Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat

Hindbrain administration of MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) channel blocker, increases meal size, suggesting NMDA receptors in this location participate in control of food intake. However, dizocilpine (MK-801) reportedly antagonizes some non-NMDA ion channels. Therefore, to further assess hindbrain NMDA receptor participation in food intake control, we measured deprivation-induced intakes of 15% sucrose solution or rat chow after intraperitoneal injection of either saline vehicle or D(-)-2-amino-5-phosphonopentanoic acid (AP5), a competitive NMDA receptor antagonist, to the fourth ventricular, or nucleus of the solitary tract (NTS). Intraperitoneal injection of AP5 (0.05, 0.1, 1.0, 3.0, and 5.0 mg/kg) did not alter 30-min sucrose intake at any dose (10.7 +/- 0.4 ml, saline control) (11.0 +/- 0.8, 11.2 +/- 1.0, 11.2 +/- 1.0, 13.1 +/- 2.2, and 11.0 +/- 1.9 ml, AP5 doses, respectively). Fourth ventricular administration of both 0.2 mug (16.7 +/- 0.6 ml) and 0.4 mug (14.9 +/- 0.5 ml) but not 0.1 and 0.6 mug of AP5 significantly increased 60-min sucrose intake compared with saline (11.2 +/- 0.4 ml). Twenty-four hour chow intake also was increased compared with saline (AP5: 31.5 +/- 0.1 g vs. saline: 27.1 +/- 0.6 g). Furthermore, rats did not increase intake of 0.2% saccharin after fourth ventricular AP5 administration (AP5: 9.8 +/- 0.7 ml, vs. saline: 10.5 +/- 0.5 ml). Finally, NTS AP5 (20 ng/30 nl) significantly increased 30- (AP5: 17.2 +/- 0.7 ml vs. saline: 14.6 +/- 1.7 ml), and 60-min (AP5: 19.4 +/- 0.6 ml vs. saline: 15.5 +/- 1.4 ml) sucrose intake, as well as 24-h chow intake (AP5: 31.6 +/- 0.3 g vs. saline: 26.1 +/- 1.2 g). These results support the hypothesis that hindbrain NMDA receptors participate in control of food intake and suggest that this participation also may contribute to control of body weight over a 24-h period.     

Comparison of the effects of neuropeptide Y and adrenergic transmitters on LH release and food intake in male rats

In view of the recent demonstrations that Neuropeptide Y (NPY) and adrenergic transmitters coexist in neurons of the rat brain, we have compared the effects of intraventricular (Ivt) injections of NPY and catecholamines on LH release and food intake in intact male rats. Of the three catecholamines, dopamine (DA), norepinephrine (NE) and epinephrine (E), only E (5.3 micrograms or 15.9 micrograms/rat) significantly stimulated LH release, although NE and E (5.3 micrograms/rat) were equally effective in eliciting food intake in satiated rats. Ivt administration of 10 micrograms NPY significantly stimulated LH release, whereas either lower (0.5 or 2 micrograms/rat) or higher (25 micrograms/rat) doses were ineffective. In contrast, NPY at doses of 0.5 - 10 micrograms/rat increased cumulative food intake in a dose-related fashion. These findings present preliminary evidence of the physiological correlates of the neuronal coexistence of adrenergic transmitters and NPY in the brain and raise the possibility that NPY may normally act either independently, in concert with or via adrenergic systems to evoke LH release and feeding responses in the rat.     

