Nasal administration of leptin dose-dependently increases dopamine and serotonin outflow in the rat nucleus accumbens.

Leptin is an anorexigenic hormone that acts via its receptor (LepR) to regulate the hypothalamic arcuate nucleus circuitry to mediate energy homeostasis and feeding behavior. Moreover, leptin decreases the reward value of natural and artificial rewards, and low levels of circulating leptin have been implicated in several mood disorders linking leptin to the mesolimbic system. Therefore, the purpose of this study was to assess whether and to what extent an acute intranasal application of leptin is able to modulate monoamine neurotransmitters in the nucleus accumbens (NAc). Microdialysis experiments were carried out in freely moving Wistar rats and in LepR-deficient Zucker rats (LepRfa/fa). Samples were analysed for the levels of dopamine (DA), serotonin (5-HT), and their metabolites using high-performance liquid chromatography with electrochemical detection. We show that in Wistar rats, nasal application of leptin dose-dependently increased extracellular DA and 5-HT levels in the NAc. By contrast, in the LepRfa/fa rats, nasal application of 0.12 mg/kg leptin failed to increase levels of either DA or 5-HT, but their metabolites (DOPAC and HIAA, respectively) were significantly decreased. In addition, leptin interaction with the melanocortin system was tested. Nasal co-administration of leptin and the melanocortin receptor antagonist, SHU9119, completely abolished the leptin-induced increase of both DA and 5-HT outflow in the NAc. These results indicate a marked leptin effect on the basal ganglia-related reward system involving melanocortin receptors.

Electrical high frequency stimulation modulates GABAergic activity in the nucleus accumbens of freely moving rats.

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective treatment option for those affected by obsessive compulsive disorder, who do not respond to pharmacological treatment strategies. Yet, little is known about the mechanism by which DBS achieve its therapeutic effects. Previous studies have shown an increase in GABA levels due to high frequency stimulation (HFS) in the rat caudate putamen. Here, the effect of high frequency stimulation in the nucleus accumbens of conscious and freely moving rats was characterized using unilateral but simultaneous microdialysis and HFS with a frequency of 124 Hz and 0.5 mA current. Extracellular levels of neurotransmitters - GABA, glutamate, dopamine, serotonin and their metabolites were quantified by means of HPLC with electrochemical detection. Basal levels of GABA were significantly increased in animals of the stimulation group compared to the control group without HFS. The levels of other neurotransmitters were unaffected. The influence of NMDA receptor antagonist, memantine (5 mg/kg) on the effect of HFS was investigated by subcutaneous administration of memantine on the day of the experiment. Memantine (without stimulation) enhanced basal GABA and dopamine levels. However, under the influence of both memantine and HFS, GABA levels were not affected by HFS whereas dopamine levels decreased during the stimulation period. The results of our study demonstrate that HFS in the nucleus accumbens of freely moving rats induces selective increase in GABA outflow and show a possible involvement of NMDA receptors in the mechanistic action of HFS.

Transmitter self-regulation by extracellular glutamate in fresh human cortical slices.

Glutamate is thought to be the most important excitatory neurotransmitter in the CNS, while glutamine predominantly serves as a precursor and metabolite in the glutamate-glutamine cycle. To verify the interaction between intrinsic extracellular glutamate, y-aminobutyric acid (GABA) levels and glial glutamine outflow in human tissue, fresh brain slices from human frontal cortex were incubated in superfusion chambers in vitro. Human neocortical tissue was obtained during surgical treatment of subcortical brain tumors. For superfusion experiments, the white matter was separated and discarded from the gray matter, which finally contained all six neocortical layers. Outflows of endogenous glutamate, GABA and glutamine were established after a 40-min washout period and amounts were simultaneously quantified after two-phase derivatization by high-performance liquid chromatography with electrochemical detection. Under basal conditions, amounts of glutamate could be found 20-fold in comparison to the inhibitory neurotransmitter GABA, whereas this excitatory predominance markedly declined after veratridine-induced activation. The basal glutamate:glutamine ratio of extracellular levels was approximately 1:2. Blockade or activation of the voltage-gated sodium channel by tetrodotoxin or veratridine significantly modulated glutamate levels, but the glutamate:glutamine ratio was nearly constant with 1:2. When the EAAT blocker TBOA was employed, glutamine remained nearly unchanged whereas glutamate significantly enhanced. These results led us to suggest that glutamine release through glial SN1 is related to EAAT activity that can be modulated by intrinsic extracellular glutamate in human cortical slices.