Amygdala enterostatin induces c-Fos expression in regions of hypothalamus that innervate the PVN

Enterostatin selectively inhibits the intake of the dietary fat after both central and peripheral administration. Our previous studies have shown that a central site of action is the central nucleus of amygdala. Serotonergic agonists administered into the paraventricular nucleus (PVN) inhibit fat intake and serotonergic antagonists block the feeding suppression induced by amygdala enterostatin, suggesting that there are functional connections between the PVN and amygdala that affect the feeding response to enterostatin. Our purpose was to identify the anatomic and functional projections from the amygdala to the PVN and hypothalamic area that are responsive to enterostatin, by using a retrograde tracer fluorogold (FG) and c-Fos expression. Rats were injected with fluorogold unilaterally into the PVN and a chronic amygdala cannula was implanted ipsilaterally. After 10 days recovery, rats were injected with either enterostatin (0.1 nmol) or saline vehicle (0.1 microl) into the amygdala and sacrificed 2 h later by cardiac perfusion under anesthesia. The brains were subjected to dual immunohistochemistry to visualize both FG and c-Fos-positive cells. FG/c-Fos double-labeled cells were found in forebrain regions including the PVN, amygdala, lateral hypothalamus (LH), ventral medial hypothalamus (VMH) and arcuate nucleus (ARC). The data provides the first anatomical evidence that enterostatin activates amygdala neurons that have functional and anatomic projections directly to the PVN and also activates neurons in the arcuate, LH and VMH, which innervate the PVN.     

Feeding behavior after metergoline or GR-46611 injections into the paraventricular nucleus of the hypothalamus in the pigeon

The present study examined changes in spontaneous behavior of free-feeding pigeons in response to local injections of metergoline (MET, an antagonist of 5-HT(1/2) receptors; 5, 10 and 20 nmol), GR-46611 (GR, a 5-HT(1B/1D) agonist; 0.6 and 6 nmol) or vehicle into the paraventricular hypothalamic nucleus (PVN). When infused into the PVN, MET and GR promptly and reliably elicited feeding at their higher doses, without affecting drinking or non-ingestive behaviors (locomotion, exploration, preening, sleep) during the first hour after injection. Both GR- and MET-evoked ingestive responses were associated only with an increase in feeding duration, with no changes in latency to start feeding. In a second series of experiments, the effective doses of MET (20 nmol) and GR (6 nmol) were injected into other diencephalic areas. This exploratory study revealed that intense feeding responses to both MET and GR local injections are also observed in the n. medialis hypothalami posterioris and in the adjacent n. lateralis hypothalami posterioris (PMH/PLH complex, in the caudoventral hypothalamus) and in the n. magnocellularis preopticus (PPM, in the caudal preoptic region). The behavioral profiles associated with these hyperphagic responses were nucleus-specific: in the PMH/PLH, MET-induced feeding was accompanied by an increase in total feeding duration and by a reduction in the latency to start feeding, while ingestive responses evoked by MET in the PPM were associated only with an increase in feeding duration (similar to that observed in the PVN experiments). No ingestive effects were observed after intracerebroventricular (ICV, lateral ventricle) injections of MET (10, 30, 100 or 300 nmol), while ICV injections of GR (3, 15 or 30 nmol) increased feeding only at the higher dose [Da Silva RA, De Oliveira ST, Hackl LPN, Spilere CI, Faria MS, Marino-Neto J, Paschoalini MA. Ingestive behaviors and metabolic fuels after central injections of 5-HT1A and 5-HT1D/1B receptors agonists in the pigeon. Brain Res, 2004;1026:275-283]. These data indicate the presence of a tonic inhibitory influence on feeding behavior exerted by 5-HT afferents on these hypothalamic areas, and suggest that these inputs, possibly mediated by non-rodent-type 5-HT1D/1B receptors, can affect both satiety and satiation mechanisms.     

