Growth changes after inhalant abuse and toluene exposure: A systematic review and meta-analysis of human and animal studies.

Inhalant abuse is a significant public health issue, particularly for adolescents, the predominant group of inhalant users. Adolescence is a critical growth period, and inhalant abuse has been associated with growth impairments, including reduced body weight and height. However, the extent to which inhalant abuse affects growth remains unquantified, and potential moderators remain unknown. To address this knowledge gap, a systematic review and meta-analysis of clinical human and preclinical animal studies utilizing toluene exposure (the primary solvent in abused products) was conducted. Five-hundred and sixty-nine studies were screened; 31 met inclusion criteria, yielding 64 toluene-control comparisons for body weight and 6 comparisons for height. Toluene exposure was negatively associated with body weight ( d = -0.73) and height ( d = -0.69). Concentration of inhaled toluene, but not duration, moderated the effect of toluene exposure on body weight, with more severe impairments at higher concentrations. Differences in effect size for body weight were observed for study characteristic subgroups including sex, age at first exposure, administration route and species. However, these findings should be interpreted cautiously due to low study numbers. Growth impairments, particularly during adolescence, can cause long-term health consequences. These effects on growth are therefore an important clinical outcome for individuals with a history of inhalant abuse.

Brain substrates of unhealthy versus healthy food choices: influence of homeostatic status and body mass index.

BACKGROUND/OBJECTIVES: Unhealthy dietary choices are a major contributor to harmful weight gain and obesity. This study interrogated the brain substrates of unhealthy versus healthy food choices in vivo, and evaluated the influence of hunger state and body mass index (BMI) on brain activation and connectivity. SUBJECTS/METHODS: Thirty adults (BMI: 18-38 kg m-2) performed a food-choice task involving preference-based selection between beverage pairs consisting of high-calorie (unhealthy) or low-calorie (healthy) options, concurrent with functional magnetic resonance imaging (fMRI). Selected food stimuli were delivered to participants using an MRI-compatible gustometer. fMRI scans were performed both after 10-h fasting and when sated. Brain activation and hypothalamic functional connectivity were assessed when selecting between unhealthy-healthy beverage pairings, relative to unhealthy-unhealthy and healthy-healthy options. Results were considered significant at cluster-based family-wise error corrected P<0.05. RESULTS: Selecting between unhealthy and healthy foods elicited significant activation in the hypothalamus, the medial and dorsolateral prefrontal cortices, the anterior insula and the posterior cingulate. Hunger was associated with higher activation within the ventromedial and dorsolateral prefrontal cortices, as well as lower connectivity between the hypothalamus and both the ventromedial prefrontal cortex and dorsal striatum. Critically, people with higher BMI showed lower activation of the hypothalamus-regardless of hunger state-and higher activation of the ventromedial prefrontal cortex when hungry. CONCLUSIONS: People who are overweight and obese have weaker activation of brain regions involved in energy regulation and greater activation of reward valuation regions while making choices between unhealthy and healthy foods. These results provide evidence for a shift towards hedonic-based, and away from energy-based, food selection in obesity.

Less is more: Caloric regulation of neurogenesis and adult brain function.

Calorie intake is essential for regulating normal physiological processes and is fundamental to maintaining life. Indeed, both extremes of calorie intake result in increased morbidity and mortality. In this review, we discuss the effect of calorie intake on adult brain function, with an emphasis on the beneficial effects of mild calorie restriction. Recent findings relating to the regenerative and protective effects of the gastrointestinal hormone, ghrelin, suggest that it may underlie the beneficial effects of calorie restriction. We discuss the putative cellular mechanisms underlying the action of ghrelin and their possible role in supporting healthy brain ageing.

Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid ß (Aß1-40) administration in mice.

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid ß peptide 1-40 (Aß1-40 ) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aß1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y-maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aß1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aß1-40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aß1-40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium-binding adapter expressing microglial in the rostral hippocampus. Finally, Aß1-40 blocked long-term potentiation induced by high-frequency stimulation and this effect could be acutely blocked with co-administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Exercise training does not enhance hypothalamic responsiveness to leptin or ghrelin in male mice.

