Electrophysiological and neurochemical effects of antidiabetic sulphonylurea tolbutamide in the rat ventral tegmental area and prefrontal cortex

Abstract

Tolbutamide is an orally administered sulphonylurea, used in the management of non‐insulin‐dependent diabetes mellitus. This class of drug acts on the sulphonyureas receptors(SUR) through blockage of ATP‐regulated K‐channels to release insulin. Some studies have revealed the presence of sulphonylureas binding sites in the substantia nigra. However, there is very little documented data about the presence of these receptors in the ventral tegmental area (VTA) and prefrontal cortex(PFC).Here, using in vivo extracellular single unit recordings, we have investigated the electrophysiological effects of acute intravenous administration of tolbutamide (20mg/kg) on VTA dopamine and PFC pyramidal neurons. We also examined in vitro the effects of this drug on dopamine transporter activity using striatum and tegmental synaptosomes.Adult Sprague Dawley rats were deeply anaesthetised with chloral hydrate (400mg/kg) and urethane (1.5 g/kg) and placed in a stereotaxic instrument for VTA dopamine/GABA and PFC pyramidal neurons recordings, respectively. Appropriately, blood level glucose was monitored with glucometer to avoid hypoglycermia followed by administration with 2ml/kg of 20% glucose subsequent to tolbutamide injection, when necessary. Furthermore, we studied tolbutamide(30μM) effects on striatal synaptosome preparation for dopamine transporter activity through in vitro [3H]‐dopamine radiometric uptake assay technique.In the VTA, administration of tolbutamide induced biphasic effects on the basal activity of most of the dopamine neurons tested: large inhibition (up to 100%) during a relatively short period (1–3 min), caused by hyperpolarisation, followed by a long‐lasting excitatory effect (40% of the baseline activity). Significant increased burst activity was also observed. This initial inhibitory effect was insensitive to a pre‐administration of the dopamine D2 antagonist(eticlopride100μg/kg). Interestingly, presumed GABAergic VTA neurons exhibit only a monophasic significant excitatory effect following tolbutamide administration. In the prefrontal cortex, tolbutamide also induced a monophasic excitatory effect in a dose dependent manner on most of the presumed pyramidal neurons tested. Neurochemical in vitro investigation revealed a statistically significant partial decrease (p<0.05) in specific dopamine synaptosomal uptake at relatively high concentration of tolbutamide (30 μM) an indication of possible direct modulation of dopamine turn‐over.In conclusion, tolbutamide induced a unique biphasic effect in the VTA dopamine neurons. The large but short lasting inhibitory effect is hypothesised to be mediated by GABA interneurons which are found to be immediately activated by the drug. Future works are needed to understand the function of this putative metabolic‐sensitive modulation of dopamine neuronal activity.Support or Funding InformationSelf funded international student, supported by the university bursary department.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.