Serotonin stimulates hypothalamic mRNA expression and local release of neurohypophysial peptides

The neurotransmitter serotonin (5-HT) stimulates the secretion of vasopressin and oxytocin, and 5-HT is involved in the mediation of the vasopressin and oxytocin response to stress. In male Wistar rats, we investigated the 5-HT receptors involved in the 5-HT-induced increase of mRNA expression of vasopressin and oxytocin in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The 5-HT precursor, 5-hydroxytryptophan, injected in combination with the 5-HT reuptake inhibitor, fluoxetine, increased oxytocin mRNA expression in the PVN, and the concentration of vasopressin and oxytocin in plasma, whereas mRNA in the SON was not affected. Intracerebroventricular infusion of 5-HT agonists selective for the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptor increased oxytocin mRNA in the SON and PVN. Infusion of agonists selective for the 5-HT2A + 2C receptor increased vasopressin mRNA in the PVN, whereas none of the 5-HT agonists affected vasopressin mRNA in the SON. All the 5-HT agonists infused increased peripheral oxytocin concentration and vasopressin was increased by stimulation of the 5-HT2A, 5-HT2C and 5-HT3 receptor. Intracerebroventricular infusion of 100 nmol 5-HT increased the extracellular hypothalamic concentration of vasopressin as measured by microdialysis in the PVN. To evaluate the involvement of hypothalamic-pituitary system in the 5-hydroxytryptophan and fluoxetine-induced vasopressin secretion, rats were immunoneutralized with a specific anti-corticotropin-releasing hormone antiserum. This treatment reduced plasma vasopressin and oxytocin responses. We conclude that stimulation with 5-hydroxytryptophan or 5-HT agonists increases mRNA expression of oxytocin in the PVN and the SON via stimulation of at least 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors. Vasopressin mRNA in the PVN was increased only via the 5-HT2 receptor, whereas vasopressin mRNA in the SON does not seem to be affected by 5-HT stimulation. Corticotropin-releasing hormone appears to be partly involved in the mediation of 5-HT induced vasopressin and oxytocin secretion.     

S-(+)-fenfluramine-induced nociceptive behavior in mice: Involvement of interactions between spinal serotonin and substance P systems

Intrathecal (i.t.) administration into mice of S-(+)-fenfluramine (0.01-0.1nmol), a serotonin (5-hydroxytryptamine, 5-HT) releaser, produced a behavioral response consisting of scratching, biting and licking. Here, we report the behavioral characteristics and the involvement of interactions between 5-HT and substance P (SP) systems in the S-(+)-fenfluramine-induced behavioral response. The S-(+)-fenfluramine-induced behavioral response peaked at 5-15min and almost disappeared at 20min after injection. The behavior induced by S-(+)-fenfluramine (0.1nmol) was dose-dependently inhibited by an intraperitoneal injection of morphine (0.02-0.5mg/kg), suggesting that the behavioral response is related to nociception. The S-(+)-fenfluramine-induced nociceptive behavior was significantly inhibited by pretreatment with 5-HT antiserum and co-administration of ketanserin, a selective 5-HT2 receptor antagonist. However, WAY-100635, a selective 5-HT1A receptor antagonist, and ramosetron, a selective 5-HT3 receptor antagonist, were not active. On the other hand, SP antiserum and RP67580, a selective neurokinin-1 (NK1) receptor antagonist, significantly inhibited S-(+)-fenfluramine-induced nociceptive behavior. These results suggest that i.t.-administered S-(+)-fenfluramine releases SP through the activation of 5-HT2 receptors subsequent to 5-HT release, and, as a result, produces nociceptive behavior.     

