Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs

Intraportal delivery of serotonin enhanced net hepatic glucose uptake (NHGU) during a hyperinsulinemic hyperglycemic clamp, but serotonin elevated catecholamines and can cause gastrointestinal distress. We hypothesized that the selective serotonin reuptake inhibitor (SSRI) fluvoxamine would enhance NHGU without side effects. Arteriovenous difference and tracer ([3-(3)H]glucose) techniques were used in conscious 42-h-fasted dogs. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. Saline (SAL) was infused intraportally during 0-90 min (P1), and fluvoxamine was infused intraportally at 0.5, 1, and 2 mug.kg(-1).min(-1) from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively, in the FLUV group (n = 8). The SAL group (n = 9) received intraportal saline during 0-270 min. NHGU in SAL was 13.9 +/- 1.7 and 17.0 +/- 2.0 mumol.kg(-1).min(-1) in P3-P4, respectively, while NHGU in FLUV averaged 19.7 +/- 2.8 and 26.6 +/- 3.0 mumol.kg(-1).min(-1) (P < 0.05 vs. SAL). Net hepatic carbon retention was greater (P < 0.05) in FLUV than in SAL (17.6 +/- 2.6 vs. 13.9 +/- 2.7 and 23.8 +/- 3.0 vs. 14.4 +/- 3.3 mumol.kg(-1).min(-1) in P3-P4, respectively), and final hepatic glycogen concentrations were 50% greater in FLUV (P < 0.005). Nonhepatic glucose uptake was greater in SAL than in FLUV at 270 min (P < 0.05). Catecholamine concentrations remained basal, and the animals evidenced no distress. Thus fluvoxamine enhanced NHGU and hepatic carbon storage without raising circulating serotonin concentrations or causing stress, suggesting that hepatic-targeted SSRIs might be effective in reducing postprandial hyperglycemia in individuals with diabetes or impaired glucose tolerance.     

Interaction of free fatty acids and epinephrine in regulating hepatic glucose production in conscious dogs

To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated (Delta 568 +/- 77 and Delta 527 +/- 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 +/- 73 to 1,633 +/- 101 and 746 +/- 112 to 1,898 +/- 237 micromol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 +/- 0.3 to 3.1 +/- 0.4 mg x kg(-1) x min(-1) (P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 +/- 0.2 to 2.1 +/- 0.3 mg x kg(-1) x min(-1)) in response to Po-EPI+FFA. Net hepatic glycogenolysis decreased from 1.7 +/- 0.2 to 0.9 +/- 0.2 and 1.6 +/- 0.2 to 0.7 +/- 0.2 mg x kg(-1) x min(-1) by 30 min in HG+FFA and HG+SAL. Hepatic gluconeogenic flux to glucose 6-phosphate increased from 0.6 +/- 0.1 to 1.2 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; by 3 h) and 0.7 +/- 0.1 to 1.6 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; at 90 min) in HG+FFA and Po-EPI+FFA. The gluconeogenic parameters remained unchanged in the Po-EPI+SAL and HG+SAL groups. In conclusion, increased FFA markedly changed the mechanism by which EPI stimulated hepatic glucose production, suggesting that its overall lipolytic effect may be important in determining its effect on the liver.     

Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dog

Epinephrine increases net hepatic glucose output (NHGO) mainly via increased gluconeogenesis, whereas glucagon increases NHGO mainly via increased glycogenolysis. The aim of the present study was to determine how the two hormones interact in controlling glucose production. In 18-h-fasted conscious dogs, a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which one of four protocols was instituted. In G + E, glucagon (1.5 ng x kg(-1) x min(-1); portally) and epinephrine (50 ng x kg(-1) x min(-1); peripherally) were increased; in G, glucagon was increased alone; in E, epinephrine was increased alone; and in C, neither was increased. In G, E, and C, glucose was infused to match the hyperglycemia seen in G + E ( approximately 250 mg/dl). The areas under the curve for the increase in NHGO, after the change in C was subtracted, were as follows: G = 661 +/- 185, E = 424 +/- 158, G + E = 1178 +/- 57 mg/kg. Therefore, the overall effects of the two hormones on NHGO were additive. Additionally, glucagon exerted its full glycogenolytic effect, whereas epinephrine exerted its full gluconeogenic effect, such that both processes increased significantly during concurrent hormone administration.     