NMDA channels control meal size via central vagal afferent terminals

The N-methyl-D-aspartate (NMDA) ion channel blocker MK-801 administered systemically or as a nanoliter injection into the nucleus of the solitary tract (NTS), increases meal size. Furthermore, we have observed that ablation of the NTS abolishes increased meal size following systemic injection of dizocilpine (MK-801) and that MK-801-induced increases in intake are attenuated in rats pretreated with capsaicin to destroy small, unmyelinated, primary afferent neurons. These findings led us to hypothesize that NMDA receptors on central vagal afferent terminals or on higher-order NTS neurons innervated by these vagal afferents might mediate increased food intake. To evaluate this hypothesis, we examined 15% sucrose intake after 50-nl MK-801 injections ipsilateral or contralateral to unilateral nodose ganglion removal (ganglionectomy). On the side contralateral to ganglionectomy, vagal afferent terminals would be intact and functional, whereas ipsilateral to ganglionectomy vagal afferent terminals would be absent. Three additional control preparations also were included: 1) sham ganglionectomy and 2) subnodose vagotomy either contralateral or ipsilateral to NTS cannula placement. We found that rats with subnodose vagotomies increased their sucrose intake after injections of MK-801 compared with saline, regardless of whether injections were made contralateral (12.6 +/- 0.2 vs. 9.6 +/- 0.3 ml) or ipsilateral (14.2 +/- 0.6 vs. 9.7 +/- 0.4 ml) to vagotomy. Rats with NTS cannula placements contralateral to nodose ganglionectomy also increased their intake after MK-801 (12.2 +/- 0.9 and 9.2 +/- 1.1 ml for MK-801 and saline, respectively). However, rats with placements ipsilateral to ganglionectomy did not respond to MK-801 (8.0 +/- 0.5 ml) compared with saline (8.3 +/- 0.4 ml). We conclude that central vagal afferent terminals are necessary for increased food intake in response to NMDA ion channel blockade. The function of central vagal afferent processes or the activity of higher-order NTS neurons driven by vagal afferents may be modulated by NMDA receptors to control meal size.     

Effect of intraperitoneal CCK-8 on food intake and brain orexin-A after 48 h of fasting in the rat

We investigated the interactions of the peripheral satiety peptide cholecystokinin and the brain orexin-A system in the control of food intake. The effect of an intraperitoneal (i.p.) injection of sulfated cholecystokinin octapeptide (in this article called CCK) (5 microg/kg, 4.4 nmol/kg) or of phosphate-buffered saline (PBS, vehicle control) on 48 h fasting-induced feeding and on orexin-A peptide content was analyzed in diverse brain regions innervated by orexin neurons and involved in the control of food intake. Administration of CCK after a 48 h fast reduced fasting-induced hyperphagia (P<0.05). I.p. CCK increased the orexin-A content in the posterior brainstem of 48 h fasted rats by 35% (P<0.05). Fed animals receiving CCK had 48% higher orexin-A levels in the posterior brainstem than fasted rats (P<0.05). In the lateral hypothalamus, fasting decreased orexin-A levels by 50% as compared to fed rats (P<0.05). In the septal nuclei, the combination of fasting and CCK administration reduced orexin-A contents compared to fed PBS and CCK animals by 13% and 17%, respectively (P<0.05). These results suggest a convergence of pathways activated by peripheral CCK and by fasting on the level of orexin-A released in the posterior brainstem and provide evidence for a novel interaction between peripheral satiety signaling and a brain orexigen in the control of food intake.     

Role for NMDA receptors in visceral nociceptive transmission in the anterior cingulate cortex of viscerally hypersensitive rats

We have identified colorectal distension (CRD)-responsive neurons in the anterior cingulate cortex (ACC) and demonstrated that persistence of a heightened visceral afferent nociceptive input to the ACC induces ACC sensitization. In the present study, we confirmed that rostral ACC neurons of sensitized rats [induced by chicken egg albumin (EA)] exhibit enhanced spike responses to CRD. Simultaneous in vivo recording and reverse microdialysis of single ACC neurons showed that a low dose of glutamate (50 microM) did not change basal ACC neuronal firing in normal rats but increased ACC neuronal firing in EA rats from 18 +/- 2 to 32 +/- 3.8 impulses/10 s. A high dose of glutamate (500 microM) produced 1.95-fold and a 4.27-fold increases of ACC neuronal firing in sham-treated rats and in EA rats, respectively, suggesting enhanced glutamatergic transmission in the ACC neurons of EA rats. Reverse microdialysis of the 3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainite receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) reduced basal and abolished CRD-induced ACC neuronal firing in normal rats. In contrast, microdialysis of N-methyl-d-aspartate (NMDA) receptor antagonist AP5 had no effect on ACC neuronal firing in normal rats. However, AP5 produced 86% inhibition of ACC neuronal firing evoked by 50 mmHg CRD in the EA rats. In conclusion, ACC nociceptive transmissions are mediated by glutamate AMPA receptors in the control rats. ACC responses to CRD are enhanced in viscerally hypersensitive rats. The enhancement of excitatory glutamatergic transmission in the ACC appears to mediate this response. Furthermore, NMDA receptors mediate ACC synaptic responses after the induction of visceral hypersensitivity.     

