Biomedical subjects

R D Palmiter

Publications and source records attributed to R D Palmiter.

At least 19 recordsLinked to original sources

PubMed2003

Lack of vesicular zinc in mossy fibers does not affect synaptic excitability of CA3 pyramidal cells in zinc transporter 3 knockout mice.

Zinc is found throughout the CNS in synaptic vesicles of glutamatergic neurons and has been suggested to have a modulatory role in the brain because of its interaction with voltage- and ligand-gated ion channels. We took advantage of zinc transporter 3 knockout mice, which lack vesicular zinc, to study the possible physiological role of this heavy metal in hippocampal mossy fiber neurotransmission. We examined postsynaptic responses evoked by mossy fiber activation, recorded in CA3 pyramidal cells in hippocampal slices prepared from zinc transporter 3 knockout and wild-type mice. Field-potential response threshold and amplitude, input-output curves, and paired-pulse evoked responses were the same in slices from zinc transporter 3 knockout and wild-type mice. Furthermore, neither amplitude nor duration of pharmacologically isolated N-methyl-D-aspartate, non-N-methyl-D-aspartate, GABA(A), and GABA(B) receptor-mediated postsynaptic potentials differed between zinc transporter 3 knockout and wild-type mice. There was no difference in the magnitude of epileptiform discharges evoked by repetitive stimulation or kainic acid application. However, in slices from zinc transporter 3 knockout mice, there was greater attenuation of GABA(A)-mediated inhibitory postsynaptic potentials during tetanic stimulation compared with slices from wild-type animals. We conclude that lack of vesicular zinc in mossy fibers does not significantly affect the mossy fiber-associated synaptic excitability of CA3 pyramidal cells; however, zinc may modulate GABAergic synaptic transmission under conditions of intensive activation.

Animals↗

PubMed2001

Genetic comparison of seizure control by norepinephrine and neuropeptide Y.

Epilepsy is a disease of neuronal hyperexcitability, and pharmacological and genetic studies have identified norepinephrine (NE) and neuropeptide Y (NPY) as important endogenous regulators of neuronal excitability. Both transmitters signal through G-protein-coupled receptors, are expressed either together or separately, and are abundant in brain regions implicated in seizure generation. NPY knock-out (NPY KO) and dopamine beta-hydroxylase knock-out (DBH KO) mice that lack NE are susceptible to seizures, and agonists of NE and NPY receptors protect against seizures. To examine the relative contributions of NE and NPY to neuronal excitability, we tested Dbh;Npy double knock-out (DKO) mice for seizure sensitivity. In general, DBH KO mice were much more seizure-sensitive than NPY KO mice and had normal NPY expression, demonstrating that an NPY deficiency did not contribute to the DBH KO seizure phenotype. DKO mice were only slightly more sensitive than DBH KO mice to seizures induced by kainic acid, pentylenetetrazole, or flurothyl, although DKO mice were uniquely prone to handling-induced seizures. NPY contributed to the seizure phenotype of DKO mice at high doses of convulsant agents and advanced stages of seizures. These data suggest that NE is a more potent endogenous anticonvulsant than NPY, and that NPY has the greatest contribution under conditions of extreme neuronal excitability.

Animals↗

PubMed2001

Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation.

Motor stereotypies are abnormally repetitive behaviors that can develop with excessive dopaminergic stimulation and are features of some neurologic disorders. To investigate the mechanisms required for the induction of stereotypy, we examined the responses of dopamine-deficient (DD) mice to increasing doses of the dopamine precursor L-DOPA. DD mice lack the ability to synthesize dopamine (DA) specifically in dopaminergic neurons yet exhibit robust hyperlocomotion relative to wild-type (WT) mice when treated with L-DOPA, which restores striatal DA tissue content to approximately 10% of WT levels. To further elevate brain DA content in DD mice, we administered the peripheral L-amino acid decarboxylase inhibitor carbidopa along with L-DOPA (C/l-DOPA). When striatal DA levels reached >50% of WT levels, a transition from hyperlocomotion to intense, focused stereotypy was observed that was correlated with an induction of c-fos mRNA in the ventrolateral and central striatum as well as the somatosensory cortex. WT mice were unaffected by C/L-DOPA treatments. A D1, but not a D2, receptor antagonist attenuated both the C/L-DOPA-induced stereotypy and the c-fos induction. Consistent with these results, stereotypy could be induced in DD mice by a D1, but not by a D2, receptor agonist, with neither agonist inducing stereotypy in WT mice. Intrastriatal injection of a D1 receptor antagonist ameliorated the stereotypy and c-fos induction by C/L-DOPA. These results indicate that activation of D1 receptors on a specific population of striatal neurons is required for the induction of stereotypy in DD mice.