Vagal cooling and concomitant portal norepinephrine infusion do not reduce net hepatic glucose uptake in conscious dogs

We examined the role of efferent neural signaling in regulation of net hepatic glucose uptake (NHGU) in two groups of conscious dogs with hollow perfusable coils around their vagus nerves, using tracer and arteriovenous difference techniques. Somatostatin, intraportal insulin and glucagon at fourfold basal and basal rates, and intraportal glucose at 3.8 mg.kg(-1).min(-1) were infused continuously. From 0 to 90 min [period 1 (P1)], the coils were perfused with a 37 degrees C solution. During period 2 [P2; 90-150 min in group 1 (n = 3); 90-180 min in group 2 (n = 6)], the coils were perfused with -15 degrees C solution to eliminate vagal signaling, and the coils were subsequently perfused with 37 degrees C solution during period 3 (P3). In addition, group 2 received an intraportal infusion of norepinephrine at 16 ng.kg(-1).min(-1) during P2. The effectiveness of vagal suppression was demonstrated by the increase in heart rate during P2 (111 +/- 17, 167 +/- 16, and 105 +/- 13 beats/min in group 1 and 71 +/- 6, 200 +/- 11, and 76 +/- 6 beats/min in group 2 during P1-P3, respectively) and by prolapse of the third eyelid during P2. Arterial plasma glucose, insulin, and glucagon concentrations; hepatic blood flow; and hepatic glucose load did not change significantly during P1-P3. NHGU during P1-P3 was 2.7 +/- 0.4, 4.1 +/- 0.6, and 4.0 +/- 1.2 mg.kg(-1).min(-1) in group 1 and 5.0 +/- 0.9, 5.6 +/- 0.7, and 6.1 +/- 0.9 mg.kg(-1).min(-1) in group 2 (not significant among periods). Interruption of vagal signaling with or without intraportal infusion of norepinephrine to augment sympathetic tone did not suppress NHGU during portal glucose delivery, suggesting the portal signal stimulates NHGU independently of vagal efferent flow.     

Design of a selective insulin receptor tyrosine kinase inhibitor and its effect on glucose uptake and metabolism in intact cells

An inhibitor of the insulin receptor tyrosine kinase (IRTK), (hydroxy-2-naphthalenyl-methyl) phosphonic acid, was designed and synthesized and was shown to be an inhibitor of the biological effects of insulin in vitro. With a wheat germ purified human placental insulin receptor preparation, this compound inhibited the insulin-stimulated autophosphorylation of the 95-kDa beta-subunit of the insulin receptor (IC50 = 200 microM). The ability of the kinase to phosphorylate an exogenous peptide substrate, angiotensin II, was also inhibited. Half-maximal inhibition of basal and insulin-stimulated human placental IRTK activity was found at concentrations of 150 and 100 microM, respectively, with 2 mM angiotensin II as the peptide substrate. The inhibitor was found to be specific for tyrosine kinases over serine kinases and noncompetitive with ATP. The inhibitor was converted into various (acyloxy)methyl prodrugs in order to achieve permeability through cell membranes. These prodrugs inhibited insulin-stimulated autophosphorylation of the insulin receptor 95-kDa beta-subunit in intact CHO cells transfected with human insulin receptor. Inhibition of insulin-stimulated glucose oxidation in isolated rat adipocytes and 2-deoxyglucose uptake into CHO cells was observed with these prodrugs. Our data provide additional evidence for the involvement of the insulin receptor tyrosine kinase in the regulation of glucose uptake and metabolism. These results and additional data reported herein suggest that this class of prodrugs and inhibitors will be useful for modulating the activity of a variety of tyrosine kinases.     

Higher levels of aggression are observed in socially dominant toadfish treated with the selective serotonin reuptake inhibitor, fluoxetine

The following study set out to test the hypothesis that acute treatment with the selective serotonin reuptake inhibitor, fluoxetine, would result in a rise in circulating 5-HT levels and consequently a decrease in territorial aggression in the Gulf toadfish, Opsanus beta. Size-matched pairs of toadfish were implanted intraperitoneally with the same dose of fluoxetine (0, 10 or 25 μg g^− 1). After a social interaction between a pair of fish, circulating levels of serotonin (5-HT; 5-hydroxytryptamine) and cortisol were measured and relative mRNA expression of the 5-HT_1A receptor in the toadfish brain was determined using quantitative (real-time) PCR (qPCR). Behavioral endpoints such as the number of aggressive acts and swimming activity were also quantified so that dominant and subordinate fish could be identified. Fluoxetine treatment resulted in an increase in circulating levels of 5-HT, regardless of social status. Circulating cortisol concentrations were unaffected by fluoxetine, but were significantly higher in subordinate individuals when compared to dominant fish. Toadfish brain 5-HT_1A receptor mRNA expression was not affected by treatment or social status. Lastly and contrary to our predictions, fluoxetine treatment resulted in an increase in the number of aggressive acts made by dominant individuals, with no differences in the level of aggression or swimming activity of subordinate fish. This study is the first to describe elevated aggression in a teleost fish with elevated circulating levels of 5-HT.     