Orexin-A does not stimulate food intake in old rats

Aging is associated with a progressive decrease in appetite and food intake. Both A and B orexins, expressed in specific neurons of the lateral hypothalamic area, have been implicated in the regulation of sleep and feeding. In this study, the stimulatory effect of intracerebroventricular administration of the orexins on food intake was compared between young (4-mo-old) and old (25- to 27-mo-old) male Wistar rats. A stainless steel cannula was implanted stereotactically into the left lateral ventricle. After a 7-day recovery period, different doses (0-30 nmol) of orexins were injected into the left lateral ventricle without anesthesia. Food and water consumptions were measured at 1, 2, and 4 h after injection. The protein levels of orexin receptors, a specific receptor for orexin-A (OX1R) and a receptor for both orexin-A and -B (OX2R), in the hypothalamus were determined by Western blot analysis and compared between young and old rats. Intracerebroventricular administration of orexin-A stimulated food intake in a dose-dependent manner in young rats. However, no effects were observed at any dose in old rats. The protein level of OX1R in the hypothalamus was significantly lower in old rats than in young rats, although the protein level of OX2R was comparable between groups. Results of the present study indicate that the function of the orexin system is diminished in old rats. The decrease in the OX1R protein level in the hypothalamus could be responsible for orexin-A's lack of stimulation of food intake in old rats.     

Cholinergic neurotransmission participates in increased food intake induced by NMDA receptor blockade

MK-801, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, enhances gastric emptying while increasing food intake. Although our previously reported results implicate the vagus in MK-801's effect on feeding, it is not clear whether vagal motor fibers participate in the feeding response. Control of gastric emptying is exerted, in part, by cholinergic vagal motor neurons. Therefore, we examined the ability of MK-801 to increase meal size in the presence or absence of the muscarinic receptor antagonist atropine methyl nitrate. Both central and systemic administration of MK-801 significantly increased intake of 15% sucrose. Intraperitoneal injection of atropine abolished MK-801-induced increase in sucrose intake, whereas administration into the fourth ventricle had no effect. To determine whether augmentation of cholinergic tone produces an enhancement of food intake in the absence of MK-801, we tested the ability of cisapride, a gastric prokinetic agent that promotes acetylcholine release through an action on presynaptic serotonin (5-HT4) receptors, to increase sucrose consumption. Cisapride (500 microg/kg ip) induced a small but significant increase in 15% sucrose intake (15.5 +/- 0.5 ml) compared with NaCl (13.0 +/- 0.6 ml). Furthermore, when MK-801 (100 microg/kg ip) was given in combination with cisapride, intake was significantly higher (19.8 +/- 0.9 ml) than following either agent given alone. Pretreatment with atropine abolished the cisapride-induced increase in intake (12.1 +/- 0.9 ml) as well as the increased intake induced by combining MK-801 and cisapride. These results suggest that blockade of NMDA-gated ion channels in the hindbrain increases food intake, in part, via a peripheral muscarinic cholinergic mechanism.     