5-HT(1B) receptor knockout mice show no adaptive changes in 5-HT(1A) receptor function as measured telemetrically on body temperature and heart rate responses

Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT(1A) and 5-HT(1B) receptor. The present study focuses on putative adaptive changes in the 5-HT(1A) receptor system in mice that lack 5-HT(1B) receptors (5-HT(1B) KO). 5-HT(1A) receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT(1A) receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT(1A) receptor activation by flesinoxan (0.1-3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT(1B) KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT(1A) receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT(1B) KO mice showed no shift in 5-HT(1A) receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT(1A) receptor function in 5-HT(1B) KO mice as measured telemetrically on body temperature and heart rate responses.     

Expression of type 1 corticotropin-releasing hormone (CRH) receptor mRNA in the hypothalamic paraventricular nucleus following restraint stress in CRH-deficient mice

Previous studies have demonstrated that various types of stress increase type 1 corticotropin-releasing hormone (CRH) receptor (currently abbreviated to CRF1 receptor) mRNA in the hypothalamic paraventricular nucleus (PVN) of rats, but not mice. This study investigated whether different sensitivities of glucocorticoid-mediated negative feedback effects can explain this species difference in stress-induced PVN CRF1 receptor mRNA expression. First, the CRF1 receptor mRNA level in the PVN of CRH knockout (KO) mice during acute restraint stress was compared with that in wild-type (WT) mice. Consistent with previous findings, WT mice showed no induction of CRF1 receptor mRNA in the PVN following acute restraint, regardless of normal hypothalamic-pituitary-adrenocortical responses. In contrast, CRF1 receptor mRNA in the PVN of CRH KO mice was increased following 2 h of restraint. Since the response of tyrosine hydroxylase (TH) mRNA in the locus coeruleus (LC) to restraint was similar between CRH KO and WT mice, it is unlikely that enhanced noradrenergic input into the PVN was responsible for the CRF1 receptor mRNA induction in CRH KO mice. Second, to determine whether CRH KO per se or a low corticosterone response to stress is required to induce CRF1 receptor mRNA expression in the PVN in mice, the response of adrenalectomized WT mice was examined. Acute restraint increased the CRF1 receptor mRNA level in the PVN of adrenalectomized WT mice, similar to the case for CRH KO mice. TH mRNA in the LC showed similar increases in sham and adrenalectomized WT mice. These results indicate that PVN CRF1 receptor mRNA is much more sensitive to glucocorticoid-mediated negative feedback in mice than in rats, such that a normal increase in plasma corticosterone during stress can mask CRF1 receptor mRNA induction in the PVN of mice.     

Altered presynaptic function in monoaminergic neurons of monoamine oxidase-A knockout mice

Monoamine oxidase-A knockout (MAO-A KO) mice have elevated brain serotonin (5-HT) and noradrenaline (NA) levels, and one would therefore anticipate increased monoamine release and compensatory changes in other aspects of presynaptic monoamine function. In this study we used voltammetry in brain slices from the locus coeruleus (LC), dorsal raphe (DRN) and striatum (CPu) in 7-week-old MAO-A KO and C3H control mice to measure stimulated monoamine efflux and its control by amine transporters and autoreceptors. In LC, peak NA efflux on stimulation (99 pulses, 100 Hz) was higher in MAO-A KO than C3H mice (938 +/- 58 nm cf. 511 +/- 42 nm; P < 0.001). The NA uptake half time (t(1/2)) was longer in MAO-A KO than in C3H mice (6.0 +/- 0.9 s cf. 1.9 +/- 0.3 s; P < 0.001) and the selective NA reuptake inhibitor desipramine (50 nm) had a smaller effect in MAO-A KO mice. NA transporter binding was significantly lower in the LC of MAO-A KO mice compared to C3H controls (P < 0.01) but not in the DRN. The alpha 2 agonist dexmedetomidine (10 nm) decreased stimulated NA efflux more in C3H than in MAO-A KO mice (73.3% cf. 29.6% inhibition, P < 0.001). In DRN, peak 5-HT efflux on stimulation (99 pulses, 100 Hz) was greater (P < 0.01) in MAO-A KO (262 +/- 44 nm) than C3H mice (157 +/- 16 nm). Moreover, 5-HT uptake t(1/2) was longer (P < 0.05) in MAO-A KO than in C3H mice (8.8 +/- 1.1 s cf. 4.9 +/- 0.6 s, P < 0.05) and the effect of citalopram (75 nm) was attenuated in MAO-A KOs. Serotonin transporter binding was also lower in both the DRN and LC of MAO-A KO mice. The 5-HT(1A) agonist 8-OH-DPAT (1 microm) decreased 5-HT efflux more in C3H than in MAO-A KO mice (38.3% inhibition cf. 21.6%, P < 0.001). In contrast, there were no significant differences between MAO-A KO and C3H mice in CPu dopamine efflux and uptake and the effect of the D(2/3) agonist quinpirole was similar in the two strains. In summary, MAO-A KO mice show major dysregulation of monoaminergic presynaptic mechanisms such as autoreceptor control and transporter kinetics.     

