Visiting Researcher/Teaching Assistant
Room 0G.433, David Keir Building
School of Psychology
Queen's University Belfast
Belfast, BT7 1NN
Northern Ireland, UK
+44 (0)28 9097 4336
My research has focused on the behavioural pharmacology of linked aspects of animal and human behaviour.
Our investigations concerning the neurotransmitter serotonin (5-HT) have delineated a role of for the subreceptors 5-HT1A and 5-HT1B in the control of murine agonistic behaviour. These results suggest the important potential of 5-HT1A agents for the control of anxiety and agonistic behaviour. From this view point, I have examined, in collaboration with Dr. Paul Mitchell (Dept. Pharmacy and Pharmacology, University of Bath), the influences of (+)-WAY-100135, a new 5-HT1A antagonist, on murine social and agonistic behaviour. Whilst (+)-WAY-100135 has been demonstrated not to exert an anxiolytic influence in rats, this is the first study to report that this compound also does not show an anxiolytic influence on murine behaviour.
Considerable controversy still exists concerning the role of 5-HT1A receptors in murine aggression. Our data corroborate some, but not all, previous reports for the role of these sites in aggression I propose to also examine the role of 5-HT2 receptors in murine social and agonistic behaviour, since disagreement centres on whether 5-HT1B or 5-HT2 receptors influence aggression via an anxiogenic effect.
This work, performed in collaboration with Dr. Robert Rauche, School of Psychology, QUB and Kevin Dyer, PhD student, is designed to determine why patients who have suffered some form of closed head injury often display aggressive behaviour. The background to this research lies in the relationship between specific brain areas and behaviour.
The frontal lobes/pre-frontal cortex are the primary neurobiological regulators of human aggression This has received support from neuroimaging studies and neuropsychological testing of executive function. An established method of studying the role of brain structures in aggression is to examine individuals with injury to those structures, thus allowing researchers to examine what happens when their function is impaired. The majority of investigations into biological etiologies of aggression, including frontal lobe/pre-frontal cortical dysfunction, have not controlled for certain confounds and use aggression measures with either poor or unknown psychometric properties This investigation will examine neuropsychological functioning associated with frontal lobes. Aggression will be measured using a validated aggression questionnaire, controlling for confounds such as socially desirable responding, gender, socioeconomic status, education, handedness and age.
I have developed a paradigm which employs latent inhibition in the rat as an animal model of psychosis. This work, performed in collaboration with Professor David King, Department of Therapeutics and Pharmacology, QUB, and two graduated PhD students Karen Trimble and David Gracey, demanded considerable effort in producing computer software to monitor stimuli and record the animals’ behavioural responses. The purpose of this research is to use the model of latent inhibition in the rat to assess the potential clinical efficacy of new compounds developed as neuroleptic agents. To-date, we have tested the effects of proven neuroleptic compounds such as haloperidol, clozapine and remoxipride which demonstrate an enhancement of LI. The data obtained for atypical neuroleptics, such as clozapine, demonstrates the robustness of the LI model in that this paradigm can detect neuroleptic-like actions that result from manipulations of neurotransmitters other than dopamine. We are now proceeding to evaluate the influences of novel compounds on LI with a view to assessing potential clinical applications. Funds received from Zeneca (£15,000) will be used towards this research.
Professor King and I have now developed a human paradigm, based on our animal work, to assess LI in healthy volunteers and schizophrenics. Preliminary data with the antipsychotic agent chlorpromazine indicate a successful demonstration of the compound’s enhancement of LI in healthy volunteers; a result consistent with our animal data. This paradigm will be used in conjunction with other psychological (CANTAB software) and physiological (eye movement tests) to assess the onset/treatment of schizophrenia.
Based on animal and human studies, it has been suggested that the orbitofrontal cortex is activated during a range of paradigms that include guessing tasks, delayed matching tasks, sentence completion and decision making. The orbitofrontal cortex has also been proposed to play an important role in the behavioural manifestations, symptoms and cognitive impairments observed in schizophrenia, perhaps in relation to neuronal structure abnormalities.
Although the 5-HT system may be important in normal function, treatment and pathogenesis of cognitive disorders in man, such evidence is lacking in animal studies. For example, the role of 5-HT, as determined by 5-HT depletion techniques, in animal models of cognition has produced equivocal results. Forebrain serotonin depletion, achieved by infusion of the 5-HT neurotoxin 5,7-dihydroxytryptamine, has been reported to facilitate rodent acquisition of operant visual discrimination .By contrast, acute depletion of brain 5-HT in rats, induced by administering an amino acid load deficient in tryptophan, has been reported to be without effect on operant conditioning and locomotor behaviour. To the best of the authors’ knowledge, the effects of tryptophan depletion have not been examined with respect to animal models of schizophrenia, such as Latent Inhibition (LI). Furthermore, the role of 5-HT subreceptors in rodent orbitofrontal cortex control of cognition and rodent models of schizophrenia (LI) remains to be elucidated.
iven the evidence for the function of 5-HT subreceptors in the rat and guinea pig orbitofrontal cortex, we propose to examine the suggestion that the effects of tryptophan depletion on rodent behaviour may be mediated by 5-HT1A and 5-HT2 receptors located in the orbitofrontal cortex.
