FATTY ACIDS AS CELL SIGNALS IN INGESTIVE BEHAVIORS.

Common dietary fatty acids, including palmitic acid, stearic acid, oleic acid, and polyunsaturated fatty acids, have been studied in the context of overall dietary fat and shown to impact on several types of behaviors, most prominently cognitive behaviors and ingestive behaviors. The independent effects of these fatty acids have been less well-delineated. Several studies implicate these common fatty acids in modulation of the CNS immune/inflammatory response as a key mediator of behavioral effects. However, signaling actions of the fatty acids to regulate cell structure and neuronal or synaptic function have been identified in numerous studies, and the relevance or contribution(s) of these to ingestive behavioral outcomes represent an area for future study. Finally, fatty acids are precursors of endocannabinoids and their structural congeners. Being highly dynamic and complex, the endocannabinoid system plays a key role ingestive behavior via cellular and synaptic mechanisms, thus representing another important area for future study.

Effect of dietary palmitic and stearic acids on sucrose motivation and hypothalamic and striatal cell signals in the rat.

We have reported that motivation for sucrose is increased in rats fed a moderate (31%) mixed-fat diet for 4-6 wk. In this study, rats were fed diets containing 32% stearic (STEAR) or palmitic (PALM) acid, and behavior, metabolic profile, and cell signals were compared with those of rats fed a matched low-fat diet (LF; 11% fat) diet. Rats fed STEAR or PALM increased sucrose motivation relative to LF rats (one-way ANOVA for lever presses; P = 0.03). Diet did not change fasting glucose, insulin, total cholesterol, triglycerides, intravenous glucose tolerance test glucose profile, percent body fat, or total kilocalories, although kilocalories as fat were increased (ANOVA, P < 0.05). Cell signals were assessed in rats ranked from high to low sucrose motivation. Diet did not alter Thr and Ser phosphorylation of Akt in the medial hypothalamus (HYP) and striatum (STR). However, Ser phosphorylation of GSK3Β was decreased in HYP and STR from both high- and low-performer tertiles of STEAR and PALM rats (ANOVA within each brain region, P < 0.05). Two histone 3 (H3) modifications were also assessed. Although there was no effect of diet on the transcription-repressive H3 modification, H3K27me3, the transcription-permissive H3 modification, H3K4me3, was significantly decreased in the HYP of high performers fed PALM or STEAR (ANOVA, P = 0.013). There was no effect of diet on H3K4me3 levels in HYP of low performers, or in STR. Our findings suggest signal-specific and brain region-specific effects of PALM or STEAR diets and may link downstream signaling effects of GSK3Β activity and H3 modifications with enhanced motivational behavior.

Cerebrospinal fluid biomarkers for Alzheimer's and vascular disease vary by age, gender, and APOE genotype in cognitively normal adults.

BACKGROUND: This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and cerebrovascular injury across the life span of cognitively normal adults. METHODS: CSF amyloid beta1-42 (Aß42), phospho-tau-181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100. RESULTS: CSF total tau and p-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aß42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × Îµ4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01). CONCLUSIONS: Female APOE-ε4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.

Multiple lipopolysaccharide (LPS) injections alter interleukin 6 (IL-6), IL-7, IL-10 and IL-6 and IL-7 receptor mRNA in CNS and spleen.