Animals↗

PubMed2001

Leptin-regulated endocannabinoids are involved in maintaining food intake.

Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.

Animals↗

PubMed2001

Removing zinc from synaptic vesicles does not impair spatial learning, memory, or sensorimotor functions in the mouse.

Zinc-enriched (ZEN) neurons are distributed widely throughout the brain and spinal cord. Synaptic vesicle zinc in these neurons is thought to function as a neuromodulator upon its release into the synaptic cleft. Consistent with this possibility, zinc or zinc chelators can alter spatial learning, working memory, and nociception in rodents. Here we use zinc transporter-3 (ZnT3) knockout mice, which are depleted of synaptic vesicle zinc, to assess the consequences of removing this potential neuromodulator on the behavior of adult mice. ZnT3 knockout mice performed equally as well as wild-type mice in the rotarod, pole, and cagetop tests of motor coordination. They exhibited normal thermal nociception in the hot-plate and tail-flick tests, and had similar olfactory, auditory and sensorimotor gating capabilities as wild-type mice. ZnT3 knockout mice behaved similarly as wild-type mice in the open field test and in the elevated plus maze test of anxiety. They exhibited normal learning and memory in the passive avoidance, Morris water maze, and fear conditioning tasks, and normal working and reference memory in a water version of the radial arm maze. We conclude that synaptic vesicle zinc is not essential for mice to be able to perform these tasks, despite the abundance of ZEN neurons in the relevant regions of the CNS. Either the neuromodulatory effects of zinc are not relevant for the tasks tested here, or mice are able to compensate easily for the absence of synaptic vesicle zinc.

Animals↗

PubMed2001

Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice.

Dopamine-deficient (DD) mice cannot synthesize dopamine (DA) in dopaminergic neurons due to selective inactivation of the tyrosine hydroxylase gene in those neurons. These mice become hypoactive and hypophagic and die of starvation by 4 weeks of age. We used gene therapy to ascertain where DA replacement in the brain restores feeding and other behaviors in DD mice. Restoration of DA production within the caudate putamen restores feeding on regular chow and nest-building behavior, whereas restoration of DA production in the nucleus accumbens restores exploratory behavior. Replacement of DA to either region restores preference for sucrose or a palatable diet without fully rescuing coordination or initiation of movement. These data suggest that a fundamental difference exists between feeding for sustenance and the ability to prefer rewarding substances.

Adenoviridae↗

PubMed2001

Alpha(1) and beta(2) adrenoreceptor agonists inhibit pentylenetetrazole-induced seizures in mice lacking norepinephrine.

It has been known for many years that norepinephrine (NE) is a potent endogenous anticonvulsant, yet there is confusion as to which receptor(s) mediate this effect. This is probably due to multiple factors, including the importance of distinct signaling pathways for different seizure paradigms, a lack of comprehensive pharmacological studies, and difficulty in interpreting existing pharmacological results due to the presence of endogenous NE. We sought to circumvent these problems by testing the anticonvulsant activity of selective agonists for most known adrenoreceptors (ARs) in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack endogenous NE. Dbh -/- mice are hypersensitive to pentylenetetrazole (PTZ)-induced seizures, demonstrating that endogenous NE inhibits PTZ-induced seizures in the wild type. Pretreatment of Dbh -/- mice with an alpha(1)AR or beta(2)AR, but not an alpha(2)AR or beta(1)AR agonist significantly protected against PTZ-induced seizures. In contrast, only the beta(2)AR agonist showed anticonvulsant activity in heterozygous controls. Furthermore, an alpha(1)AR antagonist exacerbated PTZ-induced seizures in control mice, whereas a beta(2)AR antagonist had no effect. We conclude that activation of the alpha(1)AR is primarily responsible for the anticonvulsant activity of endogenous NE in the murine PTZ model of epilepsy. Endogenous NE probably does not activate the beta(2)AR under these conditions, but exogenous activation of the beta(2)AR produces an anticonvulsant effect.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2000

A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.

Melanocortin-4 receptor (Mc4r)-null mice exhibit late-onset obesity. To determine whether aberrant metabolism contributes to the obesity, food consumption by Mc4r-null mice was restricted to (pair-fed to) that consumed by wild-type (WT) mice. Pair-fed Mc4r-null females maintained body weights intermediate to that of WT and nonpair-fed Mc4r-null females, whereas pairfeeding normalized the body weights of Mc4r-null male mice. Fat pad and circulating leptin levels were elevated in both male and female pair-fed Mc4r-null mice compared with WT mice. Oxygen consumption of Mc4r-null mice with similar body weights as WT controls was reduced by 20%. Locomotor activity of young nonobese Mc4r-null males was significantly lower than that of WT males; however, locomotion of young nonobese females was normal. Core body temperature of Mc4r-null mice was normal, and they responded normally to cold exposure. Young nonobese Mc4r-null females were unable to induce uncoupling protein 1 (UCP1) in brown adipose tissue in response to peripheral leptin administration, whereas UCP1 mRNA was increased by 60% in the WT females. These results indicate that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in melanocortin-3 receptor-null mice.

