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Publication Title | Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats

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Neuropharmacology 47 (2004) 1170–1179

Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats

Paola Fadda a,b, Lianne Robinson a, Walter Fratta b, Roger G. Pertwee a, Gernot Riedel a,

a Department of Biomedical Science, School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK

b B.B. Brodie Department of Neuroscience and Center of Excellence ‘‘Neurobiology of Dependence’’, University of Cagliari, Cittadella Universitaria Monserrato, Cagliari, Italy

Received 22 April 2004; received in revised form 29 June 2004; accepted 17 August 2004

Abstract

Cannabinoid receptors in the brain (CB1) take part in modulation of learning, and are particularly important for working and short-term memory. Here, we employed a delayed-matching-to-place (DMTP) task in the open-field water maze and examined the effects of cannabis plant extracts rich in either D9-tetrahydrocannabinol (D9-THC), or rich in cannabidiol (CBD), on spatial working and short-term memory formation in rats. D9-THC-rich extracts impaired performance in the memory trial (trial 2) of the DMTP task in a dose-dependent but delay-independent manner. Deficits appeared at doses of 2 or 5 mg/kg (i.p.) at both 30 s and 4 h delays and were similar in severity compared with synthetic D9-THC. Despite considerable amounts of D9-THC present, CBD-rich extracts had no effect on spatial working/short-term memory, even at doses of up to 50 mg/kg. When given con- comitantly, CBD-rich extracts did not reverse memory deficits of the additional D9-THC-rich extract. CBD-rich extracts also did not alter D9-THC-rich extract-induced catalepsy as revealed by the bar test. It appears that spatial working/short-term memory is not sensitive to CBD-rich extracts and that potentiation and antagonism of D9-THC-induced spatial memory deficits is dependent on the ratio between CBD and D9-THC.

# 2004 Elsevier Ltd. All rights reserved.

Keywords: Cannabis extract; THC; Cannabidiol; Working memory; Water maze; Rat

www.elsevier.com/locate/neuropharm

1. Introduction

Several studies provide compelling evidence that can- nabis and its major psychoactive component D9-tetra- hydrocannabinol (D9-THC) can cause impairments in immediate recall (Darley et al., 1974), working and short-term memory (Miller and Branconnier, 1983; Fletcher et al., 1996) and memory retrieval (Block and Ghoneim, 1993) in man. Similar deficits, especially in short-term memory, have been confirmed in animal studies following systemic administration of D9-THC or other synthetic cannabinoids as well as endogenous ligands such as anandamide. Working memory reflects the transient storage and processing of information and

Corresponding author. Tel.: +44-1224-555758; fax: +44-1224- 555719.

E-mail address: g.riedel@abdn.ac.uk (G. Riedel).

0028-3908/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2004.08.009

is dependent on the online processing within neuronal circuits. Typically, working memory in animals is tes- ted by means of delayed-non-matching to sample (DNMTS) tasks or in maze learning like the 8-arm radial maze or T-maze. D9-THC or WIN55,212-2 treat- ment led to delay-dependent performance deficits in DNMTS paradigms (Hampson and Deadwyler, 1998, 1999, 2000) and selective working memory impairments in radial maze and T-maze in rat and mice (Nakamura et al., 1991; Molina-Holgado et al., 1995; Lichtman and Martin, 1996; Jentsch et al., 1997; Nava et al., 2001). These tasks have in common that animals must adopt a win-shift strategy and performance falls to chance within several seconds or minutes. In contrast, working memory in the open-field water maze requires a win-stay strategy. It is also sensitive to D9-THC treat- ment in mice (Varvel et al., 2001; Da Silva and Taka- hashi, 2002).

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