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1.
Behav Brain Res ; 347: 234-241, 2018 07 16.
Article in English | MEDLINE | ID: mdl-29555337

ABSTRACT

Central serotonin systems have long been associated with the control of feeding behavior and the modulation of behavioral effects of psychostimulants. 5-HT2C receptors are present in hypothalamic centers such as the arcuate nucleus (ARC), controlling homeostatic regulation of food intake, as well as in the ventral tegmental area (VTA), a region involved in motivation aspects in multiple behaviors, including feeding. In the present study, we investigated whether the 5-HT2C receptors control amphetamine-evoked locomotor activity and regulate food consumption. Localized microinjections into the VTA or the ARC were used to assess the effects of a highly selective 5-HT2C receptor agonist, AR231630, on the locomotor stimulant effect of amphetamine as well as on food intake. AR231630 injected into the VTA, but not into the ARC, dose-dependently reduced locomotor activity elicited by amphetamine. Unexpectedly, intra-ARC injection of AR231630 did not reduce food intake even at the dose of 10 µg, whereas intra-VTA injection of the same dose of AR231630 did. In addition, we showed that pretreatment with the selective 5-HT2C receptor antagonist SB242084 infused into the VTA partially prevented hypophagia induced by peripheral administration of AR231630. We can conclude that 5-HT2C receptor in the VTA, but not in the ARC, participates in both homeostatic and hedonic food intake and brain reward function.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Feeding Behavior/physiology , Motor Activity/physiology , Piperazines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Reward , Ventral Tegmental Area/metabolism , Aminopyridines/pharmacology , Amphetamine/pharmacology , Animals , Arcuate Nucleus of Hypothalamus/drug effects , Central Nervous System Stimulants/pharmacology , Eating/drug effects , Eating/physiology , Feeding Behavior/drug effects , Food Deprivation , Indoles/pharmacology , Male , Motivation/drug effects , Motivation/physiology , Motor Activity/drug effects , Rats, Sprague-Dawley , Serotonin 5-HT2 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Ventral Tegmental Area/drug effects
2.
Diabetes ; 63(6): 2015-25, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24520125

ABSTRACT

Type 1 diabetes is thought to be an autoimmune condition in which self-reactive T cells attack insulin-secreting pancreatic ß-cells. As a proinflammatory cytokine produced by ß-cells or macrophages, interleukin-1ß (IL-1ß) represents a potential therapeutic target in diabetes. We reasoned IL-1ß blockade could be combined with islet antigen-specific approaches involving GAD of 65 kDa (GAD65)-expressing plasmids, as previously shown in combination therapies (CTs) with anti-CD3. Thus, we investigated whether anti-IL-1ß antibody alone or combined with GAD65 vaccine could reverse diabetes development in a virus-induced mouse model. Given alone, anti-IL-1ß had no effect on diabetes, while GAD65 plasmid resulted in 33% disease reversal after a 5-week observation. However, CTs cured 53% of animals and prevented worsening of glycemic control in nonprotected individuals for up to 12 weeks. While the GAD65 vaccine arm of the CT was associated with increased forkhead box p3(+) regulatory T-cell frequency in pancreatic lymph nodes, islet infiltration by CD11b(+/high) cells was less frequent upon CT, and its extent correlated with treatment success or failure. Altogether, our CTs provided prolonged improvement of clinical and immunological features. Despite unsuccessful clinical trials using anti-IL-1ß monotherapy, these data hold promise for treatment of type 1 diabetic patients with IL-1ß blockade combined with antigen-specific vaccines.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/immunology , Glutamate Decarboxylase/genetics , Interleukin-1beta/immunology , Islets of Langerhans/immunology , Vaccines, DNA/pharmacology , Animals , Antibodies/pharmacology , CD11b Antigen/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/virology , Drug Therapy, Combination , Genetic Therapy , Glutamate Decarboxylase/immunology , Interleukin-1beta/antagonists & inhibitors , Mice , Mice, Mutant Strains , Mice, Transgenic , Pancreas/immunology , Remission Induction
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