Animals↗

PubMed2000

Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.

Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons.

Animals↗

PubMed2000

Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: evidence against synaptic vesicle origin.

In several brain injury models, zinc accumulates in degenerating neuronal somata. Suggesting that such zinc accumulation may play a causal role in neurodegeneration, zinc chelation attenuates neuronal death. Because histochemically reactive zinc is present in and released from synaptic vesicles of glutamatergic neurons in the forebrain, it was proposed that zinc translocation from presynaptic terminals to postsynaptic neurons may be the mechanism of toxic zinc accumulation. To test this hypothesis, kainate seizure-induced neuronal death was examined in zinc transporter 3 gene (ZnT3)-null mice, a strain that completely lacks histochemically reactive zinc in synaptic vesicles. Intraperitoneal injection of kainate induced seizures to a similar degree in wild type and ZnT3-null mice. Staining of hippocampal sections with a zinc-specific fluorescent dye, N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulfonamide, revealed that zinc accumulated in degenerating CA1 and CA3 neurons in both groups, indicating that zinc originated from sources other than synaptic vesicles. Injection of CaEDTA into the cerebral ventricle almost completely blocked zinc accumulation in ZnT3-null mice, suggesting that increases in extracellular zinc concentrations may be a critical event for zinc accumulation. Arguing against the possibility that zinc accumulation results from nonspecific breakdown of zinc-containing proteins, injection of kainate into the cerebellum did not induce zinc accumulation in degenerating granule neurons. Taken together, these results support the existing idea that zinc is released into extracellular space and then enters neurons to exert a cytotoxic effect. However, the origin of zinc is not likely to be synaptic vesicles, because zinc accumulation robustly occurs in ZnT3-null mice lacking synaptic vesicle zinc.

Animals↗

PubMed2000

Zinc-enriched (ZEN) terminals in mouse olfactory bulb.

The present study was designed to localize zinc-enriched (ZEN) terminals in mouse olfactory bulb by means of ZnT3 immunocytochemistry (ICC) and zinc autometallography (AMG). The immunocytochemical staining of ZnT3 was closely correlated with the AMG pattern. ZEN terminals were defined as terminals showing both ZnT3 immunoreactivities and AMG granules. At the light microscopic level, dense staining patterns for ZnT3 immunoreactivity were seen in the granule cell layer and the olfactory glomerular layer. At the ultrastructural level, ZEN terminals were restricted to presynaptic terminals with single or multiple postsynaptic thickenings. The postsynaptic profiles contacting ZEN terminals appeared to be dendrites or somata of granule cells in the granule cell layer and periglomerular cells and mitral/tufted (M/T) cells in the olfactory glomerular layer. This suggests that two main sources of ZEN terminals are present in mouse olfactory bulb: (1) centrifugal fibres making asymmetrical synapses with granule cells and periglomerular cells, and (2) olfactory receptor terminals contacting dendritic profiles of M/T cells or periglomerular cells. The close correlation between ZEN terminals and the glutamatergic system is discussed.

Animals↗

PubMed2000

Ethanol-associated behaviors of mice lacking norepinephrine.

Although norepinephrine (NE) has been implicated in animal models of ethanol consumption for many years, the exact nature of its influence is not clear. Lesioning and pharmacological studies examining the role of NE in ethanol consumption have yielded conflicting results. We took a genetic approach to determine the effect of NE depletion on ethanol-mediated behaviors by using dopamine beta-hydroxylase knockout (Dbh -/-) mice that specifically lack the ability to synthesize NE. Dbh -/- males have reduced ethanol preference in a two-bottle choice paradigm and show a delay in extinguishing an ethanol-conditioned taste aversion, suggesting that they drink less ethanol in part because they find its effects more aversive. Both male and female Dbh -/- mice are hypersensitive to the sedative and hypothermic effects of systemic ethanol administration, and the sedation phenotype can be rescued pharmacologically by acute replacement of central NE. Neither the decreased body temperature nor changes in ethanol metabolism can explain the differences in consumption and sedation. These results demonstrate a significant role for NE in modulating ethanol-related behaviors and physiological responses.

