were recorded and cariprazine was administered systemically by intravenous injection or locally through iontophoresis. In the DRN, cariprazine induced a complete inhibition of the firing of 5-HT neurons, which was fully reversed by the selective 5-HT1A antagonist WAY100.635. In the LC, the inhibitory effect of the preferential 5-HT2A agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) was reversed by cariprazine with an ED50 value of 67 µg/kg, i.v., and it did not block the inhibitory effect of the α2-adrenergic agonist clonidine. In the hippocampus, when cariprazine was administered by iontophoresis, it inhibited the firing of pyramidal neurons, but it did not dampen the suppressant effect of 5-HT. These results indicate that, in vivo, cariprazine acts as a 5-HT1A agonist in the DRN, as an antagonist on 5-HT2A receptors controlling the firing of NE neurons, and is a full agonist at 5-HT1A receptors located on pyramidal neurons of the hippocampus. The modulatory actions of cariprazine on the 5-HT and NE systems may contribute to its reported effectiveness in depressive episodes.

An excitatory role for norepinephrine (NE) in the regulation of luteinizing hormone (LH) release was first suggested when it was demonstrated that noradrenergic receptor antagonists were able to block ovulation. More recently it has been proposed that NE has both an excitatory role and an inhibitory role in the neuroendocrine regulation of LH release. The excitatory effects may be mediated by alpha-adrenergic receptors and the inhibitory effects may be mediated via beta-adrenergic receptors. These experiments were performed to better understand the role of NE, the receptor type through which NE exerts its effects, and the role of the two major NE pathways in the brain, on LH secretion in the rat. To further understand the role of NE in pulsatile LH release, NE or one of its agonists was infused into the third ventricle of ovariectomlzed rats pretreated with an adrenergic antagonist. In the second set of experiments ascending noradrenergic pathways were electrically stimulated to determine their effect on pulsatile LH release. These experiments demonstrated that the inhibitory effect of NE on pulsatile LH release is blocked when alpha-1- or alpha-2- receptors are blocked but not when beta-receptors are blocked. Electrical stimulation experiments in unprimed ovariectomlzed rats demonstrated that activation of the dorsal noradrenergic tract (DNT) but not the ventral noradrenergic tract (VNT) inhibited pulsatile LH release. Another series of experiments were performed to determine the role NE in the regulation of LH release in the steroid-primed ovariectomlzed rat. These experiments demonstrated that activation of alpha- or beta-adrenergic receptors inhibited the LH surge when adrenergic agonists are infused during the rising phase of the surge. In a similar manner electrical stimulation of either the DNT or VNT inhibited LH release if stimulation occured during the rising phase of the surge. The inhibitory effects of the DNT appear to be via activation of alpha-adrenergic receptors since inhibition was prevented by an alpha-adrenergic antagonist. Under a variety of steroidal conditions and stimulation parameters, activation of the DNT or VNT did not enhance LH release. The lone exception to this was stimulation of the VNT in anaesthetized, steroid-primed ovariectomized rats pretreated with an alpha-adrenergic antagonist. In this case stimulation of the VNT did enhance LH release over non-stimulated and electrically stimulated, saline-treated controls. These results suggest that LH release is enhanced by stimulation of the VNT only when alpha-adrenergic receptors are blocked. In conclusion, it is evident from these studies that activation of alpha-adrenergic receptors either by intraventricular infusion of NE or alpha-agonists, as well as electrical stimulation of noradrenergic tracts inhibits LH secretion. This suggests that the inhibitory effects of NE may be more of a factor in the regulation of LH release than has been previously proposed. In conclusion, NE, in addition to its well established excitatory role, may also have an important inhibitory role in the regulation of LH release. It appears that both inhibitory and excitatory effects of NE on LH release may be mediated by both alpha- and beta-receptors. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

The hypothesis that the noradrenergic projection from the locus coeruleus (LC) to the cerebral cortex and hippocampus is an important neural substrate for learning was evaluated. Maze performance was studied in rats receiving either electrolytic lesions of the LC, or 6-hydroxydopamine (6-0HDA) injections into the region of the dorsal tegmental noradrenergic projection. In contrast to the results of an earlier report (Anlezark, Crow, and Greenway, 1973), LC lesions did not disrupt the acquisition of a running response for food reinforcement in an L-shaped runway, even though hippocampal-cortical noradrenaline (NA) was reduced to 29%. Greater telencephalic NA depletions (to 6 percent of control levels) produced by 6-0HDA also failed to disrupt the acquisition of this behaviour or impair the acquisition of a food reinforced position habit in a T-maze. Neither locomotor activity nor habituation to a novel environment was affected by the 6-0HDA lesions. Rats with such lesions were, however, „ found to be significantly more distractible than controls during the performance of a previously trained response. In another group of rats with identical 6-OHDA injections, the establishment of a lithium chloride-induced conditioned taste aversion was not affected by the lesions. The hypothesis that telencephalic NA is of fundamental importance in learning was not supported. / Medicine, Faculty of / Graduate

The role of noradrenaline (NA) in the behavioural and pharmacological effects of morphine was evaluated in rats. Animals received specific injections of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DB) resulting in selective depletion of telencephalic NA levels and increased levels of noradrenaline in the spinal cord and cerebellum. Employing changes in the hypoactive phase of morphine-induced locomotor activity as an index of tolerance development, it was observed that injection of 6-OHDA into the dorsal noradrenergic bundle resulted in a slower rate and a lesser degree of tolerance development to morphine. The effect of the DB-6-0HDA lesion on physical dependence was assessed by measuring naltrexone-induced withdrawal in lesioned and control animals who had received chronic morphine treatment. Results indicate that although NA is important in tolerance development, it does not mediate a dominant role in withdrawal, although behavioural evidence suggesting a secondary or modulatory role is presented. The interaction of amphetamine and morphine with the dopamine (DA) system was also assessed by studying the behavioural effects of amphetamine in animals following either acute or chronic morphine treatment. It was observed that amphetamine potentiated the spontaneous locomotor hyperactivity following both acute and chronic morphine treatment. The DB-6-OHDA lesion did not affect the locomotor potentiation of amphetamine in morphine pre-treated animals, and the hypothesis that another transmitter system mediates this effect, specifically DA, is discussed. / Medicine, Faculty of / Graduate