Neuroinflammation is proposed to be an important component in the development of several central nervous system (CNS) disorders including depression, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. However, exactly how neuroinflammation leads to, or contributes to, these central disorders is unclear. The objective of the study was to examine and compare the expression of mRNAs for interleukin-6 (IL-6), IL-7, IL-10 and the receptors for IL-6 (IL-6R) and IL-7 (IL-7R) using in situ hybridization in discrete brain regions and in the spleen after multiple injections of 3mg/kg lipopolysaccharide (LPS), a model of neuroinflammation. In the spleen, LPS significantly elevated IL-6 mRNA expression, then IL-10 mRNA, with no effect on IL-7 or IL-7R mRNA, while significantly decreasing IL-6R mRNA expression. In the CNS, LPS administration had the greatest effect on IL-6 and IL-6R mRNA. LPS increased IL-6 mRNA expression only in non-neuronal cells throughout the brain, but significantly elevated IL-6R mRNA in neuronal populations, where observed, except the cerebellum. LPS resulted in variable effects on IL-10 mRNA, and had no effect on IL-7 or IL-7R mRNA expression. These studies indicate that LPS-induced neuroinflammation has substantial but variable effects on the regional and cellular patterns of CNS IL-6, IL-7 and IL-10, and for IL-6R and IL-7R mRNA expression. It is apparent that administration of LPS can affect non-neuronal and neuronal cells in the brain. Further research is required to determine how CNS inflammatory changes associated with IL-6, IL-10 and IL-6R could in turn contribute to the development of CNS neurological disorders.

Intrathecal insulin-like growth factor 1 but not insulin enhances myelin repair in young and aged rats.

One main pathological hallmark of multiple sclerosis (MS) is demyelination. Novel therapies which enhance myelin repair are urgently needed. Insulin and insulin-like growth factor 1 (IGF-1) have strong functional relationships. Here, we addressed the potential capacity of IGF-1 and insulin to enhance remyelination in an animal demyelination model in vivo. We found that chronic intrathecal infusion of IGF-1 enhanced remyelination after lysolecithin-induced demyelination in the spinal cord of young and aged rats. Aged rats showed a weaker innate remyelination capacity and are therefore a good model for progressive MS which is defined by chronic demyelination. In contrast to IGF-1, Insulin had no effect on remyelination in either age group. Our findings highlight the potential use of IGF-1 as remyelinating therapy for MS, particularly the progressive stage in which chronic demyelination is the hallmark.

Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat: Historical perspective.

UNLABELLED: Since the publication of the observation that dopaminergic neurons in the ventral tegmental area/substantia nigra of the rat express receptors for insulin and leptin, numerous studies have extended and validated these findings. Thus, these major metabolic hormones have effects on synaptic and cell signaling function of the midbrain dopamine neurons, across a range of concentrations that reflect physiologic (fasting vs. fed) and pathophysiologic (diabetes) circumstances. The capacity of metabolic hormones to alter reward behaviors, including palatability-related food intake; motivation for food; and the conditioning of place preference by food, is now appreciated as an integral part of the larger actions of these hormones to regulate caloric homeostasis. Finally, the delineation of metabolic hormone effects on the CNS reward circuitry of normal animals provides the rationale and experimental basis for evaluating dysfunction of reward circuitry in obesity and diabetes. ORIGINAL ARTICLE ABSTRACT: EXPRESSION OF RECEPTORS FOR INSULIN AND LEPTIN IN THE VENTRAL TEGMENTAL AREA/SUBSTANTIA NIGRA (VTA/SN) OF THE RAT: Recent studies have demonstrated that the metabolic hormones insulin and leptin can modulate behavioral performance in reward-related paradigms. However, specific anatomical substrate(s) within the CNS for these effects remain to be identified. We hypothesize that midbrain dopamine neurons, which have been implicated to be critical in the mediation of motivational and reward aspects of stimuli, contribute to these behavioral effects of insulin and leptin. As one approach to evaluate this hypothesis, we used double-labeling fluorescence immunohistochemistry to determine whether the midbrain dopamine neurons express insulin receptors or leptin receptors. Extensive co-expression of tyrosine hydroxylase (a marker for dopamine neurons) with both the insulin receptor and the leptin receptor was observed in the ventral tegmentum and substantia nigra. These findings suggest that midbrain dopamine neurons are direct targets of insulin and leptin, and that they participate in mediating the effects of these hormones on reward-seeking behavior. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

Modulation of Food Reward by Endocrine and Environmental Factors: Update and Perspective.