5-HT1B receptor knockout mice show a compensatory reduction in 5-HT2C receptor function

Although null mutant ('knockout') mice have provided valuable animal models to complement traditional approaches to psychopharmacology, such animals may also show complex adaptations to the induced mutation. Here we demonstrate that serotonin1B (5-HT1B) receptor knockout (KO) mice show adaptations in serotonin2C (5-HT2C) receptor-mediated functions. They show smaller reductions in food intake and locomotor activity in response to administration of 5-HT2C receptor agonists that are not accounted for by altered drug disposition. These effects are not mimicked by pretreatment of wildtype (WT) mice with a 5-HT1B receptor antagonist showing that they result from a longer term adaptation to the loss of 5-HT1B receptor function and not from a short-term interaction between 5-HT1B- and 5-HT2C-mediated functions. In addition, we show that 5-HT1B receptor KO mice have a lowered hypothalamic c-fos response to the administration of 5-HT2C receptor agonists. These results demonstrate that compensatory adaptations to the constitutive loss of 5-HT1B receptors may be an important determinant of the altered response of 5-HT1B KO mice to a variety of pharmacological challenges.     

Enterostatin suppresses food intake following injection into the third ventricle of rats

The effect on food intake of an activation peptide from pancreatic pro-colipase, called enterostatin, has been studied after parenteral or third ventricular administration. The activation peptide (enterostatin = Val-Pro-Asp-Pro-Arg = VPDPR) reduced food intake when given intraperitoneally. Low doses of this peptide also reduced food intake when given into the third ventricle, but high doses were ineffective. Enterostatin did not modify the stimulatory effects on food intake of clonidine, an alpha 2-adrenergic agonist, suggesting that its anorectic effects are not mediated via the alpha 2-adrenergic system. These data suggest that enterostatin, an activation peptide from pro-colipase, may play a role in producing satiety.     

Differential effects of NE, CLON, and 5-HT on feeding and macronutrient selection in genetically obese (ob/ob) and lean mice

The effects of central injection of norepinephrine (NE), clonidine (CLON), and 5-hydroxytryptamine (5-HT) on feeding and macronutrient selection in genetically obese ( , ob/ob) and lean mice ( ) were examined. Mice were adapted to single-energy source diets of carbohydrate, protein, and fat and then injected with NE (20–80 nmol) or CLON (5–20 nmol) immediately prior to dark onset (17h00). Measurements of nutrient intake were determined 2 h postinjection. In a separate study, obese and lean mice were deprived of food for 1 h (1700–1800) and subsequently treated with 5-HT (35–140 nmol). The results of this study demonstrate that the hyperphagic effect of NE and CLON and the anorectic effect of 5-HT are dose dependent and nutrient selective. Specifically, at the onset of the nocturnal cycle, obese and lean mice exhibit a shift in diet choice resulting in an increased preference for carbohydrate and a reduction in the proportional intake of protein and fat. At this time, central injection of NE or CLON potentiates an already enhanced preference for carbohydrate; whereas injection of 5-HT suppresses carbohydrate intake (kcal) in both phenotypes without altering fat or protein intake. However, in comparison to lean mice, obese mice showed significantly augmented hyperphagic responses to NE and CLON administration but decreased inhibition of feeding after 5-HT injection. This suggests that the stimulatory effect of α2-noradrenergic mechanisms controlling feeding and carbohydrate ingestion is enhanced in obese mice, while the inhibitory influence of serotonergic mechanisms is attenuated.     

