Cannabis reward: biased towards the fairer sex?
IS McGregor1 and JC Arnold2
1School of Psychology, University of Sydney, Sydney, Australia and 2Department of Pharmacology, Bosch Institute, University of
Sydney, Sydney, Australia
In contrast to drugs such as alcohol, amphetamine and cocaine, cannabis use in humans has proven difficult to model in
laboratory animals. Recent breakthrough discoveries of intravenous THC self-administration in rhesus monkeys and selfadministration
of the synthetic cannabinoid agonist WIN 55,212-2 in rats have allowed new studies of the genetic, neural and
environmental determinants of cannabis use. In the present issue of BJP, Fattore and colleagues further demonstrate genetic
(strain) differences in WIN 55,212-2 self-administration in rats, with Long Evans (LE) and Lister Hooded (LH), but not Sprague-
Dawley, rats self-administering this drug. They then show that female LE and LH rats self-administer more WIN 55,212-2 than
male rats. Ovariectomy abolished this sex difference, suggesting a permissive role for oestrogen in cannabis reward. This
accompanying Commentary reviews recent progress in animal models of cannabis use and highlights the role of genetic,
developmental and endocrine factors in driving cannabis use and dependence.
British Journal of Pharmacology advance online publication, 24 September 2007; doi:10.1038/sj.bjp.0707469
Keywords: cannabis; reward; reinforcement; strain; self-administration; sex differences; oestrogen; oxytocin; rat
Abbreviations: LE, Long Evans; LH, Lister hooded; NIDA, National Institute on Drug Abuse; THC, delta-9-tetrahydrocannabinol;
WIN 55,212-2, (R(þ)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]- pyrrolo[1,2,3-de]-1,4 benzoxazinyl]-
(1-naphthalenyl)-methanone mesylate]
Cannabis is the most widely used illicit drug in the world
and is generally considered to have only modest addictive
potential compared to other drugs such as nicotine, heroin
or methamphetamine. However, some users do become
dependent on cannabis, consuming the drug in a compulsive
fashion and experiencing dysphoria during abstinence.
The factors determining vulnerability to cannabis dependence
have proven difficult to untangle in human studies. In
this issue of the British Journal of Pharmacology, Fattore et al.
(2007), provide evidence from an animal model of hitherto
unexpected sex differences in cannabinoid intake in rats.
Self-administration studies provide a superior animal
model of human drug use with high face validity. The avid
self-administration of alcohol, nicotine, cocaine and
methamphetamine by rodents has been of great utility to
addiction scientists. However, cannabis self-administration
has proven notoriously difficult to obtain in laboratory
animals. A breakthrough came in 2000, when Stephen
Goldberg and colleagues at NIDA showed self-administration
of the prototypical natural cannabinoid THC in squirrel
monkeys (Tanda et al., 2000). The critical factor appeared to
be the use of very low intravenous doses of THC, analogous
to the doses present in a puff of cannabis smoke. Soon after
this, Fattore et al. (2001) showed intravenous self-administration
of low doses of the synthetic cannabinoid CB1
receptor agonist, WIN 55212-2 in rats, albeit with the
limitation that rats must be chronically food restricted for
this to occur.
Genes play a critical role in determining the proclivity
towards cannabis consumption. Earlier studies involving
intracranial self-stimulation and place preference models
indicated that different genetic strains of rats had different
motivational responses to cannabinoids, with Lewis and
Long Evans (LE) but not Fischer 344 strain rats seen as
'cannabis preferring' (Lepore et al., 1995; Gardner, 2002).
Corresponding strain differences in cannabinoid-induced
brain activation and mesolimbic dopamine release were also
evident (Arnold et al., 2001). More recently, WIN 55212-2
self-administration was reported in Lister Hooded (LH) and
LE rats, but not in Sprague-Dawley rats, who will not selfadminister
the drug (Deiana et al., 2007).
Cannabis has intake-limiting panic and anxiety-inducing
properties in a subset of human users and has anxiogenic
and aversive properties in rats (McGregor et al., 1996; Quinn
et al., 2007). If such an aversive component could be
minimized then the rewarding actions of cannabinoids
might be unmasked. Accordingly, the apparently 'rewardresistant'
Sprague-Dawley strain, will self-administer THC
directly into the nucleus accumbens and ventral tegmental
area, presumably bypassing the aversive effects of cannabinoid
stimulation of other brain sites that occur with systemic
administration (Zangen et al., 2006). Received 21 August 2007; accepted 28 August 2007
Correspondence: Professor IS McGregor, School of Psychology, University of
Sydney, Sydney, NSW 2006, Australia. E-mail:
British Journal of Pharmacology (2007), 1-3
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