Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat

Abstract

1. We have studied the effects of acute and chronic treatment with the anticonvulsant lamotrigine (LTG) on basal and stimulated extracellular 5-hydroxytryptamine (5-HT), dopamine (DA) and their metabolites in the hippocampus of freely moving rats using in vivo microdialysis. 2. Acute LTG (10 and 20 mg kg(-1)) decreased extracellular 5-HT, but had no effect on its metabolite 5-hydroxyindoleacetic acid (5-HIAA). Dialysate DA was also decreased by LTG as were its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). When transmitter release was stimulated by either 50 microm veratridine or 100 mm K(+), marked increases in the release of both transmitters occurred, but LTG was entirely without effect on this. 3. In chronic experiments, rats were dialysed after 2, 4, 7, 14 and 21 days of LTG treatment (5 mg kg(-1), twice daily). During this period a progressively different response to the drug was seen. After 2 days, basal extracellular 5-HT was significantly greater in treated rats than control rats. This effect persisted up to 14 days, but by 21 days 5-HT levels had returned to control values. 5-HIAA levels were unaltered and there was no effect of LTG on veratridine or K(+) stimulated 5-HT release. 4. Similarly, DA concentrations significantly increased after 2-7 days of LTG treatment, but returned and remained at basal values thereafter. During the treatment period LTG had no effect on extracellular DOPAC, but HVA followed a similar pattern to its parent transmitter. As with 5-HT, at no time point did LTG have any effect on stimulated DA release. 5. These neurochemical findings observed in these experiments are considered in relation to the use of LTG in bipolar disorder.

Figures

Figure 1

Effect of acute LTG on extracellular 5-HT in the hippocampus. Data are the mean±s.e.m. of six animals in each group. Administration of LTG is indicated by the arrow. *Denotes significant difference from first four basal values.

Figure 2

Effect of acute LTG on extracellular DA, DOPAC and HVA in the hippocampus. Data are the mean±s.e.m. of six animals in each group. Administration of LTG is indicated by the arrow. *Denotes significant difference from first four basal values.

Figure 3

Effect of acute LTG on veratridine (a; upper panel) or 100 mm K+-evoked (b; lower panel) 5-HT and DA in the hippocampus. Data are the mean±s.e.m. of six animals in each group. Administration of LTG is indicated by the arrow.

Figure 4

Effect of chronic LTG on extracellular 5-HT in the hippocampus. Data are the mean±s.e.m. of six animals in each group. Administration of LTG is indicated by the arrow. *Denotes significant difference from respective vehicle-treated rats using unpaired Student's t-test.

Figure 5

Effect of chronic LTG on extracellular DA and HVA in the hippocampus. Data are the mean±s.e.m. of six animals in each group. Administration of LTG is indicated by the arrow. *Denotes significant difference from respective vehicle-treated rats using unpaired Student's t-test.