Suppression of norepinephrine-elicited feeding by neurotensin: Evidence for behavioral, anatomical and pharmacological specificity

Neurotensin (NT) injected into the paraventricular hypothalamic nucleus (PVN) has been shown to suppress feeding behavior. To investigate whether this suppression generalizes to feeding elicited by norepinephrine injection, rats with bilateral PVN cannulas were injected with NT (3.0 nmol/cannula) or vehicle followed by norepinephrine (20.0 nmol/cannula). Pretreatment with NT caused a 48% reduction in feeding elicited by norepinephrine. To determine whether NT's effect resulted from non-specific behavioral effects or leakage into the periphery, NT (0.25, 1.25 or 6.0 nmol) was injected ipsilateral or contralateral to a unilateral norepinephrine (40.0 nmol) injection. Ipsilateral NT produced a dose-dependent suppression of norepinephrine-elicited feeding which was significantly greater than the effect of contralateral NT, suggesting that NT's effect was at least partially behaviorally and anatomically specific. To investigate the pharmacological specificity of the suppression, rats that ate in response to PVN norepinephrine (40.0 nmol) were given prior injections of NT or one of six NT fragments at 0.25, 1.25, 6.0 or 30.0 nmol. NT and the C-terminal fragments 3-13 and 6-13 caused a dose-dependent suppression of feeding. In contrast, none of the N-terminal fragments (i.e. 1-8, 1-11 or 1-12) were effective. This specificity rules out non-specific changes in parameters such as pH or osmotic pressure and suggests that the anorectic effect may have been mediated by NT receptors.     

Selective up-regulation of 5-HT(1B/1D) receptors during organ culture of cerebral arteries.

5-Hydroxytryptamine (5-HT) is thought to be involved in migraine headache and the pathophysiology of cerebrovascular diseases. Previous data show that organ culture induces a phenotypic change in cerebral vessels. Therefore we investigated if these changes also applied for the vasoconstrictive 5-HT receptors. Rat cerebral arteries express 5-HT2 receptors. Using organ culture we observed a phenotypic change with a selective up-regulation of 5-HT(1B/1D) receptors. This was revealed by an increased sensitivity to the selective 5-HT(1B/1D) agonist 5-CT after organ culture (pEC50(fresh) 5.6+/-0.2 and pEC50(cultured) 6.8+/-0.4). The response was inhibited by the 5-HT(1B/1D) selective antagonist GR55562 (pEC50(fresh) 5.1+/-0.2 and pEC50(cultured) 6.0+/-0.3). The organ model might mimic the phenotypic changes during cerebrovascular diseases.     

Tetraethylammonium ions block the nicotinic cholinergic receptors of cochlear outer hair cells