Thus, this study is comprised of a series of experiments that will examine the role of orbitofrontal cortex serotonergic subreceptors in the mediation of acute tryptophan depletion effects on animal models of cognition and schizophrenia. The work has awarded a grant for £568,000 from NI HSS Research and Development Office.
I will be collaborating with Dr. Eugene O’Hare, who is the PI, to investigate the biological bases of Alzheimer’s disease. This research has attracted a Knowledge Transfer Partnership (Department of Trade and Industry) grant for the sum of £192,000.
Bell, R and Brown, K. Cholinergic mechanisms in aggressive behaviour: role of muscarinic and nicotinic systems. In Central Cholinergic Mechanisms and Adaptive Dysfunctions. Singh, M.M., Warburton, D.M. and Lal, H (Eds.) Plenum. New York. (1985).
Bell, R, Warburton, D.M. and Brown, K. Drugs as research tools in psychology: cholinergic drugs and aggression. Neuropsychobiology 14: 181-192 (1985).
Bell, R and Hepper, P.G. Catecholamines and aggression in animals. Behavioural Brain Research. 23, 1-21 (1987).
Bell, R and Hobson, H. The effects of pindobind, a novel 5-HT1A antagonist, on social and agonistic behaviour in male albino mice. Pharmacology, Biochemistry and Behavior. (1993). Vol. 46 pp 67-72.
Bell, R and Hobson, H. The effects of (-)-pindolol and SDZ 216-525 on social and agonistic behaviour in male mice. Pharmacology, Biochemistry and Behavior. (1993). Vol. 46 pp 873-880.
Bell, R and Hobson, H. 5-HT1A receptor influences on rodent social and agonistic behaviour : a review and empirical study. Invited paper. Neurosciences and Biobehavioral Reviews.Vol.18 No.3 pp 325-338. 1994.
Bell, R, Donaldson, C and Gracey, D. Differential effects of CGS12066B and CP94-253 on murine social and agonistic behaviour. Pharmacology, Biochemistry and Behavior. Vol. 52 No.1 pp 7-16. 1995.
Bell, R, Mitchell, P and Hobson, H. Effects of the 5-HT1A antagonist (+) WAY 100135 on murine social and agonistic behaviour. Pharmacology, Biochemistry and Behavior. Vol.54 No.1 pp 159 - 167. 1996.
Trimble, K, Bell, R and King, D.J. Enhancement of latent inhibition in rats by the atypical antipsychotic agent remoxipride Pharmacology, Biochemistry and Behavior. Vol.56. No.4. pp 809-816. 1997.
Trimble, K, Bell, R and King, D.J. Enhancement of latent inhibition in rats at a high dose of clozapine J. Psychopharmacology. VOL 12. NO.2 pp 215 - 219 1998.
Gracey, D, Bell, R and King, D.J. Enhancement of latent inhibition in rats by the CCK antagonist proglumide Pharmacology, Biochemistry and Behavior. Vol. 59, N0. 4 pp 1053 - 1059. 1998.
Bell, R, Mitchell, P and Lynch, K. Lack of effect of the 5-HT1A antagonist WAY-100635 on murine agonistic behaviour. Pharmacology, Biochemistry and Behavior. Vol. 64, No. 3 pp 549 - 555. 1999.
Gracey, D, Bell, R and King, D.J. PD-135,158, a CCKB antagonist, enhances latent inhibition in the rat Pharmacology, Biochemistry and Behavior. Vol. 65, No. 3 pp 459 - 463..2000.
McCartan, D, Bell, R. Green, J.F. Campbell, C. Trimble, K. Pickering, A and King, D.J. The differential effects of chlorpromazine and lorazepam on latent inhibition in healthy volunteers. J. Psychopharmacology. Vol.15 (2). pp 96 – 104. 2001.
Gracey, D, Bell, R and King, D.J. Differential effects of the CCKA ligands PD-140,548 and A-71623 on latent inhibition in the rat. Progress in Neuropsychopharmacology and Biological Psychiatry. 26. pp 497 - 504. 2002.
Trimble, K, Bell, R and King, D.J. Effects of the selective D1 Antagonists SCH 39166 and NNC O1-O112 on latent inhibition in the rat. Physiology and Behavior. 77. pp 115 - 123. 2002.
Barrett, S, Bell, R, Watson, D and King, D.J Effects of amisulpride, resperidone and chlorpromazine on latent inhibition, executive function and eye movements in healthy volunteers. J. Psychopharmacology. 18(2). pp. 156 – 172. 2004.
Barrett S.L., Kelly C., Watson D.R., Bell R and King D.J. Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder. Psychological Medicine. 35(12), pp 1737 – 1746. 2005.
Dyer, K., Bell, R., McCann, J and Rauch, R. Aggression after traumatic brain injury: Analysing socially desirable responses and the nature of aggressive traits. Brain Injury. Vol. 20(11). pp. 1163 – 1173. 2006.
Barrett S.L., Kelly C.B., Bell, R and King D.J. Gender influences the detection of spatial working memory deficits in bipolar disorder. Bipolar Disorders. In press. 2007.