Faculty & Staff   

Building:McIntyre
Room: 1320
Phone: 514-398-3616 ext. 1 (office) or ext. 2 (lab)
Fax:514-398-2045

E-mail: paul.clarke@mcgill.ca

Research Area:

Neuropsychopharmacology and Behavioural Neuroscience

Research Description:

I spent my formative years in Africa, was educated in England, and received postdoctoral training at NIMH (Bethesda, USA) and UBC (Vancouver, Canada).

Overview: We are mainly interested in how drugs affect brain function, and more particularly why drugs such as nicotine, amphetamine and cocaine are so addictive. Here, forebrain dopamine is a key player, but exactly what sort of message is conveyed by dopamine is unclear. For example, some neuropharmacologists believe that dopamine plays a specialized role in reward, while others envisage a more general role in helping the organism react to biologically important stimuli.

Dopamine and behaviour: Several drugs of abuse boost dopaminergic transmission, and this action underlies their rewarding and arousing effects. We have shown that these behavioral effects can be differentiated anatomically, in the sense that they occur in different dopamine-innervated parts of the forebrain. We therefore hypothesize that dopamine may serve several different functions, depending critically on the precise brain area where it is released. Hence, dopamine would have very different effects in caudate-putamen vs. nucleus accumbens vs. olfactory tubercle. We are exploring this idea using a combination of behavioural and neurochemical approaches in lab rats (e.g. intravenous self-administration, conditioned place preference, lesions, and - coming soon - in vivo voltammetry).

Nicotine and tobacco addiction: Among addictive drugs, nicotine is especially puzzling since it does not always appear particularly rewarding in animal models. We think standard animal models may not fully capture the effects of nicotine that motivate tobacco smoking in humans, and we are trying to create new ones. For example, we have recently developed a novel nicotine self-administration procedure which we believe may provide a better model of nicotine delivery as experienced by cigarette smokers; we are using this new procedure in order to examine afresh how nicotine serves as a reinforcer. We are also investigating other chemicals in tobacco smoke that could potentially contribute to tobacco addiction. Furthermore, we have also discovered a drug that blocks nicotine's central actions for several months – not a "cure" for smoking, but a start perhaps.

Rat ultrasonic vocalizations: Rats seem silent to us, but they are in fact quite vocal - but at frequencies beyond our hearing range. The ultrasonic (20-70 kHz) vocalizations made by adult rats are remarkably varied in their acoustic properties, suggesting that they may convey quite complex information. Of course, we would very much like to know what these calls mean, and whether they can be of use in animal models of human disorders such as drug addiction, depression and anxiety.

I am also an external member of the Center for Studies in Behavioral Neurobiology at Concordia University. http://csbn.concordia.ca/Faculty/Clarke/

Selected Publications:

Scardochio T, Clarke PBS (2012) Inhibition of 50-kHz ultrasonic vocalizations by dopamine receptor subtype-selective agonists and antagonists in rats. Psychopharmacology, http://dx.doi.org/10.1007/s00213-012-2931-6

Wright JM, Dobosiewicz MRS, Clarke PBS (2012) The role of dopaminergic transmission through D1-like and D2-like receptors in amphetamine-induced rat ultrasonic vocalizations. Psychopharmacology, http://dx.doi.org/10.1007/s00213-012-2871-1

Wright, JM, Deng L, Clarke PBS (2012) Failure of rewarding and locomotor stimulant doses of morphine to promote adult rat 50-kHz ultrasonic vocalizations. Psychopharmacology, http://dx.doi.org/10.1007/s00213-012-2776-z

Wright, JM, Dobosiewicz MRS, Clarke PBS (2012) Alpha- and beta-adrenergic receptors differentially modulate the emission of spontaneous and amphetamine-induced 50-kHz ultrasonic vocalizations in adult rats. Neuropsychopharmacology 37(3): 808-21 http://dx.doi.org/10.1038/npp.2011.258

Sorge RE, Clarke PBS (2011) Self-Administration: Nicotine, in Animal Models of Drug Addiction, ed. M.C. Olmstead, Humana Press. Chapter 4 pp 101-132.