An involvement of serotonin (5-HT) 1A receptors in the etiology of psychiatric disorders has been suggested. Hypo-responsiveness of the 5-HT1A receptor is linked to anxiety and constitutive deletion of the 5-HT1A receptor produces anxiety-like behaviors in the mouse. Evidence that 5-HT1A receptor inactivation increases the therapeutic effects of antidepressants has also been presented. The present studies used in vivo microdialysis and homologous recombination techniques to examine the contribution of 5-HT1A autoreceptors to these effects. Basal and fluoxetine-evoked extracellular concentrations of 5-HT were quantified in the striatum, a projection area of dorsal raphe neurons (DRN), of wild-type (WT) and 5-HT1A receptor knock out (KO) mice. The density of 5-HT transporters was also determined. Basal 5-HT concentrations did not differ in WT and KO mice. Fluoxetine (10 mg/kg) increased 5-HT concentrations in both genotypes. This increase was, however, 2-fold greater in KO mice. In contrast, no differences in K(+)-evoked 5-HT concentrations were seen. Similarly, neither basal nor stimulation-evoked DA differed across genotype. Autoradiography revealed no differences between genotype in the density of 5-HT transporters or post-synaptic 5-HT2A receptors, an index of 5-HT neuronal activity. These experiments demonstrate that, under basal and KCl stimulated conditions, adaptive mechanisms in the 5-HT system compensate for the lack of 5-HT1A autoreceptor regulation of DRN. Furthermore, they suggest that the absence of release-regulating 5-HT1A autoreceptors in the DRN can not account for the anxiety phenotype of KO mice. The enhanced response to fluoxetine in KO mice is consistent with pharmacological studies and suggests that adaptive mechanisms that occur in response to 5-HT1A receptor deletion are insufficient to oppose increases in 5-HT concentrations produced by acute inhibition of the 5-HT transporter.     

5-HT(2C) receptor activation inhibits appetitive and consummatory components of feeding and increases brain c-fos immunoreactivity in mice

5-Hydroxytryptamine (5-HT)(2C) and 5-HT(1B) receptors are implicated in the inhibitory modulation of feeding behaviour. However, their respective, and possibly different, roles have not been clearly identified because of a lack of selective 5-HT(2C) receptor agonists. Here, using the putative, selective 5-HT(2C) receptor agonist VER23779, we show that its effects on feeding are fully reversed by pretreatment with a selective 5-HT(2C) receptor antagonist, but unaffected by pretreatment with either a 5-HT(1B) or a 5-HT(2A) receptor antagonist. In mice eating a palatable mash, feeding ends earlier, inactivity is increased but the behavioural satiety sequence is preserved. In a second-order schedule of reinforcement with an initial, non-food-reinforced appetitive phase, VER23779 produces a much greater relative reduction in appetitive responding than the 5-HT(1B) receptor agonist CP-94,253. Increased c-fos immunoreactivity patterns following VER23779 also differ from those described for CP-94,253, in particular showing strong activation of the basolateral amygdala. The different behavioural consequences of 5-HT(2C) and 5-HT(1B) receptor activation may relate to the patterns of c-fos immunoreactivity. In particular, the basolateral amygdala may have a role in maintaining response in the appetitive phase of the second-order schedule and also be susceptible to serotonergic modulation through activation of 5-HT(2C) receptors.     

Presynaptic serotonergic modulation of 5-HT and acetylcholine release in the hippocampus and the cortex of 5-HT1B-receptor knockout mice

Lesioning of serotonergic afferents increases hippocampal ACh release and attenuates memory deficits produced by cholinergic lesions. Improved memory performance described in 5-HT1B-knockout (KO) mice might thus be due to a weaker 5-HT1B-mediated inhibitory influence of 5-HT on hippocampal ACh release. The selective delay-dependent impairment of working memory observed in these KO mice suggests, however, that cortical regions also participate in task performance, possibly via indirect influences of 5-HT on ACh release. To provide neuropharmacological support for these hypotheses we measured evoked ACh and 5-HT release in hippocampal and cortical slices of wild-type (WT) and 5-HT1B KO mice. Superfused slices (preincubated with [3H]choline or [3H]5-HT) were electrically stimulated in the absence or presence of 5-HT1B receptor ligands. In hippocampus and cortex, 5-HT1B agonists decreased and antagonists increased 5-HT release in WT, but not in 5-HT1B KO mice. In 5-HT1B KO mice, 5-HT release was enhanced in both structures, while ACh release (in nCi) was reduced. ACh release was inhibited by 5-HT1B agonists in hippocampal (not cortical) slices of WT but not of 5-HT1B KO mice. Our data (i) confirm the absence of autoinhibition of 5-HT release in 5-HT1B-KO mice, (ii) demonstrate a reduced release of ACh, and the absence of 5-HT1B-receptor-mediated inhibition of ACh release, in the hippocampus and cortex of 5-HT1B-KO mice, and (iii) are compatible with an indirect role of cortical ACh in the working memory impairment observed in these KO mice.     

