Motivation is a process that continuously changes behavior to achieve a goal and can be conceptualized as a series of steps relating to that process. Intracranial self-stimulation (ICSS) behavior is considered to consist of reward and motivational effects. Moreover, priming stimulation of ICSS behavior is known to promote motivational effects. Using the runway method and priming stimulation, rewards and motivational effects of ICSS behavior can be differentiated. We investigated whether the runway method and priming stimulation of ICSS behavior could be used to evaluate motivational effects of a drug. In the ICSS runway model, running speed was considered as a reference of motivational effect. An assessment of pharmacological drugs known to influence motivational states was also undertaken. Using our experimental methods, prominent changes were observed in running speed when animals were administered methamphetamine and nicotine. Based on our results, we conclude that the runway method may be useful for the evaluation of substances that affect motivation. This review introduces 4 types of neuronal processes involved in motivation, reward mechanisms, outlines evaluation methods, and describes motivational properties of psychoactive drugs.

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The aim of this in vitro study was to examine the possible effect of [2-methyl-5-(4-methylsulphonyl)phenyl-1-phenyl-3-(2-n-propyloxyethyl)]-1H-pyrrole (VA441), a new selective cyclooxygenase (COX)-2 inhibitor, on human osteoarthritic (OA) chondrocyte cultivated in the presence or absence of interleukin-1β (IL-1β). In particular, we assessed the effects of 1 and 10 μM of VA441, celecoxib, and indomethacin on cell viability, COX-2 and inducible nitric oxide synthase (iNOS) gene expression, prostaglandin E₂ (PGE₂) production, and nitric oxide (NO) and metalloproteinase-3 (MMP-3) release. Furthermore, we carried out morphological assessment by transmission electron microscopy (TEM). The presence of IL-1β led to a significant increase in PGE₂, MMP-3, and NO production, as well as a significant increase in gene expression of COX-2 and iNOS. All the drugs tested had a statistically significant inhibitory effect on PGE₂ production and gene expression of COX-2 stimulated by IL-1β. VA441 and celecoxib significantly suppressed IL-1β-stimulated MMP-3 and NO and iNOS gene expression in a dose-dependent manner, while indomethacin did not show any significant effect on MMP-3 and NO production or on iNOS gene expression. TEM demonstrated that IL-1β severely alters the structure of chondrocytes; after co-incubation with VA441 or celecoxib, the cells recovered their ultrastructure. Our data suggest that VA441 and celecoxib may have a beneficial effect on chondrocyte metabolism.

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TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK₂–receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK₂ receptors with a marked species difference and a 10,000-fold selectivity versus NK₁ and NK₃ receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK₂ receptor–selective agonist beta-Ala⁸-NKA(4-10) (βA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT₃–receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid–induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as βA-NKA in an isolated human colon. In conclusion, the novel NK₂-receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK₂ receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.

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Methylglyoxal (MGO) is a metabolite of glucose and perhaps mediates diabetes-related macrovascular complications including hypertension. In the present study, we examined if MGO accumulation affects vascular reactivity of isolated mesenteric artery from spontaneously hypertensive rats (SHR). Five-week-old SHR were treated with an MGO scavenger, aminoguanidine (AG), for 5 weeks. AG partially normalized increased blood pressure in SHR. In mesenteric artery from SHR treated with AG, increased accumulation of MGO-derived advanced glycation end-products was reversed. In mesenteric artery from SHR, AG normalized impaired acetylcholine (ACh)-induced relaxation and increased angiotensin (Ang) II-induced contraction. Reactive oxygen species (ROS) production increased in SHR mesenteric artery, and acute treatment with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor augmented ACh-induced relaxation. Protein expression of NOX1 and Ang II type 2 receptor (AT2R) increased in SHR mesenteric artery, which was normalized by AG. Acute treatment with an AT2R blocker but not a NOX inhibitor normalized the increased Ang II-induced contraction in SHR mesenteric artery. The present results demonstrate that MGO accumulation in mesenteric artery may mediate development of hypertension in SHR at least in part via increased ROS-mediated impairment of endothelium-dependent relaxation and AT2R-mediated increased Ang II contraction.