Importance of the hepatic arterial glucose level in generation of the portal signal in conscious dogs

The aim of this study was to determine whether the elimination of the hepatic arterial-portal (A-P) venous glucose gradient would alter the effects of portal glucose delivery on hepatic or peripheral glucose uptake. Three groups of 42-h-fasted conscious dogs (n = 7/group) were studied. After a 40-min basal period, somatostatin was infused peripherally along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)). In test period 1 (90 min), glucose was infused into a peripheral vein to double the hepatic glucose load (HGL) in all groups. In test period 2 (90 min) of the control group (CONT), saline was infused intraportally; in the other two groups, glucose was infused intraportally (22.2 micromol x kg(-1) x min(-1)). In the second group (PD), saline was simultaneously infused into the hepatic artery; in the third group (PD+HAD), glucose was infused into the hepatic artery to eliminate the negative hepatic A-P glucose gradient. HGL was twofold basal in each test period. Net hepatic glucose uptake (NHGU) was 10.1 +/- 2.2 and 12.8 +/- 2.1 vs. 11.5 +/- 1.6 and 23.8 +/- 3.3* vs. 9.0 +/- 2.4 and 13.8 +/- 4.2 micromol x kg(-1) x min(-1) in the two periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). NHGU was 28.9 +/- 1.2 and 39.5 +/- 4.3 vs. 26.3 +/- 3.7 and 24.5 +/- 3.7* vs. 36.1 +/- 3.8 and 53.3 +/- 8.5 micromol x kg(-1) x min(-1) in the first and second periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). Thus the increment in NHGU and decrement in extrahepatic glucose uptake caused by the portal signal were significantly reduced by hepatic arterial glucose infusion. These results suggest that the hepatic arterial glucose level plays an important role in generation of the effect of portal glucose delivery on glucose uptake by liver and muscle.     

Clickable photoaffinity ligands for the human serotonin transporter based on the selective serotonin reuptake inhibitor (S)-citalopram

To date, the development of photoaffinity ligands targeting the human serotonin transporter (hSERT), a key protein involved in disease states such as depression and anxiety, have been radioisotope-based (i.e., ³H or ¹²⁵I). This letter instead highlights three derivatives of the selective serotonin reuptake inhibitor (SSRI) (S)-citalopram that were rationally designed and synthesized to contain a photoreactive benzophenone or an aryl azide for protein target capture via photoaffinity labeling and a terminal alkyne or an aliphatic azide for click chemistry-based proteomics. Specifically, clickable benzophenone-based (S)-citalopram photoprobe 6 (hSERT K_i?=?0.16?nM) displayed 11-fold higher binding affinity at hSERT when compared to (S)-citalopram (hSERT K_i?=?1.77?nM), and was subsequently shown to successfully undergo tandem photoaffinity labeling-biorthogonal conjugation using purified hSERT. Given clickable photoprobes can be used for various applications depending on which reporter is attached by click chemistry subsequent to photoaffinity labeling, photoprobe 6 is expected to find value in structure-function studies and other research applications involving hSERT (e.g., imaging).     

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-min control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n = 5) were perfused with a 37 degrees C solution, while in the other (Cool, n = 6), the coils were perfused with -20 degrees C solution. Vagal blockade was verified by heart rate change (80 +/- 9 to 84 +/- 14 beats/min in Sham; 98 +/- 12 to 193 +/- 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 +/- 0.4 to 1.9 +/- 0.4 mg. kg(-1). min(-1)). Net hepatic glucose output did not change in Sham but decreased from 1.9 +/- 0.3 to 1.3 +/- 0.3 mg. kg(-1). min(-1) in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis.     

Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor

A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.     