A selective orexin-1 receptor antagonist reduces food consumption in male and female rats

A variety of evidence implicates the orexins, especially orexin-A, in the regulation of food intake, but it has not been established whether this effect is mediated by the orexin-1 or orexin-2 receptor. In the present study, a selective orexin-1 receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride (SB-334867-A), was administered intraperitoneally to rats under various conditions, and food consumption was subsequently measured over 24 h. In male rats, a single dose of SB-334867-A (30 mg/kg, i.p.) given during the light phase reduced both orexin-A-induced food intake (7 nmol, i.c.v.) and feeding stimulated by an overnight fast for 4 h. When given at the start of the dark phase, food consumption was reduced in both male and female rats over 24 h. Daily injections at the start of the dark phase for 3 days reduced natural feeding in male rats over 24 h on days one and three. These findings demonstrate direct inhibition of orexin-A induced food intake with a selective orexin-1 receptor antagonist. Furthermore, the suppression of nocturnal feeding and food intake stimulated by an overnight fast supports other evidence that orexin-A is involved in the regulation of natural feeding and suggests that orexin-1 receptor antagonists could be useful in the treatment of obesity.     

Neuropeptide FF exerts pro- and anti-opioid actions in the parabrachial nucleus to modulate food intake

Neurons that synthesize the morphine modulatory peptide neuropeptide FF (NPFF; Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) densely innervate the parabrachial nucleus (PBN), an area implicated in regulating food intake. We analyzed opioid-related actions of NPFF in feeding in adult male Sprague-Dawley rats. Unilateral infusion of 2 nmol/0.5 microl of the mu-opioid receptor agonist [d-Ala2,NMe-Phe4,glycinol5]enkephalin (DAMGO) into the lateral PBN increased 4-h food intake from 0.7 +/- 0.1 to 3.3 +/- 0.3 g. NPFF (1.25-5.0 nmol) prevented this hyperphagic mu-opioidergic action. In rats fed after 4-h deprivation (baseline = 12.3 +/- 0.3 g/2 h), 5 nmol of NPFF did not alter and larger doses (10 and 20 nmol) actually increased food intake (+36, 54%). Twenty nanomoles also elevated intake of freely feeding rats (from 0.7 +/- 0.1 to 5.1 +/- 1.0 g/4 h). The opioid receptor blocker naloxone (10 nmol) antagonized this increase. These data reveal both pro- and anti-opioid actions of NPFF in the PBN to modulate feeding. The mechanisms for the opposite actions of low and high concentrations of this neuropeptide in parabrachial regulation of food intake remain to be determined.     

Interaction Between Central Opioidergic and Glutamatergic Systems on Food Intake in Neonatal Chicks: Role of NMDA,AMPA and mGLU1 Receptors

The present study was designed to examine the role of opioidergic and glutamatergic systems on feeding behavior in neonatal meat-type chicken. In experiment 1, FD₃ neonatal broilers ICV injected with (A) saline, (B) DAMGO (µ-opioid receptor agonist, 125 pmol), (C) MK-801 (NMDA glutamate receptors antagonist, 15 nmol) and (D) combination of DAMGO plus MK-801. Experiments 2–5 were similar to experiment 1, except FD₃ chicks ICV injected with CNQX (AMPA glutamate receptors antagonist, 390 nmol), AIDA (mGLU₁ receptors antagonist, 2 nmol), LY341495 (mGLU₂ receptors antagonist, 150 nmol) and UBP1112 (mGLU₃ receptors antagonist, 2 nmol) instead of MK-801, respectively. In experiments 6–10, FD₃ chicks ICV injected as the same as procedure to the experiments 1–5, except to inject with DPDPE (δ-opioid receptor agonist, 40 nmol) instead of the DAMGO. The experiments 11–15 were similar to the experiments 1–5, except neonatal broilers ICV injected with U-50488H (κ-opioid receptor agonist, 30 nmol) instead of DAMGO. Then the cumulative food intake measured until 120 min post injection. According to the results, ICV injection of DAMGO, significantly decreased food intake (P?<?0.05) while DPDPE and U-50488H increased feeding behavior compared to the control group (P?<?0.05). Co-injection of the DAMGO?+?MK-801 and DAMGO?+?AIDA, significantly decreased DAMGO-induced hypophagia in neonatal chicks (P?<?0.05). Also, co-injection of the DPDPE?+?CNQX significantly amplified DPDPE induced feeding behavior (P?<?0.05). These results suggested interconnection between central opioidergic and glutamatergic systems on feeding behavior mediates via µ- and δ-opioid receptor with NMDA, AMPA and mGLU₁ receptors in FD₃ neonatal broilers. These findings may shed light on the circuitry underlying interconnection between central opioidergic and glutamatergic systems on feeding behavior.     

