Role of 5-HT1A and 5HT2A in cocaine-mediated modulation of GABA release from the thalamic reticular nucleus

B. GOITIA; N. WEISSTAUB; J. GINGRICH; E. GARCIA-RILL; V. BISAGNO; F. J. URBANO

Washington

Congreso; 2014 SFN Annual Meeting; 2014

SFN

Methylphenidate (MPH), a drug widely used to treat children diagnosed with ADHD, and cocaine (Coc) inhibit the re-uptake of dopamine and norepinephrine. Cocaine, unlike MPH, also inhibits the re-uptake of serotonin (5-HT). Previously, we observed that the frequency of spontaneous GABA release from thalamic reticular nucleus (Ret) neurons is increased in slices from mice treated with a Coc binge (3 i.p. injections, 15mg/kg each, 1 hour apart) but not in those from animals treated with an MPH binge, suggesting that the effect of Coc is mediated by changes in serotonergic transmission. Thus, we investigated the effect of 5-HT receptors agonists and antagonists in control and Coc treated thalamocortical slices from mice using patch clamp. Additionally, we administered Coc to mice lacking 5-HT2A receptors. We first recorded miniature inhibitory post-synaptic potentials (mIPSPs) from ventrobasal neurons using thalamocortical slices from control mice in the presence of 5-HT and 5-HT1A or 5HT2A/2C agonists ((±)-8-OH-DPAT, (±)-DOI hydrochloride; both 10ìM) and antagonists (NAN-190 hydrobromide, ketanserin; both 25ìM). Our results show that the effect of bath-applied 5-HT (100 ìM, >15min) on mIPSP frequency resembles that of Coc (5-HT, Coc vs. control, Kruskal Wallis test, p<0.05), and that even though both types of agonists led to an increase in frequency, the effect of the 5-HT1A agonist was stronger (8-OH-DPAT=347% increase, DOI=129% increase; 8-OH-DPAT vs. DOI vs. control, Kruskal Wallis test, p<0.05). Surprisingly, the 5HT2A antagonist also had the same effect (Kruskal Wallis test, p<0.05), which could be explained by a biphasic action of 5HT2A receptors at the GABAergic afferents terminals from Ret neurons. We then analyzed the effect of 5-HT 100 ìM applied locally (?puff?) onto ventrobasal neurons during recordings of mIPSCs from mice lacking 5-HT2A receptors (both control or injected with a Coc binge). In both cases, the application of 5-HT resulted in a reduction of the mIPSPs frequency that after the puff recovered to initial values only in the control group (post-puff frequency was 96% of the initial value in control group vs. 58% in Coc binge group, Wilcoxon Mann-Whitney test, p=0.0075). Our findings suggest that Coc-induced effects on thalamic serotonergic transmission might be mediated by presynaptic 5-HT receptors (on the terminals of Ret neurons), and that these effects could be responsible for thalamocortical abnormalities observed in cocaine addicts and animal models of Coc intake.