Prior eccentric contractions impair maximal insulin action on muscle glucose uptake in the conscious rat

Asp, Sven, Allan Watkinson, Nicholas D. Oakes, and Edward W. Kraegen. Prior eccentric contractions impair maximal insulin action on muscle glucose uptake in the conscious rat.J. Appl. Physiol. 82(4):1327-1332, 1997.Our aim was to examine the effect of prioreccentric contractions on insulin action locally in muscle in theintact conscious rat. Anesthetized rats performed one-leg eccentriccontractions through the use of calf muscle electrical stimulationfollowed by stretch of the active muscles. Two days later, basal andeuglycemic clamp studies were conducted with the rats in the awakefasted state. Muscle glucose metabolism was estimated from2-[¹⁴C(U)]deoxy-D-glucoseandD-[3-³H]glucose administration, and comparisons were made between the eccentrically stimulated and nonstimulated (control) calfmuscles. At midphysiological insulin levels, effects ofprior eccentric exercise on muscle glucose uptake were notstatistically significant. Maximal insulin stimulation revealed reducedincremental glucose uptake above basal(P < 0.05 in the red gastrocnemius;P < 0.1 in the white gastrocnemiusand soleus) and impaired net glycogen synthesis in all eccentricallystimulated muscles (P < 0.05). Weconclude that prior eccentric contractions impair maximal insulin action (responsiveness) on local muscle glucose uptake and glycogen synthesis in the conscious rat.

     

Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus

Maternal use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) is associated with an increased risk for persistent pulmonary hypertension of the newborn (PPHN), but little is known about 5-HT signaling in the developing lung. We hypothesize that 5-HT plays a key role in maintaining high pulmonary vascular resistance (PVR) in the fetus and that fetal exposure to SSRIs increases 5-HT activity and causes pulmonary hypertension. We studied the hemodynamic effects of 5-HT, 5-HT receptor antagonists, and SSRIs in chronically prepared fetal sheep. Brief infusions of 5-HT (3-20 μg) increased PVR in a dose-related fashion. Ketanserin, a 5-HT 2A receptor antagonist, caused pulmonary vasodilation and inhibited 5-HT-induced pulmonary vasoconstriction. In contrast, intrapulmonary infusions of GR127945 and SB206553, 5-HT 1B and 5-HT 2B receptor antagonists, respectively, had no effect on basal PVR or 5-HT-induced vasoconstriction. Pretreatment with fasudil, a Rho kinase inhibitor, blunted the effects of 5-HT infusion. Brief infusions of the SSRIs, sertraline and fluoxetine, caused potent and sustained elevations of PVR, which was sustained for over 60 min after the infusion. SSRI-induced pulmonary vasoconstriction was reversed by infusion of ketanserin and did not affect the acute vasodilator effects of acetylcholine. We conclude that 5-HT causes pulmonary vasoconstriction, contributes to maintenance of high PVR in the normal fetus through stimulation of 5-HT 2A receptors and Rho kinase activation, and mediates the hypertensive effects of SSRIs. We speculate that prolonged exposure to SSRIs can induce PPHN through direct effects on the fetal pulmonary circulation.     

Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis

BACKGROUND: The use of antidepressant medications and the resulting costs have increased dramatically in recent years, partly because of the introduction of selective serotonin reuptake inhibitors (SSRIs). An assessment of the clinical and economic aspects of SSRIs compared with the older tricyclic antidepressants (TCAs) was initiated to generate information for purchasers of these drugs as well as clinicians. One component of this study was an examination of the adverse effects associated with the use of these drugs. METHODS: Searches of bibliographic databases (for January 1980 through May 1996) and manual scanning of both peer-reviewed publications and other documents were used to identify double-blind, randomized controlled trials involving at least one SSRI and one TCA. For the study of adverse effects, only trials that had at least 20 patients in each trial arm and that reported rates of adverse effects in both arms were retained. In total 84 trials reporting on 18 adverse effects were available. Meta-analyses were undertaken to calculate pooled differences in rates of adverse effects. The question of whether the method of eliciting information from patients about adverse effects made a difference in the findings was also examined. Finally, differences in drop-out rates due to adverse effects were calculated. RESULTS: The crude rates of occurrence of adverse effects ranged from 4% (palpitations) to 26% (nausea) for SSRIs and from 4% (diarrhea) to 27% (dry mouth) for TCAs. The differences in the rates of adverse effects between the 2 types of drugs ranged from 14% more with SSRIs (for nausea) to 11% more with TCAs (for constipation). The results did not depend on the method of eliciting information from patients. There were no statistically significant differences between drug classes in terms of drop-outs due to adverse effects. INTERPRETATION: SSRIs and TCAs are both associated with adverse effects, although the key effects differ between the drug classes. Further explanation of the adverse effects and their relation to discontinuation of medication will require better studies involving prospective collection of quality-of-life data.     

