IntroductIonObesity, in addition to being a risk factor for cardiovascular and metabolic diseases, has been implicated in degrading cognitive operation (1). Elias et al. (2) found that obesity was associated with lower cognitive functioning in late middleaged and elderly (55-88 years) men, but not women. This association is independent of other cardiovascular risk factors. Gustafson et al. (3) also found that overweight at older ages (79-88 years) is a risk factor for dementia, particularly the Alzheimer's disease. Additionally, obesity in the midlife (40-45 years) is a risk factor for dementia and Alzheimer's disease in American (both sexes) (4) and in Swedish men (5). Impaired spatial memory and hippocampal synaptic plasticity were also reported in genetically obese animal models (6,7). However, instead of genetic factors, consumption of high-fat diet (HFD) is conceived to be a common cause of obesity in humans (8). Therefore, the animal models of HFD-induced obesity could better mimic the pathological changes in obese humans.The impairment of cognitive functions has been observed in several rodent models of HFD-induced obesity but most of these studies were limited to using one sex of animals, mostly the males (9-12), or short-term (<6 months) HFD feeding (13). In an obese mouse model with long-term (up to 9-12 months) HFD feeding, we have previously reported that the Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high-fat diet (HFD)-induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9-12 months) gained significantly more weights than the sex-specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step-down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open-field and hot-plate tests. Although, basal synaptic transmission characteristics (input-output transfer and paired-pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long-term potentiation (LTP) and long-term depression (LTD)) were lower at the Schaffer collateral-CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex-specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metab...

Orexin A and B are hypothalamic peptides known to modulate arousal, feeding and reward via OX1 and OX2 receptors. Orexins are also antinociceptive in the brain but their mechanism(s) of action remain unclear. Here, we investigated the antinociceptive mechanism of orexin A in the rat ventrolateral periaqueductal gray (vlPAG), a midbrain region crucial for initiating descending pain inhibition. In vlPAG slices, orexin A (30-300 nM) depressed GABAergic evoked inhibitory postsynaptic currents (IPSCs). This effect was blocked by an OX1 (SB 334867), but not OX2 (Compound 29), antagonist. Orexin A increased the paired-pulse ratio of paired IPSCs, and decreased the frequency, but not amplitude, of miniature IPSCs. Orexin A-induced IPSC depression was mimicked by WIN 55,212-2, a cannabinoid 1 (CB1) receptor agonist. AM 251, a CB1 antagonist, reversed depressant effects by both agonists. Orexin A-induced IPSC depression was prevented by U73122 and tetrahydrolipstatin, inhibitors of phospholipase C (PLC) and diacylglycerol lipase (DAGL), respectively, and enhanced by URB602, which inhibits enzymatic degradation of 2-arachidonoylglycerol (2-AG). Moderate DAGLα, but not DAGLβ, immunoreactivity was observed in the vlPAG. Orexin A produced an overall excitatory effect on evoked postsynaptic potentials and hence increased vlPAG neuronal activity. Intra-vlPAG microinjection of orexin A reduced hot-plate nociceptive responses in rats in a manner blocked by SB 334867 and AM 251. Therefore, orexin A may produce antinociception by activating postsynaptic OX1 receptors, stimulating synthesis of 2-AG, an endocannabinoid, through a Gq-protein-mediated PLC-DAGLα enzymatic cascade culminating in retrograde inhibition of GABA release (disinhibition) in the vlPAG.

Abstract. Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA B receptors consisting of GABA B1a and GABA B2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K + channels, activating hyperpolarization-activated cation channels, and modulating Ca 2+ current by selectively binding to the specific binding site of [3 H]gabapentin, the α 2 δ subunit of voltage-dependent Ca 2+ channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the α 2 δ subunit of spinal N-type Ca 2+ channels is very likely the analgesic action target of gabapentin.

Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and 2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission. This effect is prevented by internal GDP-β-S or inhibiting OX1Rs, CB1Rs, phospholipase C or DAGL, and potentiated by inhibiting 2-AG degradation. These results suggest that restraint stress activates LH orexin neurons, releasing orexins into the VTA to activate postsynaptic OX1Rs of dopaminergic neurons and generate 2-AG through a Gq-protein-phospholipase C-DAGL cascade. 2-AG retrogradely inhibits GABA release through presynaptic CB1Rs, leading to VTA dopaminergic disinhibition and reinstatement of cocaine CPP.