OBJECTIVE: Palatable foods are frequently high in energy density. Chronic consumption of high-energy density foods can contribute to the development of cardiometabolic pathology including obesity, diabetes, and cardiovascular disease. This article reviews the contributions of extrinsic and intrinsic factors that influence the reward components of food intake. METHODS: A narrative review was conducted to determine the behavioral and central nervous system (CNS) related processes involved in the reward components of high-energy density food intake. RESULTS: The rewarding aspects of food, particularly palatable and preferred foods, are regulated by CNS circuitry. Overlaying this regulation is modulation by intrinsic endocrine systems and metabolic hormones relating to energy homeostasis, developmental stage, or gender. It is now recognized that extrinsic or environmental factors, including ambient diet composition and the provocation of stress or anxiety, also contribute substantially to the expression of food reward behaviors such as motivation for, and seeking of, preferred foods. CONCLUSIONS: High-energy density food intake is influenced by both physiological and pathophysiological processes. Contextual, behavioral, and psychological factors and CNS-related processes represent potential targets for multiple types of therapeutic intervention.

The contribution of brain reward circuits to the obesity epidemic.

One of the defining characteristics of the research of Ann E. Kelley was her recognition that the neuroscience underlying basic learning and motivation processes also shed significant light upon mechanisms underlying drug addiction and maladaptive eating patterns. In this review, we examine the parallels that exist in the neural pathways that process both food and drug reward, as determined by recent studies in animal models and human neuroimaging experiments. We discuss contemporary research that suggests that hyperphagia leading to obesity is associated with substantial neurochemical changes in the brain. These findings verify the relevance of reward pathways for promoting consumption of palatable, calorically dense foods, and lead to the important question of whether changes in reward circuitry in response to intake of such foods serve a causal role in the development and maintenance of some cases of obesity. Finally, we discuss the potential value for future studies at the intersection of the obesity epidemic and the neuroscience of motivation, as well as the potential concerns that arise from viewing excessive food intake as an "addiction". We suggest that it might be more useful to focus on overeating that results in frank obesity, and multiple health, interpersonal, and occupational negative consequences as a form of food "abuse".

Moderate high fat diet increases sucrose self-administration in young rats.

We have previously reported that a moderately high fat diet increases motivation for sucrose in adult rats. In this study, we tested the motivational, neurochemical, and metabolic effects of the high fat diet in male rats transitioning through puberty, during 5-8 weeks of age. We observed that the high fat diet increased motivated responding for sucrose, which was independent of either metabolic changes or changes in catecholamine neurotransmitter metabolites in the nucleus accumbens. However, AGRP mRNA levels in the hypothalamus were significantly elevated. We demonstrated that increased activation of AGRP neurons is associated with motivated behavior, and that exogenous (third cerebroventricular) AGRP administration resulted in significantly increased motivation for sucrose. These observations suggest that increased expression and activity of AGRP in the medial hypothalamus may underlie the increased responding for sucrose caused by the high fat diet intervention. Finally, we compared motivation for sucrose in pubertal vs. adult rats and observed increased motivation for sucrose in the pubertal rats, which is consistent with previous reports that young animals and humans have an increased preference for sweet taste, compared with adults. Together, our studies suggest that background diet plays a strong modulatory role in motivation for sweet taste in adolescent animals.

Ghrelin increases the motivation to eat, but does not alter food palatability.

Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., "liking") and the motivation to self-administer (i.e., "wanting") food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability.

Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation.

