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Neuropharmacology Laboratory

Group Head

Dr Richard Loiacono

BSc(Hons) PhD

Tel: +61 3 9905 4859
Fax: +61 3 9905 5851

Specific Interests

My laboratory is interested in investigating the role of ionotropic receptor families (eg: glutamate, GABA and nicotinic receptors) in neurological disorders such Parkinson’s Disease, Alzheimer’s Disease and Schizophrenia, as well in the neurodegenerative / neuroadaptive processes that may be associated with these diseases.

Current projects

Nicotinic Receptors, Dopaminergic and Serotonergic Neurotransmission and Schizophrenia:- Schizophrenia is a common and complex disorder with a range of symptoms including auditory hallucinations, delusions and flattened affect. A substantial component of schizophrenic symptomatolgy appears to arise from deficiencies in an ability to automatically filter or “gate” irrelevant thoughts and sensory stimuli from intruding into conscious awareness. In schizophrenic patients, there is a higher than normal prevalence of tobacco smoking (90%). Several studies have since demonstrated that nicotine, administered either through smoking or gum, transiently normalizes some of the symptoms of schizophrenia, including several sensory gating deficits. Conversely, worsening of symptoms occurs following smoking cessation. We believe the most interesting finding to date is that schizophrenic smokers show a significantly greater clinical response to the atypical antipsychotic clozapine than do schizophrenic non-smokers. The aim of this project is to understand why nicotine potentiates the beneficial actions of atypical antipsychotics such as clozapine. Our hypothesis is that nicotine affects clinical responses to clozapine by altering dopamine or 5HT receptor populations which clozapine normally targets (see below) and that this would be reflected in the way such receptor systems regulate the release of dopamine from areas of brain important in schizophrenia.

APoE, statins cholesterol and Alzheimer's Disease:- The pathophysiology of Alzheimer’s disease is thought to be due to the accumulation of beta-amyloid in the brain. beta-amyloid is derived from APP (amyloid precursor protein). Through different enzymic pathways (alpha, beta and gamma secretases) APP can give rise to APPs? which is neuroprotective and has trophic effects or beta-amyloid; which is neurotoxic and neurodegenerative. There is evidence to suggest an important link exists between beta-amyloid, cholesterol and Alzheimer’s disease; the prevalence of Alzheimer’s disease is reduced in people taking cholesterol-lowering agents (HMG-CoA reductase inhibitors / statins such as simvastatin). There is now some evidence suggesting that statins reduce beta-amyloid production both in vitro and in vivo; and that this might be due to the shunting of APP towards the increased production of APPs and decreased production of beta-amyloid. Nicotinic receptor activation has been shown to be neuroprotective in models for both Parkinson’s and Alzhiemer’s disease. Recent evidence has shown that beta-amyloid can interact with a specific subtype of the nicotinic receptor and this may be relevant in the progression of neurodegenerative diseases. The aim of this project is to study the effect of statins on the levels of APP and various secretase enzymes (BACE, TACE, PS1 and PS2) in mice and rats. Our hypothesis is that statins do regulate the secretase enzymes. Additionally this project will examine whether the interaction between beta-amyloid and nicotininc receptors is altered by statins. There is scope within the project to examine these factors in a transgenic mouse model that has altered lipid metabolism and shows an increased production of beta-amyloid and beta-amyloid plaque

Histamine Receptors in the Brain :- Brain histamine is involved in the regulation of arousal state, brain energy metabolism, locomotor activity, autonomic and vestibular functions, feeding, drinking, sexual, behavior, and analgesia. Histamine H3 receptors are presynaptically located, are negatively coupled to adenylyl cyclase and mediate presynaptic inhibition of neuronal histamine release as well as other neurotransmitters. Our preliminary studies and the recently published work by other investigators indicate that histamine H3 receptors are widely distributed in mammalian brain. High densities are found in the basal ganglia (important in locomotion and affected in Parkinson’s Disease) as well as the cortex and hippocampus (important in learning and memory and affected in Alzheimer’s Disease). We suspect that histamine H3 receptors may also be important in the actions of some the antipsychotic agents used in Schizophrenia

Nicotinic Receptors in Parkinson's Disease:- There are 2 main types of nicotinic receptor present in brain, the alpha4 and the alpha7 type, although many additional types also exist. Nicotinic receptors are largely localized to basal ganglia structures; and thus are of direct relevance to the fine control of movement. Interestingly, in Parkinson’s disease there is a loss of nicotinic receptors in these regions. Our studies have focused on whether nicotinic receptor activation can slow the neurodegeneration seen in Parkinson’s disease. We have already shown that the activation alpha4 type nicotinic receptor is important in preventing neurodegeneration in animal models of Parkinson’s disease. What we don’t know is whether these are the only types of nicotinic receptors involved

Endocannabinoids in Neuroprotection:- The endocannabinoid systems comprises the endogenous lipids anandamide and 2-arachidonoylglycerol (2-AG), the proteins responsible for their biosynthesis, uptake and inactivation, and the receptors through which their responses are mediated; the cannabinoid receptors (CB1 and CB2). This system is proposed to be involved in various neurodegenerative diseases such as Parkinson's and Huntington's diseases as well as Multiple Sclerosis. It has been demonstrated that the endocannabinoid system can protect neurons against some forms of neuronal damage.

Members of Laboratory

Ms Nicola Ingram (PhD Student)
Ms Fiona Kennon (PhD Student)
Mr Leigh Brown (BSc Hons Student)
Ms Sarah Brooker (BSc Hons Student)