The relationship between lamotrigine concentration and change in resting motor threshold in a rodent model of motor cortex stimulation.

SUMMARY: The anticonvulsant sodium channel blocker lamotrigine (LTG) increases resting motor threshold (RMT) measured using transcranial magnetic stimulation (TMS) of the motor cortex in humans. However, studies suggest a weak relationship between LTG plasma concentration and increase in RMT. This undermines the possibility to use the technique to investigate the dose-efficacy relationship of lamotrigine or novel sodium channel blocking drugs. In order to investigate this relationship further, we have examined blood and brain concentrations of LTG in parallel with the drugs effects on RMT in a model in which electrical-stimulation is used to activate the motor cortex of propofol-anaesthetised rats. LTG (3-20 mg/kg s.c.) significantly increased RMT (P<0.001). There was a significant (P<0.01) positive correlation between LTG blood and brain concentration and increase in RMT; however correlation-coefficients were low (brain: r(2)=0.26 and blood r(2)=0.25), with evidence for non-responders, similar to human studies. The results show that the variation in RMT response is unlikely to be due to pharmacokinetic differences between subjects, and suggest that biological differences may underpin the variability. Understanding the source of this variability will be an important goal and, assuming some relationship between the effects of LTG on motor pathway excitability and the drugs anticonvulsant efficacy, could lead to a means to identify epilepsy patients that may be more likely to respond to treatment.

The CB1 receptor antagonist, SR141716A, prevents high-frequency stimulation-induced reduction of feedback inhibition in the rat dentate gyrus following perforant path stimulation in vivo.

Endocannabinoids acting through CB(1) receptors are thought to regulate GABAergic and glutamatergic neurotransmission and may modulate long-term potentiation (LTP). High-frequency stimulation (HFS) of the medial perforant path to induce LTP was studied in the dentate gyrus with or without the selective CB(1) receptor antagonist, SR141716A in isoflurane-anaesthetised rats. HFS significantly increased the slope of the field excitatory post-synaptic potential (fEPSP) and the amplitude of the population spike (PS; P<0.001 in each case; n=6). Following administration of SR141716A, HFS no longer increased fEPSP slope, whereas PS amplitude potentiation remained significant (P<0.0001; n=6). Paired-stimuli revealed that HFS significantly reduced inhibition observed at intervals of 10 ms (P<0.01; n=6), and produced a leftward shift of the interval-inhibition curve (P<0.05; n=6). Following administration of SR141716A, HFS no longer reduced inhibition at the 10 ms interval, but a leftward shift in the interval-inhibition curve was still observed (P<0.05, n=6). These results indicate that LTP in the dentate gyrus reduces local circuit inhibition, consistent with a reduction of GABA release and/or duration of the post-synaptic GABA-receptor mediated response. Selective effects of SR141716A on the degree, but not the timecourse, of paired-pulse inhibition suggest that the reduction in GABA release following LTP induction is due to CB(1) activation. Results also suggest that CB(1) receptors contribute to HFS-induced potentiation of the fEPSP, but not to the mechanism underlying potentiation of PS amplitude. We suggest that CB(1) activation during HFS of the medial perforant path increases glutamate release from perforant path synapses, but inhibits release of GABA from local circuit interneurons.

Dopamine responsiveness to drugs of abuse: A shell-core investigation in the nucleus accumbens of the mouse.

The existence of subterritories within the nucleus accumbens has now been widely supported by histochemical, neurochemical, electrophysiological, as well as morphological and ultrastructural studies and suggest specific afferent and efferent systems involved in different behavioral aspects. Microdialysis studies in the rat have consistently shown that most drugs of abuse increase extracellular dopamine levels preferentially in the shell subregion of the nucleus accumbens. The study of the relative roles of NAc subregions may considerably help our understanding of the neurobiological basis of drug addiction. Accordingly, the aim of the present work was to extend the outcome of rat studies to the mouse species. Five major drugs of abuse were systemically and acutely administered to mice with a microdialysis probe implanted in either the shell or the core. A statistical comparison was performed on data transformed as percentage values of baseline dopamine vs. logarithmic values with baseline dopamine as a covariate. Results show a significant increase in dopamine levels in both the shell and core subregions following cocaine, amphetamine, nicotine, ethanol, and morphine treatments. A difference between shell and core after cocaine, nicotine, and morphine was evident when data were analyzed as percent values of baseline. However, such a shell-core dichotomy became no longer significant when ANOVA was applied on the statistically more appropriate logarithmic transformation of data with baseline as a covariate. The significant baseline differences among groups of mice (dopamine levels in the shell significantly lower compared with dopamine levels in the core) may have compromised, at least in part, the statistical procedure usually applied in microdialysis studies. These findings suggest that a careful evaluation of the data is required when subtle changes in extracellular levels of DA are measured.