UNLABELLED: Childhood obesity is associated with type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). Recent studies have found associations between vitamin D deficiency (VDD), insulin resistance (IR), and NAFLD among overweight children. To further explore mechanisms mediating these effects, we fed young (age 25 days) Sprague-Dawley rats with a low-fat diet (LFD) alone or with vitamin D depletion (LFD+VDD). A second group of rats was exposed to a Westernized diet (WD: high-fat/high-fructose corn syrup) that is more typically consumed by overweight children, and was either replete (WD) or deficient in vitamin D (WD+VDD). Liver histology was assessed using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system and expression of genes involved in inflammatory pathways were measured in liver and visceral adipose tissue after 10 weeks. In VDD groups, 25-OH-vitamin D levels were reduced to 29% (95% confidence interval [CI]: 23%-36%) compared to controls. WD+VDD animals exhibited significantly greater hepatic steatosis compared to LFD groups. Lobular inflammation as well as NAFLD Activity Score (NAS) were higher in WD+VDD versus the WD group (NAS: WD+VDD 3.2 ± 0.47 versus WD 1.50 ± 0.48, P < 0.05). Hepatic messenger RNA (mRNA) levels of Toll-like receptors (TLR)2, TLR4, and TLR9, as well as resistin, interleukins (IL)-1ß, IL-4, and IL-6 and oxidative stress marker heme oxygenase (HO)-1, were higher in WD+VDD versus WD animals (P < 0.05). Logistic regression analyses showed significant associations between NAS score and liver mRNA levels of TLRs 2, 4, and 9, endotoxin receptor CD14, as well as peroxisome proliferator activated receptor (PPAR)γ, and HO-1. CONCLUSION: VDD exacerbates NAFLD through TLR-activation, possibly by way of endotoxin exposure in a WD rat model. In addition it causes IR, higher hepatic resistin gene expression, and up-regulation of hepatic inflammatory and oxidative stress genes.

Sucrose self-administration and CNS activation in the rat.

We have previously reported that administration of insulin into the arcuate nucleus of the hypothalamus decreases motivation for sucrose, assessed by a self-administration task, in rats. Because the pattern of central nervous system (CNS) activation in association with sucrose self-administration has not been evaluated, in the present study, we measured expression of c-Fos as an index of neuronal activation. We trained rats to bar-press for sucrose, according to a fixed-ratio (FR) or progressive-ratio (PR) schedule and mapped expression of c-Fos immunoreactivity in the CNS, compared with c-Fos expression in handled controls. We observed a unique expression of c-Fos in the medial hypothalamus (the arcuate, paraventricular, retrochiasmatic, dorsomedial, and ventromedial nuclei) in association with the onset of PR performance, and expression of c-Fos in the lateral hypothalamus and the bed nucleus of stria terminalis in association with the onset of FR performance. c-Fos expression was increased in the nucleus accumbens of both FR and PR rats. Our study emphasizes the importance of both hypothalamic energy homeostasis circuitry and limbic circuitry in the performance of a food reward task. Given the role of the medial hypothalamus in regulation of energy balance, our study suggests that this circuitry may contribute to reward regulation within the larger context of energy homeostasis.

Leptin regulates energy balance and motivation through action at distinct neural circuits.

BACKGROUND: Overconsumption of calorically dense foods contributes substantially to the current obesity epidemic. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. The current study asked whether leptin signaling within the lateral hypothalamus (LH) and midbrain is involved in effort-based responding for food rewards and/or the modulation of mesolimbic dopamine. METHODS: The contribution of endogenous leptin signaling for food motivation and mesolimbic dopamine tone was examined after viral-mediated reduction of the leptin receptor within LH and midbrain neurons in male rats. RESULTS: Knockdown of leptin receptors selectively in the LH caused increased body weight, caloric consumption, and body fat in rats maintained on a calorically dense diet. Knockdown of leptin receptors selectively in midbrain augmented progressive ratio responding for sucrose and restored high-fat, diet-induced suppression of dopamine content in the nucleus accumbens. CONCLUSIONS: In summary, endogenous leptin signaling in the hypothalamus restrains the overconsumption of calorically dense foods and the consequent increase in body mass, whereas leptin action in the midbrain regulates effort-based responding for food rewards and mesolimbic dopamine tone. These data highlight the ability of leptin to regulate overconsumption of palatable foods and food motivation through pathways that mediate energy homeostasis and reward, respectively.

Energy regulatory signals and food reward.

The hormones insulin, leptin, and ghrelin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis, acting at medial hypothalamic sites. Here, we summarize research demonstrating that, in addition to direct homeostatic actions at the hypothalamus, CNS circuitry that subserves reward and is also a direct and indirect target for the action of these endocrine regulators of energy homeostasis. Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, the midbrain dopamine (DA) and opioidergic pathways. Ghrelin can increase food reward behaviors, and support midbrain DA neuronal function. We summarize discussion of behavioral, systems, and cellular evidence in support of the contributions of reward circuitry to the homeostatic roles of these hormones in the CNS. The understanding of neuroendocrine modulation of food reward, as well as food reward modulation by diet and obesity, may point to new directions for therapeutic approaches to overeating or eating disorders.