Altered fear circuits in 5-HT(1A) receptor KO mice.

The study of genetically altered mice has been used successfully to determine the influence of different neurotransmitter receptors on fear and anxiety. Mice with a genetic deletion of the serotonin 1A receptor (5-HT(1A)R knockout [KO]) have been shown to be more fearful in a number of behavioral conflict tests, confirming the important role of this receptor in modulating anxiety. Factor analysis of the behavior of WT and 5-HT(1A)R KO mice in the open field test shows that locomotion and anxiety measures segregate independently, supporting the idea that the anxious behavior of the KO mice is not the result of altered locomotion. KO mice also show increased anxiety in the novelty-suppressed feeding task, which differs from the other conflict tests in the motivational drive of the animals. In response to a discrete aversive stimulus, foot shock, the KO mice show increased freezing and increased tachycardia. However, activation of the hypothalamic-pituitary-adrenal axis in response to stress appears to be slightly blunted in the KO animals. Together, these data support the idea that the 5-HT(1A)R modulates an important fear circuit in the brain. The dual function of the 5-HT(1A)R as both a presynaptic autoreceptor, negatively regulating serotonin activity, and a postsynaptic heteroreceptor, inhibiting the activity of nonserotonergic neurons in forebrain structures, has complicated interpretation of the anxious phenotype of these KO mice. A more complete understanding of the function of the 5-HT(1A)R awaits further study of its role in behaving animals using tissue-specific antagonists and novel transgenic mice with tissue-specific expression of the receptor.     

5-HT(2A/2C) receptor antagonists in the paraventricular nucleus attenuate the action of DOI on NPY-stimulated eating.

Hypothalamic neuropeptide Y (NPY) and serotonin (5-HT)-containing neurons are believed to exert an interactive effect on ingestive behavior. The present study examined the ability of two serotonergic antagonists, spiperone (SPIP), a 5-HT2A antagonist, and mianserin (MIAN), a 5-HT(2A/2C) antagonist, to block the inhibitory action of the 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on NPY-stimulated eating. Drugs were injected directly into the paraventricular nucleus (PVN), the perifornical (PFH) or the ventromedial hypothalamus (VMH) at the onset of the dark cycle. PVN, PFH and VMH injections of NPY potentiated food intake although only PVN pretreatment with DOI (5-20 nmol) suppressed NPY-induced eating. SPIP or MIAN, injected immediately prior to PVN DOI, reversed the suppressive effect of DOI on NPY feeding. These findings are consistent with other recent data showing that 5-HT2A receptors within the PVN modulate NPY's effect on food intake at the start of the nocturnal period.     

Central injection of 5-hydroxytryptamine reduces food intake in obese and lean mice.

The effects of intracerebroventricular (ICV) administration of 5-hydroxytryptamine creatinine sulphate complex (5-HT), 35-140 nmol, on food intake in genetically obese (ob/ob) and lean mice were investigated. 5-HT (70-140 nmol) decreased feeding in a dose-related manner on 1 h and 2 h postinjection measures. Intake in lean mice was reduced by over 70% of the control condition. Obese mice, however, demonstrated a reduced sensitivity to the anorectic effect of 5-HT, and reduced 1 h intake by only 40% of saline control. Although these results are consisted with a role for serotonin in the control of food intake in mice, the altered sensitivity of the ob/ob to serotonergic stimulation may result, in part, from an impaired satiety control mechanism in this mutant.