The effect of adolescent inhalant abuse on energy balance and growth

The abuse of volatile solvents such as toluene is a significant public health concern, predominantly affecting adolescents. To date, inhalant abuse research has primarily focused on the central nervous system; however, inhalants also exert effects on other organ systems and processes, including metabolic function and energy balance. Adolescent inhalant abuse is characterized by a negative energy balance phenotype, with the peak period of abuse overlapping with the adolescent growth spurt. There are multiple components within the central and peripheral regulation of energy balance that may be affected by adolescent inhalant abuse, such as impaired metabolic signaling, decreased food intake, altered dietary preferences, disrupted glucose tolerance and insulin release, reduced adiposity and skeletal density, and adrenal hypertrophy. These effects may persist into abstinence and adulthood, and the long-term consequences of inhalant-induced metabolic dysfunction are currently unknown. The signs and symptoms resulting from chronic adolescent inhalant abuse may result in a propensity for the development of adult-onset metabolic disorders such as type 2 diabetes, however, further research investigating the long-term effects of inhalant abuse upon energy balance and metabolism are needed. This review addresses several aspects of the short- and long-term effects of inhalant abuse relating to energy and metabolic processes, including energy balance, intake and expenditure; dietary preferences and glycemic control; and the dysfunction of metabolic homeostasis through altered adipose tissue, bone, and hypothalamic-pituitary-adrenal axis function.Rose Crossin, Ashleigh Qama, Zane B. Andrews, Andrew J. Lawrence, Jhodie R. Dunca

Neuroendocrine mechanisms that connect feeding behavior and stress

Research during the past decade highlights the strong link between appetitive feeding behavior, reward and motivation. Interestingly, stress levels can affect feeding behavior by manipulating hypothalamic circuits and brain dopaminergic reward pathways. Indeed, animals and people will increase or decrease their feeding responses when stressed. In many cases acute stress leads to a decrease in food intake, yet chronic social stressors are associated to increases in caloric intake and adiposity. Interestingly, mood disorders and the treatments used to manage these disorders are also associated with changes in appetite and body weight. These data suggest a strong interaction between the systems that regulate feeding and metabolism and those that regulate mood. This Research Topic aims to illustrate how hormonal mechanisms regulate the nexus between feeding behavior and stress. It focuses on the hormonal regulation of hypothalamic circuits and/or brain dopaminergic systems, as the potential sites controlling the converging pathways between feeding behavior and stress

Ghrelin's Role in the Hypothalamic-Pituitary-Adrenal Axis Stress Response: Implications for Mood Disorders

Contains fulltext : 155371.pdf (publisher's version ) (Closed access)Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic-pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal nucleus, the hippocampus, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite; therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders

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.R Crossin, A J Lawrence, Z B Andrews, L Churilov, J R Duncan, J R Dunca

Adolescent inhalant abuse results in adrenal dysfunction and a hypermetabolic phenotype with persistent growth impairments

Abstract not availableRose Crossin, Zane B. Andrews, Natalie A. Sims, Terence Pang, Michael Mathai, Jonathan H. Gooi, Aneta Stefanidis, Brian J. Oldfield, Andrew J. Lawrence, Jhodie R. Dunca

Uncoupling protein-2 promotes nigrostriatal dopamine neuronal function

Uncoupling protein 2 (UCP2) is known to promote neuroprotection in many forms of neurological pathologies including Parkinson's disease. Here, we examined the hypothesis that UCP2 also mediates aspects of normal nigrostriatal dopamine (DA) function. Mice lacking UCP2 exhibited reduced dopamine turnover in the striatum as measured by the 3,4-dihydoxyphenylacetic acid/dopamine (DOPAC/DA) ratio, reduced tyrosine hydroxylase immunoreactivity (TH IR) in the substantia nigra pars compacta (SNc) and reticulata, striatum and nucleus accumbens. UCP2-knockout (KO) mice also had reduced dopamine transporter immunoreactivity (DAT IR) in the SNc but not other brain regions examined. In order to determine if these biochemical deficits are transcribed into behavioural deficits, we examined locomotor function in UCP2-KO mice compared to wild-type (WT) controls. UCP2-KO mice exhibited significantly reduced total movement distance, movement velocity and increased rest time compared to wild-type controls. These results suggest that UCP2 is an important mitochondrial protein that helps to maintain normal nigrostriatal dopamine neuronal function and a reduction in UCP2 levels may predispose individuals to environmental causes of Parkinson's disease

Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism

Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration. Copyrigh