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Moghaddam 1998), and which can be reversed by blocking glutamate release (Moghaddam
and Adams 1998).
Over the longer term, behavioural sensitisation, the process by which the behavioural
effect of a drug is enhanced with repeated applications, and which may contribute to drug
addiction and craving (Robinson and Berridge 1993; Hyman 1996), has been postulated to be
mediated by synaptic or structural plasticity in the mPFC. Treatment of animals with
amphetamine leads to a marked enhancement of dendritic length and spine density (Uranova
et al. 1989; Robinson and Kolb 1999). 3,4-methylenedioxymetamphetamine (MDMA)-
induced behavioural sensitisation is prevented by blocking 5HT 2C receptors in the mPFC
(Ramos et al. 2005a) or by lesioning the mPFC (Ramos et al. 2005b). Repetitive treatment
with methamphetamine impairs LTP evoked by tetanic stimulation (10 trains of stimuli at 250
Hz for 200 ms) of hippocampal inputs to the mPFC in vivo, an effect that can be blocked by a
D1 receptor antagonist (Ishikawa et al. 2005).
Lesioning the PFC also prevents the development of cocaine-induced behavioural
sensitisation (Tzschentke 2001). However, in contrast to methamphetamine, repeated cocaine
administration, at a level sufficient to induce behavioural sensitisation, facilitates the
induction of LTP (evoked by bursts of EPSP-spike pairs) at layer 2/3 inputs to layer 5
pyramidal neurons in the prelimbic mPFC in vitro. This action is mediated by a reduction in
inhibitory drive through activation of D1 receptors, PKA and a subsequent reduction in the
surface expression of the GABA A ￿1 subunit (Huang et al. 2007a). Repeated treatment with
cocaine also impairs LTD mediated by group 2 mGluRs at layer 5 inputs to layer 5 pyramidal
neurons (Huang et al. 2007b). This latter effect of cocaine is mediated by activation of D1
receptors, leading to elevations in cAMP. Cyclic AMP is subsequently broken down to
adenosine, which then acts at adenosine A 3 receptors to activate PKC, inhibiting group 2
mGluR function, possibly by uncoupling the receptors from their G proteins. The functional
significance of the opposite effects of amphetamine and cocaine on plasticity in the mPFC is
not known at present.
Finally, acute treatment of lysergic acid diethylamine (LSD) or nicotine induces
expression of a number of genes in the PFC that encode proteins that have been shown to play
a role in synaptic plasticity. These include c-fos and activity related cytoskeletal protein (arc;
Nichols et al. 2003; Schochet et al. 2005).
7. C ONCLUSION
In summary, synapses in the mPFC are highly plastic, displaying several types of short-
term as well as long-term plasticity. Short-term plasticity is observed during trains of EPSPs
as well as during repetitive suprathreshold stimulation, and is therefore likely to be induced
during basal transmission and during the repetitive firing observed during working memory
tasks. Such heterogeneity of short-term plasticity in the mPFC is likely to be important for its
role in the rapid switching of attention during cognitive processing, reducing distractions and
endowing the mPFC with highly flexible computational abilities. Long-term synaptic
plasticity is important for learning sequences of behavioural responses, or “rules” to different
sensory contexts, and for consolidation of memories that are acquired elsewhere in the brain,
such as in the hippocampus or amygdala. Thus it is now well established that in addition to
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