The detection of hormone and nutrient signals by the hypothalamus is blunted in obesity and contributes to dysregulated energy homeostasis. We investigated whether aerobic exercise training would improve long-term hypothalamic sensitivity to both leptin and ghrelin, independent of acute exercise-induced signalling. Male C57Bl/6J mice were fed either a chow or high-fat diet for 6 weeks, then remained sedentary on their respective diet, or completed 6 weeks of treadmill exercise training with a progressive increase in exercise volume and intensity. Food intake and hypothalamic signalling were assessed in mice injected with leptin or ghrelin at least 24 h after the last exercise bout. Exercise training reduced body mass, increased daily food intake and improved glucose tolerance. Intraperitoneal leptin administration reduced food intake in lean and obese mice, and this was not enhanced after exercise training. Leptin-mediated activation of phosphorylated signal transducer and activator of transcription 3 in the arcuate nucleus and ventromedial nucleus of the hypothalamus was not enhanced with exercise training. Ghrelin increased food intake and c-Fos positive neurones in the hypothalamus in lean and obese mice, and these physiological and molecular responses were not enhanced with exercise training. This suggests that the previously reported exercise effects on sensitising hypothalamic signalling and food intake responses may be limited to the period immediately after an exercise bout, and are not a result of stable structural or molecular changes that occur with exercise training.

Investigation of the presence of ghrelin in the central nervous system of the rat and mouse.

Ghrelin and ghrelin receptor agonist have effects on central neurons in many locations, including the hypothalamus, caudal brain stem, and spinal cord. However, descriptions of the distributions of ghrelin-like immunoreactivity in the CNS in published work are inconsistent. We have used three well-characterized anti-ghrelin antibodies, an antibody to the unacylated form of ghrelin, and a ghrelin peptide assay in rats, mice, ghrelin knockout mice, and ghrelin receptor reporter mice to re-evaluate ghrelin presence in the rodent CNS. The stomach served as a positive control. All antibodies were effective in revealing gastric endocrine cells. However, no specific staining could be found in the brain or spinal cord. Concentrations of antibody 10 to 30 times those effective in the stomach bound to nerve cells in rat and mouse brain, but this binding was not reduced by absorbing concentrations of ghrelin peptide, or by use of ghrelin gene knockout mice. Concentrations of ghrelin-like peptide, detected by enzyme-linked immunosorbent assay in extracts of hypothalamus, were 1% of gastric concentrations. Ghrelin receptor-expressing neurons had no adjacent ghrelin immunoreactive terminals. It is concluded that there are insignificant amounts of authentic ghrelin in neurons in the mouse or rat CNS and that ghrelin receptor-expressing neurons do not receive synaptic inputs from ghrelin-immunoreactive nerve terminals in these species.

Diet-induced obesity attenuates fasting-induced hyperphagia.

Obesity impairs arcuate (ARC) neuropeptide Y (NPY)/agouti-releated peptide (AgRP) neuronal function and renders these homeostatic neurones unresponsive to the orexigenic hormone ghrelin. In the present study, we investigated the effect of diet-induced obesity (DIO) on feeding behaviour, ARC neuronal activation and mRNA expression following another orexigenic stimulus, an overnight fast. We show that 9 weeks of high-fat feeding attenuates fasting-induced hyperphagia by suppressing ARC neuronal activation and hypothalamic NPY/AgRP mRNA expression. Thus, the lack of appropriate feeding responses in DIO mice to a fast is caused by failure ARC neurones to recognise and/or respond to orexigenic cues. We propose that fasting-induced hyperphagia is regulated not by homeostatic control of appetite in DIO mice, but rather by changes in the reward circuitry.

Analysis of mRNAs that are enriched in the post-synaptic domain of the neuromuscular junction.

The identity of synaptically-enriched genes was investigated by comparing the abundance of various mRNAs in the synaptic and extra-synaptic regions of the same muscle fibers. The mRNAs for several known synaptic proteins were significantly elevated in the synaptic region when measured by real-time PCR. The synaptic mRNAs were then further analyzed using microarrays and real-time PCR to identify putative regulators of the neuromuscular junction (NMJ). MRF4 was the only member of the MyoD family that was concentrated at the mature NMJ, suggesting that it may have a unique role in the maintenance of post-synaptic specialization. Three potential regulators of the NMJ were identified and confirmed by real-time PCR: glia maturation factor gamma was concentrated at the NMJ whereas Unr protein and protein tyrosine phosphatase were repressed synaptically. The identification of synaptically-repressed genes may indicate that synaptic specialization is created by a combination of positive and negative signals.

Neuroendocrine regulation of prolactin secretion during late pregnancy: easing the transition into lactation.

