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Title: The involvement of nicotinic cholinergic receptors in drug abuse
Author: Metaxas, Athanasios
ISNI:       0000 0004 2691 2120
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 2010
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The prevalence of nicotine addiction suggests that interactions of neuronal nicotinic cholinergic receptors (nAChRs) with illicit substances and multiple neurotransmitter systems are involved in mediating the rewarding properties of nicotine, cocaine, and morphine. Hence, the overall aim of this thesis was to investigate the role of nAChRs in rendering nicotine, a weak primary reinforcer, to be so widely abused. Interactions between nAChRs and cocaine were investigated at the behavioural and receptor density levels, following chronic cocaine treatment and withdrawal. The effects of blockade of different nAChR subtypes on the development of cocaine-induced behaviours were investigated using dihydro-β-erythroidine (DhBE; 2.0 mg/kg/inj, i.p.) and methyllycaconitine (MLA; 5.0 mg/kg/inj, i.p.). Nicotinic receptor antagonism produced very distinct behaviours in C57BL/6 mice, treated for 14 days with a steady dose, 'binge' administration protocol of cocaine (15.0 mg/kg/inj, i.p.). α4β2* nAChR blockade by DhBE prolonged cocaine-induced horizontal locomotor activity, reduced vertical activity, and diminished stereotypy sensitization. On the contrary, α7 nicotinic receptor antagonism by MLA resulted in the delayed expression of cocaine-induced rearing sensitization and induced a unique, intense grooming phenotype in cocaine-treated animals. To further understand the mechanisms behind this behavioural dissociation, quantitative autoradiography of heteromeric and homomeric nAChRs was performed using [125I]epibatidine and [125I]α-bungarotoxin, respectively. Following 'binge' cocaine administration, α4β2** nAChR density was increased in the ventral tegmental area (VTA) and substantia nigra compacta of cocaine-treated animals, compared to saline controls. Moreover, following 14 days of abstinence from cocaine treatment, α7 nAChR density was decreased in the VTA of cocaine withdrawn animals, compared to controls. These cocaine-induced, subtype- and brain region-specific alterations in nAChR density were not observed following 8 days of treatment with escalating doses of 'intermittent' morphine, nor after the acute and prolonged withdrawal of C57BL/6 mice from morphine administration. An investigation into the mechanism of interactions between nicotinic cholinergic and adenosinergic systems was performed using CD1 mice with a genetic deletion of the adenosine A2A receptor. Following 14 days of nicotine hydrogen salt administration at 24 mg/kg/day via omotic minipumps, quantitative autoradiography of [125I]epibatidine and [125I]α-bungarotoxin binding sites revealed significant genotype x treatment interaction effects on α7 nAChR density. Although chronic nicotine equally increased heteromeric nAChR density in wild type and mutant mice, its effects on α7 nAChRs were predominantly observed in the brains of wild type, rather than adenosine A2A receptor knockout animals. The mechanisms of nicotine reinforcement were investigated using quantitative autoradiography of cytisine-sensitive [125I]epibatidine binding sites, following the acquisition of nicotine self-administration by drug naive C57BL/6 mice. Using an operant yoked-control protocol of nicotine treatment, increased α4β2* nAChR density was observed in the ventral tegmental area and dorsal lateral geniculate nucleus of self-administering animals, compared to mice that passively received nicotine. Overall, the results of the present thesis suggest that alterations in α4β2* and/or α7 nAChR density occur following chronic treatment with nicotine and illicit substances, which are indicative of the interactions that render a weak primary reinforcer as broadly abused as nicotine.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available