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

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

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

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

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

WS-50030 [7-{4-[3-(1H-Inden-3-Yl)Propyl]Piperazin-1-Yl}-1,3-Benzoxazol- 2(3H)-One]a Novel Dopamine D2 Receptor Partial Agonist/Serotonin Reuptake Inhibitor with Preclinical Antipsychotic-Like and Antidepressant-Like Activity

The preclinical characterization of WS-50030 [7-{4-[3-(1Hinden-3-yl)propyl] piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D2 receptor (D2L Ki, 4.0 nM) and serotonin transporter (Ki, 7.1 nM), potent D2 partial agonist activity (EC50, 0.38 nM; Emax, 30%), and complete block of the serotonin transporter (IC50, 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID50, 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D2 partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole\u27s reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D2 receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants