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.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

Salmonids naturally organise into social hierarchies both in the wild and aquaculture. This thesis investigates how social rank influences the physiology and development of salmonids with different life strategies using Atlantic salmon (Salmo salar) as a model. In broad terms two types of studies were conducted. Firstly osmoregulatory traits of freshwater parr prior to smolting, maturing or remaining immature where investigated using Na+ gill uptake kinetics. Highly distinct patterns emerged, especially for Na+ uptake affinity, between future alternative phenotypes, which could potentially be used as an identification tool in otherwise visually identical fish. Examination of Na+ uptake kinetics from a social status perspective revealed that first and intermediate ranked fish, which received less aggression and had lower cortisol, were better prepared for sea water entry. In the second batch of studies brain serotonergic activity (5-HIAA/5-HT), a key regulator of agonistic behaviour in vertebrates, was examined in a range of social conditions. First, the stability of social ranks was tested by food manipulation. The most dominant fish were able to retain their high status even after being kept in nutrient poor conditions. High status was associated with a high standard metabolic rate (SMR) and low brain 5-HIAA/5-HT. Secondly, studies on hierarchies with marked bimodal size asymmetries showed that upper modal group fish (UMG) became dominant. Despite being subordinate lower modal group (LMG) individuals showed similar growth rates, serotonin turnover and cortisol to UMG fish, possibly due to high aggression and fin injury sustained by high rank fish fighting for dominance. Thirdly, the association between social dominance and developmental pathway was examined in size-matched groups of immature parr and precocious parr, with the latter obtaining higher social positions and showing higher aggression. Brain serotonin turnover revealed higher 5-HIAA/5-HT in immature parr, a phenotypic distinction that was also identified in immature salmonids in aquaculture. Plasma samples from alternative life histories (immature parr, precocious parr and smolts) were also used for a preliminary investigation of potential metabolite signatures utilising metabolomic techniques.

published_or_final_version / abstract / toc / Zoology / Master / Master of Philosophy

<p>Selective serotonin re-uptake inhibitors (SSRIs) are a new class of antidepressants used mainly for the treatment of depression and other forms of related disorders. There are a number of side effects associated with these drugs which include loss of weight, sexual dysfunction, nervousness and nausea. A fast and reliable detection method such as biosensing for the determination of the SSRIs metabolic profile is therefore essential for the appropriate dosing of these drugs. Biosensors for the determination of the SSRIs biotransformation were prepared with cytochrome P450 (2D6) isoenzyme and poly (anilinonapthalene sulfonic acid) film electrochemically deposited on gold.</p>

Serotonin (5-HT) is a well-known modulator of spinal cord excitability and motor output. In the spinal cord, the actions of 5-HT are primarily mediated by the 5-HT1AR, 5-HT2Rs and the 5-HT7R. Following a spinal cord transection, which results in a loss of supraspinal input, 5-HT agonists such as quipazine are used to provide excitation to the spinal cord to facilitate locomotor recovery. This is characterized by rhythmic alteration of left and right hindlimbs and ipsilateral flexor and extensor muscles. However, whether 5-HT has a global effect on spinal cord excitability or is confined to a specific motor group (i.e. flexors or extensors) is currently unknown. Furthermore, quipazine is used in conjunction with activity based interventions to enhance recovery following a spinal cord injury. However, the influence of limb activity on the responsiveness of the injured spinal cord to quipazine has not been examined. Lastly, the recovery of locomotion is at least in part thought to occur through an up-regulation of 5-HT receptors, although this has not been investigated in lumbar spinal cord. Chapter 2 examines whether quipazine had a differential effect on flexor and extensor motor output assessed by recording flexor and extensor reflexes, motoneurons and Ia extracellular field potentials pre- and post-quipazine. It was determined that following an acute spinal transection, quipazine induced a larger flexor monosynaptic reflex (MSR) compared to the extensor MSR due to pre-synaptic but not motoneuron modulation. Chapter 3 examines the influence of a chronic spinal transection with and without passive cycling on the hindlimb flexor and extensor MSR, both pre- and post-quipazine. It was found that three months post STx, the extensor but not flexor MSR demonstrated a hyperexcitable response, which was attenuated with passive cycling. Further, three months of passive cycling extensor MSR response to quipazine was similar to that seen in the control intact group. Chapter 4 examined 5-HT receptor expression in flexor and extensor motoneurons three months post spinalization with or without passive cycling. Following a chronic STx, the 5-HT1AR and 5-HT2CR are down regulated, whereas the 5-HT2AR is up-regulated. Passive cycling further enhanced the 5-HT2AR expression as well as up-regulated the 5-HT7R in extensor but not flexor motoneurons. Chapter 5 discusses the results and significance of these findings in detail.