Evidence for the role of hindbrain orexin-1 receptors in the control of meal size

Hypothalamic orexin neurons project to the hindbrain, and 4th-ventricle intracerebroventricular (4th-icv) injection of orexin-A treatment increases food intake. We assessed the effects of hindbrain orexin-A and the orexin-1-receptor antagonist SB334867 on meal pattern in rats consuming standard chow. When injected 4th-icv shortly before dark onset, lower doses of orexin-A increased food intake over a 2-h period by increasing the size of the first meal relative to vehicle, whereas the highest dose increased food intake by causing the second meal to be taken sooner. Conversely, hindbrain SB334867 reduced food intake by decreasing the size of the first meal of the dark phase. We also examined the effects of 4th-icv orexin-A and SB334867 on locomotor activity. Only the highest dose of orexin-A increased activity, and SB334867 had no effect. In addition, hindbrain SB334867 induced c-Fos in the nucleus of the solitary tract. These data support the suggestion that endogenous hindbrain orexin-A acts to limit satiation. Both orexin-A and the pancreatic satiation hormone amylin require an intact area postrema to affect food intake, so we asked whether 4th-icv orexin-A impairs the satiating effect of peripheral amylin treatment. Amylin reduced the size of the first meal of the dark cycle when rats were pretreated with 4th-icv saline, yet amylin was ineffective after 4th-icv orexin-A pretreatment. Using double-label immunohistochemistry, we determined that some orexin-A fibers in the area postrema are located in proximity to amylin-responsive neurons. Therefore, hindbrain orexin-A may increase food intake, in part, by reducing the ability of rats to respond to amylin during a meal.     

NMDA receptor blockade attenuates CCK-induced reduction of real feeding but not sham feeding

Systemic injection of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor ion channels, increases meal size and delays satiation. We examined whether MK-801 increases food intake by directly interfering with actions of cholecystokinin (CCK). Prior administration of MK-801 (100 microg/kg ip) reversed the inhibitory effects of CCK-8 (2 and 4 microg/kg ip) on real feeding of both liquid and solid foods. MK-801 alone did not alter 30-min sham intake of 15% sucrose compared with intake after saline. Furthermore, while CCK-8 (2 or 4 microg/kg ip) reduced sham intake, this reduction was not attenuated by MK-801 pretreatment. To ascertain whether MK-801 attenuation of CCK-induced reduction of real feeding was associated with attenuated inhibition of gastric emptying, we tested the effect of MK-801 pretreatment on CCK-induced inhibition of gastric emptying of 5-ml saline loads. Ten-minute gastric emptying was accelerated after MK-801 (3.9 +/- 0.2 ml) compared with saline vehicle (2.72 +/- 0.2 ml). CCK-8 (0.5 microg/kg ip) reduced 10-min emptying to 1.36 +/- 0.3 ml. Pretreatment with MK-801 did not significantly attenuate CCK-8-induced reduction of gastric emptying (0.9 +/- 0.4 ml). This series of experiments demonstrates that blockade of NMDA ion channels reverses inhibition of real feeding by CCK. However, neither inhibition of sham feeding nor inhibition of gastric emptying by CCK is attenuated by MK-801. Therefore, increased food intake after NMDA receptor blockade is not caused by a direct interference with CCK-induced satiation. Rather, increased real feeding, either in the presence or absence of CCK, depends on blockade of NMDA receptor participation in other post-oral feedback signals such as gastric sensation or gastric tone.     

