1: Neuropharmacology. 2008 Jun;54(7):1103-6. Epub 2008 Mar 10.

An in vivo [(18)F]MK-9470 microPET study of type 1 cannabinoid receptor binding
in Wistar rats after chronic administration of valproate and levetiracetam.

Goffin K, Bormans G, Casteels C, Bosier B, Lambert DM, Grachev ID, Van Paesschen 
W, Van Laere K.

Division of Nuclear Medicine and MOSAIC, University Hospital Leuven and
Katholieke Universiteit Leuven, Leuven, Belgium.

There is substantial evidence that the endocannabinoid system and in particular
the type 1 cannabinoid receptor (CB1R) is involved in epilepsy. We evaluated the 
in vivo effect of chronic administration of the anti-epileptic drugs valproate
(VPA) and levetiracetam (LEV) on rat brain CB1 receptors using the positron
emission tomography (PET) tracer [(18)F]MK-9470. Six Wistar rats were treated
with VPA (200mg/kg) or LEV (50mg/kg) IP daily for 2weeks. Dynamic imaging after
intravenous injection of 18MBq [(18)F]MK-9470 was performed on a FOCUS 220
microPET at baseline and after chronic treatment. Six animals were used as
controls and were injected with saline, using the same protocol. Parametric
images based on standardized uptake values (SUV) were generated and were
spatially normalized to Paxinos space. These CB1R images were analyzed using a
predefined volume of interest (VOI)-based analysis. Differences in SUV values
between chronic and baseline scans in each condition (saline, VPA and LEV
treatment) were calculated in each VOI. Direct binding affinity of the drugs at
CB1R was assessed by competitive binding assay in Chinese hamster ovarian cells
expressing human CB1R. Chronic injections of saline did not produce significant
changes in global [(18)F]MK-9470 binding (p=0.43), nor in tracer binding in
individual VOIs. We found a significant increase in global cerebral
[(18)F]MK-9470 binding after chronic VPA administration compared to sham treated 
animals (+32.5%, p<0.001), as well as in tracer binding in all individual VOIs.
After chronic administration of LEV, there was no significant change in global
cerebral CB1R binding (+6.9%, p=0.81), nor in tracer binding in individual VOIs. 
As VPA does not exhibit high affinity for CB1R (displacement of [(3)H]-SR141716A 
1.3+/-14.0%), such upregulation is most likely caused by an indirect effect on
the endocannabinoid system. This increase in CB1R tracer binding and possibly
signaling may represent a supplementary and new mechanism of VPA, but not LEV,
since activation of CB1Rs has been shown to decrease excitability and
excitotoxicity on-demand.


PMID: 18423778 [PubMed - in process]

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