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Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption, and inhibition of renal SGLT2 activity represents an innovative strategy for the treatment of hyperglycemia in diabetic patients. The present study investigated the antidiabetic effects of ipragliflozin, a SGLT2-selective inhibitor, in streptozotocin–nicotinamide-induced mildly diabetic mice, which exhibited a mild decline in glucose tolerance associated with the loss of early-phase insulin secretion. Oral administration of ipragliflozin increased urinary glucose excretion in a dose-dependent manner, an effect which was significant at doses of 0.3 mg/kg or higher and lasted over 12 h. In addition, ipragliflozin dose-dependently improved hyperglycemia and glucose intolerance with concomitant decreases in plasma insulin levels without causing hypoglycemia. Once-daily dosing of ipragliflozin (0.1 – 3 mg/kg) for 4 weeks attenuated hyperglycemia, glucose intolerance, and impaired insulin secretion. These results suggest that the SGLT2-selective inhibitor ipragliflozin increases urinary glucose excretion by inhibiting renal glucose reabsorption, improves hyperglycemia in streptozotocin–nicotinamide-induced mildly diabetic mice, and may be useful for treating type 2 diabetes.

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Ethanol is a wildly abused substance that causes various problems and damage in our society. We examined the connection between the action of ethanol and the endocannabinoid system in corticostriatal synaptic transmission by recording excitatory post-synaptic currents (EPSCs). Acute treatment of ethanol (100 mM) inhibited corticostriatal EPSCs. In the presence of AM 251 (5 μM), a cannabinoid 1 (CB₁)-receptor antagonist, or AM 404 (5 μM), a cannabinoid transporter inhibitor, the inhibition of corticostriatal EPSCs caused by ethanol was significantly reduced. This result suggests the possibility that the endocannabinoid system is involved in the action of ethanol. To support this result, brain slices were pre-treated with WIN 55,212-2 (1 μM), a CB₁-receptor agonist, following treatment of ethanol or treated with WIN 55,212-2 alone. There was no significant difference between each other, indicating that when CB₁ receptors are previously activated, the effect of ethanol is blunted. These results suggest that the activation of the endocannabinoid system is one of the possible mechanisms involved in ethanol-induced corticostriatal synaptic depression.

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Matrix metalloproteinase 9 (MMP-9) is a risk factor for cardiovascular events. The serum MMP-9 levels were measured before and 2 weeks after treatment with infliximab (3 mg/kg) in 12 rheumatoid arthritis (RA) patients. The serum average MMP-9 level was 238.5 ng/ml before treatment with infliximab in RA patients (normal range: less than 43.8 ng/ml). Infliximab reduced the serum average MMP-9 level significantly (161.66 ng/ml, P = 0.0425). The serum MMP-9 level was high in the RA patients with active disease, and it was reduced by infliximab independently of the reduction in disease activity. Thus, infliximab may reduce the risk of cardiovascular events directly.

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Neurosteroids are known as allosteric modulators of the ligand-gated ion channel superfamily. Voltage-gated sodium channels (Na_v) play an important role in mediating excitotoxic damages. Here we report the effects of neurosteroids on the function of Na_v, using voltage-clamp techniques in Xenopus oocytes expressed with the Na_v1.2 α subunit. Pregnenolone sulphate, but not pregnenolone, inhibited sodium currents (I_Na) at 3 – 100 μmol/L. The suppression of I_Na by pregnenolone sulphate was due to increased inactivation with little change in activation. These findings suggest that pregnenolone sulphate, a metabolite of pregnenolone, suppresses the function of Na_v via increased inactivation, which may contribute to the neuroprotection.

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The effect of cibenzoline, a class I antiarrhythmic drug, on Na⁺/Ca²⁺ exchange current (I_NCX) was investigated using the patch-clamp method. Cibenzoline inhibited the bi-directional I_NCX in a concentration-dependent manner. The IC₅₀ values of cibenzoline for the outward and inward components of I_NCX were 77 and 84 μM, respectively, with Hill coefficients of 1. Intracellular application of trypsin via the pipette solution did not change the inhibitory effect of cibenzoline. The inhibitory effect of cibenzoline on I_NCX at pH_o 6.5 was smaller than those at pH_o 7.4 and pH_o 8.2. We conclude that cibenzoline inhibits I_NCX in supra-therapeutic concentrations.

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