Alcohol Drinking↗

PubMed2000

Neuropeptide Y (NPY) potentiates phenylephrine-induced mitogen-activated protein kinase activation in primary cardiomyocytes via NPY Y5 receptors.

Neuropeptide Y (NPY) has been shown to participate in the cardiovascular response mediated by the sympathetic system. In this report, we investigate the growth factor properties of NPY on cardiac myocytes. Mitogen-activated protein kinases (MAPK) are key signaling molecules in the transduction of trophic signals. Therefore, the role of NPY in inducing MAPK activation was studied in mouse neonatal cardiomyocytes. Exposure of neonatal cardiomyocytes to either NPY, phenylephrine, or angiotensin II induces a rapid phosphorylation of the extracellular responsive kinase, the c-jun N-terminal kinase, and the p38 kinase as well as an activation of protein kinase C (PKC). Moreover, NPY potentiates phenylephrine-induced MAPK and PKC stimulation. In contrast, NPY has no synergistic effect on angiotensin II-stimulated MAPK phosphorylation or PKC activity. NPY effects are pertussis toxin-sensitive and calcium-independent and are mediated by NPY Y5 receptors. Taken together, these results suggest that NPY, via G(i) protein-coupled NPY Y5 receptors, could participate in the development of cardiac hypertrophy during chronic sympathetic stimulation by potentiating alpha-adrenergic signals.

Angiotensin II↗

PubMed2000

Neurobiological responses to ethanol in mutant mice lacking neuropeptide Y or the Y5 receptor.

We have previously shown that voluntary ethanol consumption and resistance are inversely related to neuropeptide Y (NPY) levels in NPY-knockout (NPY -/-) and NPY-overexpressing mice. Here we report that NPY -/- mice on a mixed C57BL/6Jx129/SvEv background showed increased sensitivity to locomotor activation caused by intraperitoneal (ip) injection of 1.5 g/kg of ethanol, and were resistant to sedation caused by a 3.5-g/kg dose of ethanol. In contrast, NPY -/- mice on an inbred 129/SvEv background consumed the same amount of ethanol as wild-type (WT) controls at 3%, 6%, and 10% ethanol, but consumed significantly more of a 20% solution. They exhibited normal locomotor activation following a 1.5-g/kg injection of ethanol, and displayed normal sedation in response to 2.5 and 3.0 g/kg of ethanol, suggesting a genetic background effect. Y5 receptor knockout (Y5 -/-) mice on an inbred 129/SvEv background showed normal ethanol-induced locomotor activity and normal voluntary ethanol consumption, but displayed increased sleep time caused by 2.5 and 3.0 g/kg injection of ethanol. These data extend previous results by showing that NPY -/- mice of a mixed C57BL/6Jx129/SvEv background have increased sensitivity to the locomotor activation effect caused by a low dose of ethanol, and that expression of ethanol-related phenotypes are dependent on the genetic background of NPY -/- mice.

Alcohol Drinking↗

PubMed2000

Seizures and neuronal damage in mice lacking vesicular zinc.

Synaptically released zinc has neuromodulatory capabilities that could result in either inhibition or enhancement of neuronal excitability. To determine the net effects of vesicular zinc release in the brain in vivo, we examined seizure susceptibility and seizure-related neuronal damage in mice with targeted disruption of the gene encoding the zinc transporter, ZnT3 (ZnT3-/- mice). ZnT3-/- mice, which lack histochemically reactive zinc in synaptic vesicles, had slightly higher thresholds to seizures elicited by the GABA(A) antagonist, bicuculline, and no differences in seizure threshold were seen in response to pentylenetetrazol or flurothyl. However, ZnT3-/- mice were much more susceptible than wild-type mice to limbic seizures elicited by kainic acid, suggesting that the net effect of hippocampal zinc on acute seizures in vivo is inhibitory. The hippocampi of ZnT3-/- mice showed typical seizure-related neuronal damage in response to kainic acid, demonstrating that damage to the targets of zinc-containing neurons can occur independently of synaptically released zinc. Mice lacking the neuronal zinc-binding protein metallothionein III (MT-III) are also more susceptible to kainic acid-induced seizures. Double knockout (ZnT3 and MT3) mice show the same response to kainic acid as ZnT3-/- mice, suggesting that ZnT3 and MT-III function in the same pathway.

Animals↗

PubMed2000

Dopamine is required for hyperphagia in Lep(ob/ob) mice.