Prolactin is an anterior pituitary hormone critical for maintaining pregnancy and lactation. Under normal conditions, prolactin secretion is tightly regulated by inhibitory dopaminergic neuronal systems within the mediobasal hypothalamus in a process known as short-loop negative feedback. This review focuses on neuroendocrine adaptations to prolactin negative feedback during late pregnancy. It is suggested that, in terms of prolactin regulation, late pregnancy is a transition period into lactation because many of the neuroendocrine adaptations promoting hyperprolactinemia in lactation develop during late pregnancy. As a consequence, the maternal brain is geared to provide unrestrained prolactin release critical for milk production, maternal care and thus survival of the offspring before parturition. The mechanisms responsible for these changes are discussed.

The roles of dopamine and the neurointermediate lobe of the pituitary in the regulation of prolactin secretion during late pregnancy in rats.

The major hypothalamic control over prolactin secretion from the anterior pituitary gland is inhibitory by means of dopamine released from tuberoinfundibular dopamine (TIDA) neurones. We have previously shown a dissociation between activity of TIDA neurones and prolactin secretion during late pregnancy, suggesting involvement of additional regulatory factors. The aim of the present study was to investigate the role of dopamine and the neurointermediate lobe (NIL) of the pituitary in the regulation of prolactin secretion during late pregnancy. To determine whether dopamine maintains inhibition of prolactin during late pregnancy, the D(2) receptor antagonist domperidone was administered at 12.00 h on days 18 and 21 of pregnancy. These times are characterized by high and low TIDA neuronal activity, respectively, and low prolactin secretion. Domperidone produced an immediate increase in plasma prolactin compared to vehicle-treated controls on both days 18 and 21. Thus, dopaminergic inhibition of prolactin secretion is maintained despite reduced TIDA neuronal activity at the end of pregnancy. The contribution of NIL-derived dopamine in regulating prolactin secretion was then examined by investigating the effect of surgical removal of the NIL. NIL removal produced significantly increased basal prolactin concentrations, indicating that dopamine from the NIL contributes to the suppression of prolactin before the antepartum prolactin surge. Furthermore, NIL removal also completely prevented the antepartum prolactin surge compared to sham-operated controls, which is consistent with the hypothesis that the NIL supplies a prolactin-releasing factor to the anterior pituitary to induce the antepartum prolactin surge.

Quantitation of prolactin receptor mRNA in the maternal rat brain during pregnancy and lactation.

Prolactin receptor (PRL-R) expression in the brain is increased in lactating rats compared with non-pregnant animals. The aim of the present study was to determine the time-course of changes in PRL-R mRNA levels during pregnancy and/or lactation, and to determine relative levels of the two forms (short and/or long form) of receptor mRNA in specific brain regions. Brains were collected from female rats on dioestrus, days 7, 14 or 21 of pregnancy, day 7 of lactation or day 7 post-weaning. Frozen, coronal sections were cut (300 microm) and specific hypothalamic nuclei and the choroid plexus were microdissected using a punch technique. Total RNA was extracted and reverse transcribed, then first strand cDNA was amplified using quantitative real-time PCR. Results showed an up-regulation of long-form PRL-R mRNA in the choroid plexus by day 7 of pregnancy compared with dioestrus, which further increased on days 14 and 21 of pregnancy and day 7 of lactation, and then decreased to dioestrous levels on day 7 post-weaning. Short-form PRL-R mRNA levels increased on day 14 of pregnancy relative to dioestrus, increased further on day 7 of lactation and decreased on day 7 post-weaning. Changes in mRNA were reflected in increased levels of PRL-R immunoreactivity in the choroid plexus during pregnancy and lactation, compared with dioestrus. In the arcuate nucleus, long-form PRL-R mRNA was increased during pregnancy. In contrast to earlier work, no significant changes in short- or long-form PRL-R mRNA expression were detected in several other hypothalamic nuclei, suggesting that changes in hypothalamic mRNA levels may not be as marked as previously thought. The up-regulation of PRL-R mRNA and protein expression in the choroid plexus during pregnancy and lactation suggest a possible mechanism whereby increasing levels of peripheral prolactin during pregnancy may have access to the central nervous system. Together with expression of long-form PRL-R mRNA in specific hypothalamic nuclei, these results support a role for prolactin in regulating neuroendocrine and behavioural adaptations in the maternal brain.

Opioid receptor subtypes involved in the regulation of prolactin secretion during pregnancy and lactation.

