Brain 5-HT receptor system in the stressed infant rat: implications for vulnerability to substance abuse.

Clinical and epidemiological studies have found an association between aversive experiences early in life and an increased risk for depression, anxiety and substance abuse. In order to elucidate the mechanisms by which adverse life events are translated into behavioral and psychological abnormalities, we used a rat model to study the impact of chronic injection and 24 h maternal deprivation on the developing rat brain. Specifically, we investigated the regulation of molecules related to the 5-HT (5-HT) system and studied the effect of desipramine administration on animals that were maternally deprived (DEP) on day 13 of life compared with non-deprived animals. We found that maternal deprivation caused an enhanced corticosterone response to an acute stress. Maternally deprived animals also showed a decrease in corticosteroid receptors and an increase in 5-HT 1A and 1B receptors restricted to the CA1 region of the hippocampus. Desipramine prevented the maternal deprivation induced up-regulation of the 5-HT 1B receptor and the enhanced adrenocortical response observed in these animals. Interestingly, non-deprived animals receiving chronic injections showed a decrease in hippocampal 5-HT1B receptor mRNA. At 80 days of age, a group of animals that were treated as infants were given the option of drinking from two identical water bottles, one bottle contained tap water, while the second contained ethanol at increasing concentrations. Animals that received chronic injections during the newborn period consumed more alcohol than those that were not injected. On the other hand, maternal deprivation did not have an impact on alcohol consumption. Alcohol preference has implications to the organism since studies of drug self-administration in laboratory animals have shown that ethanol ingestion is positively related to the use of other drugs, principally opioids and psychostimulants. Our findings suggest that the quality and/or chronicity of early life stressors can influence the neurobiological substrates that may trigger and/or predispose individuals to substance abuse in adulthood.

Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons.

CONTEXT: Diabetes in neonates nearly always has a monogenic etiology. Earlier sulfonylurea therapy can improve glycemic control and potential neurodevelopmental outcomes in children with KCNJ11 or ABCC8 mutations, the most common gene causes. OBJECTIVE: Assess the risks and benefits of initiating sulfonylurea therapy before genetic testing results become available. DESIGN, SETTING, AND PATIENTS: Observational retrospective study of subjects with neonatal diabetes within the University of Chicago Monogenic Diabetes Registry. MAIN OUTCOME MEASURES: Response to sulfonylurea (determined by whether insulin could be discontinued) and treatment side effects in those treated empirically. RESULTS: A total of 154 subjects were diagnosed with diabetes before 6 months of age. A genetic diagnosis had been determined in 118 (77%), with 73 (47%) having a mutation in KCNJ11 or ABCC8. The median time from clinical diagnosis to genetic diagnosis was 10.4 weeks (range, 1.6 to 58.2 wk). In nine probands, an empiric sulfonylurea trial was initiated within 28 days of diabetes diagnosis. A genetic cause was subsequently found in eight cases, and insulin was discontinued within 14 days of sulfonylurea initiation in all of these cases. CONCLUSIONS: Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available; however, larger numbers of cases must be studied. Given the potential beneficial effect on neurodevelopmental outcome, glycemic control, and the current barriers to expeditious acquisition of genetic testing, an empiric inpatient trial of sulfonylurea can be considered. However, obtaining a genetic diagnosis remains imperative to inform long-term management and prognosis.

Potential diagnostic utility of intermittent administration of short-acting gonadotropin-releasing hormone agonist in gonadotropin deficiency.

OBJECTIVE: To determine if intermittent, low-dose, short-acting gonadotropin-releasing hormone agonist (GnRH-agonist) administration sufficiently up-regulates pituitary-gonadal function in gonadotropin deficiency to be of diagnostic or therapeutic value. DESIGN: Case-control study. SETTING: General clinical research center. PATIENT(S): Normal adult volunteers and gonadotropin-deficiency patients. INTERVENTION(S): Low-dose leuprolide acetate administered subcutaneously at 4- to 5-day intervals up to 1 year. MAIN OUTCOME MEASURE(S): Levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses. RESULT(S): In normal men and women, low-dose GnRH-agonist repetitively transiently stimulated gonadotropins in a gender-dimorphic manner. In congenitally gonadotropin-deficient men (n = 6) and women (n = 1), none of whom had a normal LH response to an initial GnRH-agonist test dose, this regimen consistently stimulated LH to the normal baseline range within 2 weeks. Long-term GnRH-agonist administration to a partially gonadotropin-deficient man did not alleviate hypogonadism, however. Women with hypothalamic amenorrhea (n = 2) responded normally to a single GnRH-agonist injection; however, repeated dosing did not seem to induce the normal priming effect. CONCLUSION(S): The subnormal LH response to GnRH-agonist in patients with congenital gonadotropin deficiency normalized in response to repetitive intermittent GnRH-agonist administration but not sufficiently to improve hypogonadism. Hypothalamic amenorrhea patients lacked the priming response to repeated GnRH-agonist but otherwise had normal hormonal responses to GnRH-agonist. We conclude that intermittent administration of a short-acting GnRH-agonist is of potential diagnostic value in distinguishing hypothalamic from pituitary causes of gonadotropin deficiency.