Nociceptin Induces Hypophagia in the Perifornical and Lateral Hypothalamic Area

Nociceptin/orphanin FQ (N/OFQ) is known to induce food intake when administered into the lateral ventricle or certain brain areas. This is somewhat contradictory to its reward-suppressing role, as food is a strong rewarding stimulus. This discrepancy may be due to the functional diversity of N/OFQ’s target brain areas. N/OFQ has been shown to inhibit orexin and melanin-concentrating hormone (MCH) neurons, both of which are appetite-inducing cells. As the expression of these neurons is largely confined to the lateral hypothalamus/perifornical area (LH/PFA), we hypothesized that N/OFQ inhibits food intake by acting in this area. To test this hypothesis, we examined the effect of local N/OFQ infusion within the LH/PFA on food intake in the rat and found that N/OFQ decreased sugar pellet as well as chow intake. This effect was not seen when the injection site was outside of the LH/PFA, suggesting a site-specific effect. Next, to determine a possible cellular mechanism of N/OFQ action on food intake, whole cell patch clamp recordings were performed on rat orexin neurons. As previously reported in mice, N/OFQ induced a strong and long lasting hyperpolarization. Pharmacological study indicated that N/OFQ directly inhibited orexin neurons by activating ATP-sensitive potassium (KATP) channels. This effect was partially but significantly attenuated by the inhibitors of PI3K, PKC and PKA, suggesting that the N/OFQ signaling is mediated by these protein kinases. In summary, our results demonstrate a KATP channel-dependent N/OFQ signaling and that N/OFQ is a site-specific anorexic peptide.     

Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone

AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To?address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles?in controlling AgRP neurons and determining the cellular and behavioral response to fasting.     

Inhibition of food intake by central injection of anti-orexin antibody in fasted rats

It has been shown that intracerebroventricular injection of synthetic orexins stimulated food intake in rats. This pharmacological evidence suggests that orexins may have a role for the central regulation of feeding. In the present study, we investigated the hypothesis of whether endogenous orexins indeed play a vital role in feeding behavior. An anti-orexin polyclonal antibody was used throughout the study. First, we examined the specificity of the antibody to orexin by Western blot analysis and immunohistochemistry. Next, the effects of central injection of the orexin antibody on food intake in 24-h-fasted rats were evaluated. Western blot analysis revealed that the orexin antibody detected synthetic orexin-A. Immunohistochemical study showed that orexin-positive neurons were identified only in the lateral hypothalamic area, in agreement with previous reports. Neither control antibody nor the orexin antibody preabsorbed with excess amount of orexin-A detected neurons, indicating that the orexin antibody is specific. Intracisternal but not intraperitoneal injection of the orexin antibody dose-dependently suppressed feeding. All these results suggest that immunoneutralization of endogenous orexins in the brain reduced food intake. In other words, we suggest that endogenous brain orexin may have a physiologically relevant action on feeding behavior.     

哺乳、哺乳-禁乳及哺乳-禁乳后再哺乳对大鼠下丘脑胖素A免疫反应神经元的影响

为观察下丘脑胖素 A在哺乳期摄食增加和能量代谢中的作用,本研究采用脑连续切片之免疫组织化学和图像定量分析技术,对分娩后第 12 天非哺乳、持续哺乳、持续哺乳后禁哺乳过夜和持续哺乳 - 禁哺乳后再急性哺乳大鼠下丘脑胖素A免疫反应神经元的免疫反应性进行了观察和半定量分析。结果表明,分娩后持续哺乳 11 d, 大鼠的日摄食量较同期分娩的非哺乳大鼠明显增加(180%),一夜禁哺乳则明显降低哺乳大鼠的日摄食量(45%); 哺乳12 d, 大鼠下丘脑胖素 A免疫反应神经元的数目和平均染色强度较非哺乳大鼠明显增加(P<0.001,P<0.05); 禁哺乳过夜(15 h)明显降低哺乳大鼠胖素A免疫反应神经元的数目和平均染色强度(P<0.001,P<0.05),与非哺乳大鼠比较无明显差异;禁哺乳过夜后再急性哺乳2 h 明显增加禁哺乳大鼠胖素 A 免疫反应神经元的数目和平均染色强度(P<0.001,P<0.05),急性哺乳 5 h 后,虽亦明显增加禁哺乳大鼠胖素 A免疫反应性(P<0.05),但与急性哺乳 2 h 比较作用减弱。上述结果表明,持续哺乳和禁乳后再哺乳均导致下丘脑胖素A明显增加,提示哺乳期胖素A可能表达上调并可能与哺乳期摄食增加有关, 且吸乳动作与下丘脑胖素A样神经元之间可能存在某种神经或体液性联系途径。     