Feeding is a complex process responsive to sensory information related to sight and smell of food, previous feeding experiences, satiety signals elicited by ingestion and hormonal signals related to energy balance. Dopamine released in specific brain regions is associated with pleasurable and rewarding events and may reinforce positive aspects of feeding. Dopamine also influences initiation and coordination of motor activity and is required for sensorimotor functions. Thus, dopamine may facilitate integration of sensory cues related to hunger, initiating the search for food and its consumption. Dopaminergic neurons in the substantia nigra and ventral tegmental area project to the caudate putamen and nucleus accumbens, where they modulate movement and reward. There are projections from the nucleus accumbens to the lateral hypothalamus that regulate feeding. Dopamine-deficient mice (Dbh(Th/+), Th-/-; hereafter DD mice) cannot synthesize dopamine in dopaminergic neurons. They gradually become aphagic and die of starvation. Daily treatment of DD mice with L-3,4-dihydroxyphenylalanine (L-DOPA) transiently restores brain dopamine, locomotion and feeding. Leptin-null (Lep(ob/ob)) mice exhibit obesity, decreased energy expenditure and hyperphagia. As the hypothalamic leptin-melanocortin pathway appears to regulate appetite and metabolism, we generated mice lacking both dopamine and leptin (DD x Lep(ob/ob)) to determine if leptin deficiency overcomes the aphagia of DD mice. DD x Lep(ob/ob) mice became obese when treated daily with L-DOPA, but when L-DOPA treatment was terminated the double mutants were capable of movement, but did not feed. Our data show that dopamine is required for feeding in leptin-null mice.

Animals↗

PubMed1999

Norepinephrine-deficient mice have increased susceptibility to seizure-inducing stimuli.

Several lines of evidence suggest that norepinephrine (NE) can modulate seizure activity. However, the experimental methods used in the past cannot exclude the possible role of other neurotransmitters coreleased with NE from noradrenergic terminals. We have assessed the seizure susceptibility of genetically engineered mice that lack NE. Seizure susceptibility was determined in the dopamine beta-hydroxylase null mutant (Dbh -/-) mouse using four different convulsant stimuli: 2,2,2-trifluroethyl ether (flurothyl), pentylenetetrazol (PTZ), kainic acid, and high-decibel sound. Dbh -/- mice demonstrated enhanced susceptibility (i.e., lower threshold) compared with littermate heterozygous (Dbh +/-) controls to flurothyl, PTZ, kainic acid, and audiogenic seizures and enhanced sensitivity (i.e., seizure severity and mortality) to flurothyl, PTZ, and kainic acid. c-Fos mRNA expression in the cortex, hippocampus (CA1 and CA3), and amygdala was increased in Dbh -/- mice in association with flurothyl-induced seizures. Enhanced seizure susceptibility to flurothyl and increased seizure-induced c-fos mRNA expression were reversed by pretreatment with L-threo-3, 4-dihydroxyphenylserine, which partially restores the NE content in Dbh -/- mice. These genetically engineered mice confirm unambiguously the potent effects of the noradrenergic system in modulating epileptogenicity and illustrate the unique opportunity offered by Dbh -/- mice for elucidating the pathways through which NE can regulate seizure activity.

Acoustic Stimulation↗

PubMed1999

Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues.

Central administration of neuropeptide Y (NPY) potently induces feeding and its abundance in the hypothalamus increases when energy stores fall. Consequently, NPY is considered to be a physiological effector of feeding behavior. Surprisingly, NPY-deficient (NPY-/-) mice feed and grow normally with ad libitum access to food and manifest a normal hyperphagic response after fasting, suggesting that other feeding effectors may compensate for the lack of NPY. Agouti-related protein (AgRP), a melanocortin receptor antagonist, can also stimulate feeding behavior when administered centrally and is coexpressed in a majority of hypothalmamic NPY-ergic neurons, making AgRP a candidate compensatory factor. To test this possibility, we evaluated AgRP mRNA and protein expression, as well as responsiveness to centrally administered AgRP in NPY-/- mice. These studies demonstrate that hypothalamic AgRP mRNA and immunoreactivity are upregulated with fasting and that these increases are not affected by NPY deficiency. Interestingly, NPY-/- mice are hypersensitive to central administration of AgRP(83-132), yet exhibit a normal response to centrally administered MTII, a melanocortin receptor agonist. These data suggest that if AgRP compensates for the lack of NPY in NPY-/- mice, it is not at the level of AgRP synthesis and may instead involve alterations in the postsynaptic signaling efficacy of AgRP. Moreover, the effects of AgRP are not limited to its actions at the melanocortin-4 receptor (MC4R), because MC4R-deficient (MC4R-/-) mice manifest a significant response to centrally administered AgRP. These data imply that AgRP has additional targets in the hypothalamus.

Agouti-Related Protein↗