Afferent endogenous opioid neuronal systems facilitate prolactin secretion in a number of physiological conditions including pregnancy and lactation, by decreasing tuberoinfundibular dopamine (TIDA) inhibitory tone. The aim of this study was to investigate the opioid receptor subtypes involved in regulating TIDA neuronal activity and therefore facilitating prolactin secretion during early pregnancy, late pregnancy and lactation in rats. Selective opioid receptor antagonists nor-binaltorphimine (kappa-receptor antagonist, 15 micro g/5 micro l), beta funaltrexamine (mu-receptor antagonist, 5 microg/5 microl) and naltrindole (delta-receptor antagonist, 5 microg/5 microl) or saline were administered intracerebroventricularly (i.c.v.) on day 8 of pregnancy during a nocturnal prolactin surge, on day 21 of pregnancy during the ante partum prolactin surge or on day 7 of lactation before the onset of a suckling stimulus. Serial blood samples were collected at regular time intervals, via chronic indwelling jugular cannulae, before and after drug administration and plasma prolactin was determined by radioimmunoassay. TIDA neuronal activity was measured using the 3,4-dihydroxyphenylacetic acid (DOPAC) : dopamine ratio in the median eminence 2 h 30 min after i.c.v. drug injection. In each experimental condition, plasma prolactin was significantly inhibited by both kappa- and mu-receptor antagonists, whereas the delta-receptor antagonist had no effect compared to saline-injected controls. Similarly, nor-binaltorphimine and beta funaltrexamine significantly increased the median eminence DOPAC : dopamine ratio during early and late pregnancy, and lactation whereas naltrindole had no effect compared to saline-injected controls. These data suggest that TIDA neuronal activity, and subsequent prolactin secretion, is regulated by endogenous opioid peptides acting at both kappa- and mu-opioid receptors during prolactin surges of early pregnancy, late pregnancy and lactation.

Prolactin receptors in the brain during pregnancy and lactation: implications for behavior.

Numerous studies have documented prolactin regulation of a variety of brain functions, including maternal behavior, regulation of oxytocin neurons, regulation of feeding and appetite, suppression of ACTH secretion in response to stress, and suppression of fertility. We have observed marked changes in expression of prolactin receptors in specific hypothalamic nuclei during pregnancy and lactation. This has important implications for neuronal functions regulated by prolactin. In light of the high circulating levels of prolactin during pregnancy and lactation and the increased expression of prolactin receptors in the hypothalamus, many of these functions may be enhanced or exaggerated in the maternal brain. The adaptations of the maternal brain allow the female to exhibit the appropriate behavior to feed and nurture her offspring, to adjust to the nutritional and metabolic demands of milk production, and to maintain appropriate hormone secretion to allow milk synthesis, secretion, and ejection. This review aims to summarize the evidence that prolactin plays a key role in regulating hypothalamic function during lactation and to discuss the hypothesis that the overall role of prolactin is to organize and coordinate this wide range of behavioral and neuroendocrine adaptations during pregnancy and lactation.

Dissociation of prolactin secretion from tuberoinfundibular dopamine activity in late pregnant rats.

This study investigated whether the PRL surge that precedes parturition is accompanied by a decrease in activity of hypothalamic tuberoinfundibular dopamine (TIDA) neurons, as occurs during the PRL surges of early pregnancy. Serial blood samples were collected at regular intervals during early and late pregnancy via chronic indwelling jugular cannulae, and concentrations of plasma PRL were determined by RIA. In addition, pregnant rats were killed at either 1200 and 0300 h on different days throughout pregnancy. Levels of TIDA neuronal activity were estimated using concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence as an index of dopamine metabolism. During early pregnancy, plasma PRL concentrations showed characteristic diurnal and nocturnal surges peaking at 1700 and 0300 h, respectively, whereas during late pregnancy, there was a broad nocturnal surge throughout the night preceding parturition. During early pregnancy, DOPAC was elevated at 1200 h, associated with suppressed plasma PRL, whereas at 0300 h, during the nocturnal PRL surge, DOPAC was significantly reduced (P < 0.05). On the last day of pregnancy DOPAC levels were significantly reduced at both 1200 and 0300 h compared with those at 1200 h in early pregnancy regardless of the PRL concentration. This experiment was repeated with additional groups to further characterize the timing of the fall in TIDA activity during late pregnancy. DOPAC concentrations were elevated throughout the second half of pregnancy, then fell significantly between 0300-1200 h on day 21, approximately 36 h before parturition. As in the previous experiment, the timing of changes in DOPAC concentrations in the median eminence was dissociated from the antepartum PRL surge. These data indicate that the regulation of PRL secretion during late pregnancy is different from that of early pregnancy. Despite the prolonged reduction in activity of TIDA neurons during late pregnancy, PRL secretion still occurs as a nocturnal surge, suggesting that dopamine is not the only regulator of PRL secretion at this time.