SAR development of a selective 5-HT1D antagonist/serotonin reuptake inhibitor lead using rapid parallel synthesis

Incorporation of an SRI (serotonin reuptake inhibitor) pharmacophore into a selective 5-HT(1D) agonist has led to the discovery of a molecule having both 5-HT(1D) antagonist and SRI activity. RPS methodology was used to develop the SAR and identify potential approaches to reduce unwanted adrenergic alpha 1 and dopamine D(2) cross-reactivities.     

Serotonin-1A receptor function in the dorsal raphe nucleus following chronic administration of the selective serotonin reuptake inhibitor sertraline

Serotonin-1A (5-HT_1A) receptors in the dorsal raphe nucleus (DRN) function as somatodendritic autoreceptors, and therefore play a critical role in controlling serotonergic cell firing and serotonergic neurotransmission. We hypothesized that a decrease in the capacity of 5-HT_1A receptors to activate G proteins was a general mechanism by which 5-HT_1A receptors in the DRN are desensitized following chronic administration of selective serotonin reuptake inhibitors (SSRIs). Using in vivo microdialysis, we found that the ability of the 5-HT_1A receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) (0.025 mg/kg, s.c.) to decrease extracellular 5-HT levels in striatum was attenuated following chronic treatment of rats with the SSRIs sertraline or fluoxetine. This apparent desensitization of somatodendritic 5-HT_1A autoreceptor function was not accompanied by a decrease in 5-HT_1A receptor sites in the coupled, high-affinity agonist state as measured by the binding of [3H]8-OH-DPAT. In marked contrast to what was observed following chronic administration of fluoxetine, 5-HT_1A receptor-stimulated [³⁵S]GTPγS binding in the DRN was not altered following chronic sertraline treatment. Thus, desensitization of 5-HT_1A somatodendritic autoreceptor function following chronic sertraline administration appears not to be due to a decrease in the capacity 5-HT_1A receptors to activate G proteins in the DRN. Our findings suggest that the SSRIs may not be a homogeneous class of antidepressant drug with regard to the mechanism by which the function of somatodendritic 5-HT_1A autoreceptors is regulated.     

Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog

To determine the role of nitric oxide in regulating net hepatic glucose uptake (NHGU) in vivo, studies were performed on three groups of 42-h-fasted conscious dogs using a nitric oxide donor [3-morpholinosydnonimine (SIN-1)]. The experimental period was divided into period 1 (0-90 min) and period 2 (P2; 90-240 min). At 0 min, somatostatin was infused peripherally, and insulin (4-fold basal) and glucagon (basal) were given intraportally. Glucose was delivered intraportally (22.2 mumol.kg(-1).min(-1)) and peripherally (as needed) to increase the hepatic glucose load twofold basal. At 90 min, an infusion of SIN-1 (4 mug.kg(-1).min(-1)) was started in a peripheral vein (PeSin-1, n = 10) or the portal vein (PoSin-1, n = 12) while the control group received saline (SAL, n = 8). Both peripheral and portal infusion of SIN-1, unlike saline, significantly reduced systolic and diastolic blood pressure. Heart rate rose in PeSin-1 and PoSin-1 (96 +/- 5 to 120 +/- 10 and 88 +/- 6 to 107 +/- 5 beats/min, respectively, P < 0.05) but did not change in response to saline. NHGU during P2 was 31.0 +/- 2.4 and 29.9 +/- 2.0 mumol.kg(-1).min(-1) in SAL and PeSin-1, respectively but was 23.7 +/- 1.7 in PoSin-1 (P < 0.05). Net hepatic carbon retention during P2 was significantly lower in PoSin-1 than SAL or PeSin-1 (21.4 +/- 1.2 vs. 27.1 +/- 1.5 and 26.1 +/- 1.0 mumol.kg(-1).min(-1)). Nonhepatic glucose uptake did not change in response to saline or SIN-1 infusion. In conclusion, portal but not peripheral infusion of the nitric oxide donor SIN-1 inhibited NHGU.     

Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice

Abstract Substance P antagonists of the neurokinin-1 receptor type (NK1) are gaining growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurones. Our recent microdialysis experiment performed in NK1 receptor knockout mice suggested evidence of changes in 5-HT neuronal function (Froger et al. 2001). The aim of the present study was to evaluate the effects of coadministration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine with a NK1 receptor antagonist (GR205171 or L733060), given either intraperitoneally (i.p.) or locally into the dorsal raphe nucleus, on extracellular levels of 5-HT ([5-HT]ext) in the frontal cortex and the dorsal raphe nucleus using in vivo microdialysis in awake, freely moving mice. The systemic or intraraphe administration of a NK1 receptor antagonist did not change basal cortical [5-HT]ext in mice. A single systemic dose of paroxetine (4 mg/kg; i.p.) resulted in a statistically significant increase in [5-HT]ext with a larger extent in the dorsal raphe nucleus (+ 138% over basal AUC values), than in the frontal cortex (+ 52% over basal AUC values). Co-administration of paroxetine (4 mg/kg; i.p.) with the NK1 receptor antagonists, GR205171 (30 mg/kg; i.p.) or L733060 (40 mg/kg; i.p.), potentiated the effects of paroxetine on cortical [5-HT]ext in wild-type mice, whereas GR205171 (30 mg/kg; i.p.) had no effect on paroxetine-induced increase in cortical [5-HT]ext in NK1 receptor knock-out mice. When GR205171 (300 micro mol/L) was perfused by 'reverse microdialysis' into the dorsal raphe nucleus, it potentiated the effects of paroxetine on cortical [5-HT]ext, and inhibited paroxetine-induced increase in [5-HT]ext in the dorsal raphe nucleus. Finally, in mice whose 5-HT transporters were first blocked by a local perfusion of 1 micro mol/L of citalopram into the frontal cortex, a single dose of paroxetine (4 mg/kg i.p.) decreased cortical 5-HT release, and GR205171 (30 mg/kg i.p.) reversed this effect. The present findings suggest that NK1 receptor antagonists, when combined with a SSRI, augment 5-HT release by modulating substance P/5-HT interactions in the dorsal raphe nucleus.     

Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake

A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta™) has proven to be effective in clinical trials for the treatment of depression.     

Impact of continuous and pulsatile insulin delivery on net hepatic glucose uptake

The pancreas releases insulin in a pulsatile manner; however, studies assessing the liver's response to insulin have used constant infusion rates. Our aims were to determine whether the secretion pattern of insulin [continuous (CON) vs. pulsatile] in the presence of hyperglycemia 1) influences net hepatic glucose uptake (NHGU) and 2) entrains NHGU. Chronically catheterized conscious dogs fasted for 42 h received infusions including peripheral somatostatin, portal insulin (0.25 mU x kg(-1) x min(-1)), peripheral glucagon (0.9 ng x kg(-1) x min(-1)), and peripheral glucose at a rate double the glucose load to the liver. After the basal period, insulin was infused for 210 min at either four times the basal rate (1 mU x kg(-1) x min(-1)) or an identical amount in pulses of 1 and 4 min duration, followed by intervals of 11 and 8 min (CON, 1/11, and 4/8, respectively) in which insulin was not infused. A variable peripheral glucose infusion containing [3H]glucose clamped glucose levels at twice the basal level ( approximately 200 mg/dl) throughout each study. Hepatic metabolism was assessed by combining tracer and arteriovenous difference techniques. Arterial plasma insulin (microU/ml) either increased from basal levels of 6 +/- 1 to a constant level of 22 +/- 4 in CON or oscillated from 5 +/- 1 to 416 +/- 79 and from 6 +/- 1 to 123 +/- 43 in 1/11 and 4/8, respectively. NHGU (-0.8 +/- 0.3, 0.4 +/- 0.2, and -0.9 +/- 0.4 mg x kg(-1) x min(-1)) and net hepatic fractional extraction of glucose (0.04 +/- 0.01, 0.04 +/- 0.01, and 0.05 +/- 0.01 mg x kg(-1) x min(-1)) were similar during the experimental period. Spectral analysis was performed to assess whether a correlation existed between the insulin secretion pattern and NHGU. NHGU was not augmented by pulsatile insulin delivery, and there is no evidence of entrainment in hepatic glucose metabolism. Thus the loss of insulin pulsatility per se likely has little or no impact on the effectiveness of insulin in regulating liver glucose uptake.