Clarke, PBS (2010) Nicotine. In: Encyclopedia of Psychopharmacology, Ian P. Stolerman (editor), Springer Berlin, Heidelberg. Part 14, 877-882. http://dx.doi.org/10.1007/978-3-540-68706-1_303

Marcangione C, Constantin A, Clarke PBS (2010) Lack of effect of dopaminergic denervation on caudate-putamen hyperthermia or hypothermia induced by drugs and mild stressors. Pharmacol Biochem Behav 96(1):32-9. http://dx.doi.org/10.1016/j.pbb.2010.04.003

Wright, JM, Gourdon J, Clarke PBS (2010) Identification of multiple call categories within the rich repertoire of adult rat 50-kHz ultrasonic vocalizations: effects of amphetamine and social context. Psychopharmacology 211(1):1-13. http://dx.doi.org/10.1007/s00213-010-1859-y

Sorge RE, Pierre VJ, Clarke PBS (2009) Facilitation of intravenous nicotine self-administration in rats by a motivationally neutral sensory stimulus. Psychopharmacology 207:191-200. http://dx.doi.org/10.1007/s00213-009-1647-8

Sorge RE, Clarke PBS (2009) Rats self-administer intravenous nicotine delivered in a novel smoking-relevant procedure: effects of dopamine antagonists. JPET 330(2):633-640. http://dx.doi.org/10.1124/jpet.109.154641

Grant RJ, Sellings HLH, Crocker SJ, Melloni E, Park DS, Clarke PBS (2009) Effects of calpain inhibition on dopaminergic markers and motor function following intrastriatal 6-hydroxydopamine administration in rats. Neuroscience 158:558-569. http://dx.doi.org/10.1016/j.neuroscience.2008.10.023

Sellings LHL, Baharnouri G, McQuade LE, Clarke PBS (2008) Rewarding and aversive effects of nicotine are segregated within the nucleus accumbens. Eur J Neurosci 28:342-352. http://dx.doi.org/10.1111/j.1460-9568.2008.06341.x

Clarke PBS (2007) Nicotine and nicotinic receptors, and their role in smoking, Chapter 2 of Harm Reduction in Nicotine Addiction, 2007 Report of the Tobacco Advisory Group of the Royal College of Physicians (UK), London, pp. 23-44. http://www.rcplondon.ac.uk/pubs/contents/4fc74817-64c5-4105-951e-38239b09c5db.pdf

Sellings LHL, McQuade LE, Clarke PBS (2006) Characterization of dopamine-dependent rewarding and locomotor stimulant effects of intravenously-administered methylphenidate in rats. Neuroscience 141:1457-1468. http://dx.doi.org/10.1016/j.neuroscience.2006.04.040

Pradhan AAA, Siau C, Constantin A, Clarke PBS (2006) Chronic morphine administration results in tolerance to delta opioid receptor mediated antinociception. Neuroscience 141:947-954. http://dx.doi.org/10.1016/j.neuroscience.2006.04.021

Sellings LHL, McQuade LE, Clarke PBS (2006) Evidence for multiple sites within rat ventral striatum mediating cocaine conditioned place preference and locomotor activation. J Pharmacol Exp Ther 317: 1178-1187. http://dx.doi.org/10.1124/jpet.105.100339

Sellings LHL, Clarke PBS (2006) 6-hydroxydopamine lesions of nucleus accumbens core, but not medial shell, abolish amphetamine-induced conditioned activity. Synapse 59:374-377. http://dx.doi.org/10.1002/syn.20247

Pradhan AAA, Clarke PBS (2005) Pharmacologically selective block of mu opioid antinociception by anti-MOR PNA antisense in absence of detectable ex vivo knockdown. Eur J Pharmacol 506:229-236. http://dx.doi.org/10.1016/j.ejphar.2004.11.018

Pradhan AAA, Clarke PBS (2005) Comparison between δ opioid receptor functional response and autoradiographic labelling in rat brain and spinal cord. J Comp Neurol 481:416-426. http://dx.doi.org/10.1002/cne.20378

Sellings LHL, Clarke PBS (2003) Segregation of amphetamine reward and locomotor stimulation between nucleus accumbens medial shell and core. J Neurosci 23:6295-6303.