The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling.

Recent evidence suggests that leptin reduces food intake via actions in the brain circuitry of food reward, such as the ventral tegmental area (VTA), as leptin receptors are present in the VTA, and leptin injection in the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Janus kinase-signal transducer and activator of transcription (Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI 3-kinase), and mammalian target of rapamycin (mTOR). In this study, we determined whether leptin activates each of these signal transduction pathways in the VTA and whether these signaling pathways are required for VTA-leptin induced anorexia. Here, we show that pSTAT3-Tyr(705), a marker of leptin activation, was induced in a midbrain region containing the VTA and substantia nigra following either intracerebroventricular leptin or direct administration of leptin to the VTA, but these interventions failed to increase levels of either pAKT-Ser(473) or phospho-p70S6K-Thr(389), markers of IRS-PI 3-kinase and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20-h food intake and 20-h body weight was blocked by an inhibitor of Jak-2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI 3-kinase (LY-294002) or mTOR (rapamycin) in this timeframe. Taken together, these data support the hypothesis that leptin signaling in the VTA is involved in the regulation of energy balance, but, in contrast to the leptin signaling in the hypothalamus, these effects are mediated predominantly via Jak-2 signaling rather than via the IRS-PI 3-kinase or mTOR signaling pathway.

Insulin, leptin, and food reward: update 2008.

The hormones insulin and leptin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis at medial hypothalamic sites. In a previous review, we described new research demonstrating that, in addition to these direct homeostatic actions at the hypothalamus, CNS circuitry that subserves reward and motivation is also a direct and an indirect target for insulin and leptin action. Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, i.e., midbrain dopamine and opioidergic pathways. Here we summarize new behavioral, systems, and cellular evidence in support of this hypothesis and in the context of research into the homeostatic roles of both hormones in the CNS. We discuss some current issues in the field that should provide additional insight into this hypothetical model. The understanding of neuroendocrine modulation of food reward, as well as food reward modulation by diet and obesity, may point to new directions for therapeutic approaches to overeating or eating disorders.

Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin.

A limiting factor to the clinical management of diabetes is iatrogenic hypoglycemia. With multiple hypoglycemic episodes, the collective neuroendocrine response that restores euglycemia is impaired. In our animal model of recurrent hypoglycemia (RH), neuroendocrine deficits are accompanied by a decrease in medial hypothalamic activation. Here we tested the hypothesis that the medial hypothalamus may exhibit unique changes in the expression of regulatory proteins in response to RH. We report that expression of the immediate early gene FosB is increased in medial hypothalamic nuclei, anterior hypothalamus, and posterior paraventricular nucleus of the thalamus (THPVN) of the thalamus following RH. We identified the hypothalamic PVN, a key autonomic output site, among the regions expressing FosB. To identify the subtype(s) of neuronal populations that express FosB, we screened candidate neuropeptides of the PVN for coexpression using dual fluorescence immunohistochemistry. Among the neuropeptides analyzed [including oxytocin, vasopressin, thyrotropin-releasing hormone, and corticotropin-releasing factor (CRF)], FosB was only identified in CRF-positive neurons. Inhibitory gamma-aminobutyric acid-positive processes appear to impinge on these FosB-expressing neurons. Finally, we observed a significant decrease in the presynaptic marker synaptophysin within the PVN of RH-treated vs. saline-treated rats, suggesting that rapid alterations of synaptic morphology may occur in association with RH. Collectively, these data suggest that RH stress triggers cellular changes that support synaptic plasticity, in specific neuroanatomical sites, which may contribute to the development of hypoglycemia-associated autonomic failure.

Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats.