Illicit drug abuse and addiction is a major problem in New Zealand and worldwide with approximately 12% of illicit drug users classified as having drug dependence or drug-use disorders. The chronically relapsing nature of drug addiction is a prominent feature of this disorder and a significant barrier to treating addiction. Amphetamine-type drugs, more than any other class of drugs, have seen an increase in global usage since the early 1990's. The lack of approved medications for the treatment of stimulant addiction together with an increasing treatment demand drives the need for pharmaceutical intervention. Substitute treatment approaches primarily focus on the dopamine (DA) system. However, several lines of research implicate a dual role for serotonin (5-HT). Using a benztropine (BZT) analogue, JHW 007 (JHW), and an atypical antidepressant, trazodone (TRAZ), we sought to test whether the combined modulation of DA and 5-HT during a period of extinction produced greater attenuation to drug-induced reinstatement compared to either DA or 5-HT alone. One hundred and two (102) male Long Evans rats were tested using an extinction-reinstatement model of methamphetamine (MA) addiction in conditioned place preference (CPP) (n=72) and self-administration (n=30) experimental designs. We hypothesised that a combined DA/5-HT treatment would further attenuate MA-induced reinstatement. Findings showed that JHW significantly attenuated MA-induced reinstatement in our self-administration model but not CPP, while TRAZ failed to significantly attenuate reinstatement in both experiments. The combination treatment group showed a mild attenuation to drug seeking with CPP, but this finding was not significant. Due to time restrictions, we did not test the combination group using a self-administration procedure. Unfortunately we were unable to fully address our initially proposed hypothesis, but our results with JHW add further support to this BZT analogue as a promising stimulant abuse medication.

No description available.

This thesis addresses the effects of pharmacological manipulations of brain 5- hydroxytryptamine (5-HT, serotonin) and it's precursor, tryptophan, on appetite and mood in humans. Chapter 1 is a presentation of the literature reviewed in order to carry out the studies contained within this thesis. General methods are described in Chapter 2; these include biochemical methods for analysis of plasma tryptophan, and measures and assessment methodologies for analysis of appetite and mood. This chapter also contains a pilot study of the methodology adopted for lowering plasma tryptophan levels. The first experiment (Chapter 3) examines the effects of calorie controlled dieting on plasma tryptophan, mood and appetite using a longitudinal design. Dieters were compared with a matched control group, and the results demonstrated that whilst dieting does not appear to alter mood or responses to food in a laboratory setting, it does lower levels of plasma tryptophan compared with baseline and with controls. In view of the confounding variables of dieting on mood and appetite, the second experiment (Chapter 4) examined the effects of an acute, laboratory based depletion of plasma tryptophan on these parameters in healthy female volunteers acting as their own controls. Significant depletion of plasma tryptophan was not associated with alterations in mood or appetite. The third experiment (Chapter 5) addresses the issue of predisposing factors in the effects of tryptophan depletion on mood and appetite. This was carried out with a group of women who had recovered from an eating disorder (bulimia nervosa). These subjects were acting as their own controls but were also compared directly with the non-clinical group of subjects from the previous experiment. This experiment demonstrated interesting differences in the eating behaviour of the two groups, and a significant difference in baseline levels of total plasma tryptophan. There were, however, no effects of tryptophan depletion on mood or appetite in the women who had recovered from bulimia nervosa. In view of the apparent lack of effect of tryptophan depletion on mood or appetite, the remaining two experiments examine the role of specific 5-HT receptor subtypes in the control of appetite. Chapter 6 examines the effect of meta-chlorophenylpiperazine (mCPP), a 5-HT_2C receptor agonist on appetite, and Chapter 7 examines the effect of 5-HT₃ receptor blockade on amphetamine anorexia. Whilst the data from these experiments do not support a role for these receptor subtypes in appetite, it is suggested that this is a potentially fruitful area for future research. The results generated by the above experiments are discussed in Chapter 8 in the light of other research findings. The methodologies adopted for these experiments and the implications of these studies for future research are discussed.