Spinal control of erection by glutamate in rats

The lumbosacral spinal network controlling penile erection is activated by information from peripheral and supraspinal origins. We tested the hypothesis that glutamate, released by sensory afferents from the genitals, activates this proerectile network. In anesthetized intact and T8 spinalized (i.e., freed from supraspinal inhibition) male rats, the parameters of electrical stimulation of the dorsal penile nerve (DPN) that elicited intracavernous pressure (ICP) rises were determined. In T8 spinalized rats, DPN stimulations were applied in the presence of d(-)-2-amino-5-phosphonopentanoic acid (d-AP5), a competitive NMDA receptor antagonist, or of 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide (NBQX), an AMPA-kainate receptor antagonist, injected intrathecally at the lumbosacral level. Both antagonists, alone or in combination, dose dependently decreased the ICP rise and increased its latency. In conscious rats, reflexive erections were depressed by d-AP5 and NBQX, as revealed by an increased latency of the first erection and by decreases of the number of rats displaying erections, of the number of erection clusters and of the number of erections per cluster. In anesthetized ats, the combined administration of the glutamatergic agonists NMDA and AMPA elicited ICP rises in the absence of DPN stimulation. In contrast, both agonists moderately decreased the ICP rise elicited by DPN stimulation but did not affect its latency. These results support our hypothesis that glutamate, released on stimulation of the genitals and acting at AMPA and NMDA receptors, is a potent reactivator of the spinal proerectile network.     

Orexins and feeding: special occasions or everyday occurrence?

Neurons expressing prepro-orexin, the precursor of orexin-A and -B, are found in the lateral hypothalamic area, a region classically implicated in driving feeding. Orexin-A induces feeding transiently when injected centrally, and food intake can be decreased when orexin action is disrupted by immunoneutralization of orexin-A, or by pharmacological blockade of orexin receptors, or by transgenic knockout of orexin. Here, we argue that orexin neurons may act to stimulate feeding in the short term, and that important regulatory signals may be a fall in plasma glucose (stimulatory), countered by satiety signals generated by eating, such as gastric distention (inhibitory).     

Further contribution to the study of corticostriatal glutamatergic and nigrostriatal dopaminergic interactions within the striatal network: an in vivo voltammetric investigation

Summary In vivo voltammetry was used in freely moving rats to study the processes whereby striatal dopamine (DA) release is regulated by corticostriatal glutamatergic neurons. Electrical stimulation of the cerebral cortex was found to markedly increase the striatal DA-related voltammetric signal amplitude. Similar enhancements have been observed after intracerebroventricular administration of 10nmoles glutamate, quisqualate and AMPA, whereas NMDA was found to decrease the amplitude of the striatal signals. The NMDA receptor antagonist APV did not significantly affect the voltammetric signal but prevented the NMDA-induced depression of the DA-related signals. These data are in agreement with those obtained in numerous previous studies suggesting that the glutamatergic corticostriatal neurons exert activatory effects on the striatal DA release via non-NMDA receptors. The mechanism involved might be of a presynaptic nature. The role of the NMDA receptors may however consist of modulating the dopaminergic transmission phasically and in a depressive way, which would be consistent with behavioural data suggesting the existence of a functional antagonism between the activity of the corticostriatal glutamatergic and nigrostriatal dopaminergic systems.Abbreviations Glu glutamate - DA dopamine - NMDA N-methyl-D-aspartate - CPP 3-(2-carboxypiperazin-4µl)propyl-1-phosphonic acid - AMPA -amino-3-hydroxy-5-metylisoxazole-4-propionic acid - APV aminophosphonovaleric acid - DOPAC dihydroxyphenylacetic acid - HVA homovanillic acid - DARPP 32 dopamine-cAMP-regulated phosphoprotein 32 - CSF cerebrospinal fluid Laboratory associated with the University of Aix-Marseille II