Putative changes in dopaminergic neurotransmission following nicotine induced behavioural sensitisation

Behavioural sensitisation is a progressive enhancement of stereotypic or locomotor behaviour following repeated intermittent administration of a psychostimulant or stress. It is a phenomenon thought to underlie many neuropsychiatric disorders (e.g. schizophrenia, addiction, depressive disorders, dyskinesia, and psychosis) although its own mechanism remains contentious. In this thesis a multidisciplinary approach was used to investigate the role of dopamine in behavioural sensitisation. Different in vivo and ex vivo techniques were used to assess and elucidate putative changes in dopaminergic neurotransmission of behaviourally sensitised animals. If so, this improved understanding of behavioural sensitisation could provide a better understanding of the pathophysiologies of neuropsychiatric disorders and provide more insight into why existing pharmacotherapies for these disorders are able to confer only modest benefit. Moreover, this improved understanding can lead to development of new medication and more effective therapies to treat neuropsychiatric disorders and therapies that address the specific problems associated with them. Previously, an oversimplified view of neurotransmitter release was used for the development of current available drugs, i.e. stabilising either the attenuated or increased release of neurotransmitters without considering the involvement of synaptic plasticity. Therapies being used with modest effectiveness regulate dopamine transmission levels, suggesting a putative role for dopamine. The present study used chronic intermittent nicotine administration in rodents to induce behavioural sensitisation which was monitored behaviourally by measuring locomotor activity. Further studies were performed ex vivo assessing receptor binding, intracellular cAMP accumulation and electrically stimulated dopamine release. Prior to the pharmacological assessments, a novel LC-MS/MS method to measure (cyclic-) nucleotides was developed and a fast cyclic voltammetry (FCV) technique was established to measure real-time neurotransmitter release. Specific pharmacological tools were used to identify the role of dopaminergic neurotransmission in behavioural sensitisation. Finally, the ex vivo findings using tissue from sensitised and non-sensitised animals were compared to those findings obtained in vivo.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

National University of Ireland Maynooth

Year dc:date.issued

2011

Author dc:creator

• Goutier, Wouter

• Chemistry

Language dc:language

en