Findings from our laboratory and others have demonstrated that the hormone insulin has chronic effects within the CNS to regulate energy homeostasis and to decrease brain reward function. In this study, we compared the acute action of insulin to decrease intake of a palatable food in two different behavioral tasks-progressive ratios sucrose self-administration and micro opioid-stimulated sucrose feeding-when administered into several insulin-receptive sites of the CNS. We tested insulin efficacy within the medial hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, the nucleus accumbens, and the ventral tegmental area. Administration of insulin at a dose that has no chronic effect on body weight (5 mU) into the ARC significantly suppressed sucrose self-administration (75+/-5% of paired control). However, although the mu opioid DAMGO, [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin acetate salt, stimulated sucrose intake at all four CNS sites, the ventral tegmental area was the only sensitive site for a direct effect of insulin to antagonize acute (60 min) micro opioid-stimulated sucrose feeding: sucrose intake was 53+/-8% of DAMGO-induced feeding, when insulin was coadministered with DAMGO. These findings demonstrate that free feeding of sucrose, and motivated work for sucrose, can be modulated within unique sites of the CNS reward circuitry. Further, they support the interpretation that adiposity signals, such as insulin, can decrease different aspects of ingestion of a palatable food, such as sucrose, in an anatomically specific manner.

The selective serotonin reuptake inhibitor sertraline enhances counterregulatory responses to hypoglycemia.

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for patients with comorbid diabetes and depression. Clinical case studies in diabetic patients, however, suggest that SSRI therapy may exacerbate hypoglycemia. We hypothesized that SSRIs might increase the risk of hypoglycemia by impairing hormonal counterregulatory responses (CRR). We evaluated the effect of the SSRI sertraline on hormonal CRR to single or recurrent hypoglycemia in nondiabetic rats. Since there are time-dependent effects of SSRIs on serotonin neurotransmission that correspond with therapeutic action, we evaluated the effect of 6- or 20-day sertraline treatment on hypoglycemia CRR. We found that 6-day sertraline (SERT) treatment specifically enhanced the epinephrine response to a single bout of hypoglycemia vs. vehicle (VEH)-treated rats (t = 120: VEH, 2,573 +/- 448 vs. SERT, 4,202 +/- 545 pg/ml, P < 0.05). In response to recurrent hypoglycemia, VEH-treated rats exhibited the expected impairment in epinephrine secretion (t = 60: 678 +/- 73 pg/ml) vs. VEH-treated rats experiencing first-time hypoglycemia (t = 60: 2,081 +/- 436 pg/ml, P < 0.01). SERT treatment prevented the impaired epinephrine response in recurrent hypoglycemic rats (t = 60: 1,794 +/- 276 pgl/ml). In 20-day SERT-treated rats, epinephrine, norepinephrine, and glucagon CRR were all significantly elevated above VEH-treated controls in response to hypoglycemia. Similarly to 6-day SERT treatment, 20-day SERT treatment rescued the impaired epinephrine response in recurrent hypoglycemic rats. Our data demonstrate that neither 6- nor 20-day sertraline treatment impaired hormonal CRR to hypoglycemia in nondiabetic rats. Instead, sertraline treatment resulted in an enhancement of hypoglycemia CRR and prevented the impaired adrenomedullary response normally observed in recurrent hypoglycemic rats.

Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia.

The posterior paraventricular nucleus of the thalamus (THPVP) has been identified as a forebrain region that modulates the central nervous system (CNS) response to recurrent experiences of stressors. The THPVP is activated in response to a single (SH) or recurrent (RH) experience of the metabolic stress of hypoglycemia. In this study, we evaluated whether temporary experimental inactivation of the THPVP would modify the neuroendocrine response to SH or RH. Infusion of lidocaine (LIDO) or vehicle had no effect on the neuroendocrine response to SH, comparable to findings with other stressors. THPVP vehicle infusion concomitant with RH resulted in a prevention of the expected impairment of neuroendocrine responses, relative to SH. LIDO infusion with RH resulted in significantly decreased glucagon and sympathoadrenal responses, relative to SH. These results suggest that the THPVP may contribute to the sympathoadrenal stimulation induced by hypoglycemia; and emphasizes that the THPVP is a forebrain region that may contribute to the coordinated CNS response to metabolic stressors.