Central Nervous System Agents in Medicinal Chemistry - Volume 14, Issue 2, 2014

Sex hormones exert differential effects on a variety of sensitive tissues like the reproductive tract, gonads, liver, bone and adipose tissue, among others. In the brain, sex hormones act as neuroactive steroids regulating the function of neuroendocrine diencephalic structures like the hypothalamus. In addition, steroids can exert physiological effects upon cortical, limbic and midbrain structures, influencing different behaviors such as memory, learning, mood and reward. In the last three decades, the role of sex hormones on monoamine neurotransmitters in extra-hypothalamic areas related to motivated behaviors, learning and locomotion has been the focus of much research. The purpose of this thematic issue is to present the state of art concerning the effects of sex hormones on the neurochemical regulation of dopaminergic midbrain areas involved in neurobiological and pathological processes, such as addiction to drugs of abuse. We also discuss evidence of how neonatal exposure to sex hormones or endocrine disrupting chemicals can produce long-term changes on the neurochemical regulation of dopaminergic neurons in the limbic and midbrain areas.

Abnormal dopamine neurotransmission has been linked to a wide array of motor, cognitive, and psychiatric disorders. Dopamine binds and regulates intracellular signals through D1-like (D1 and D5) and D2-like (D2, D3, and D4) G-protein coupled receptors. Activation of D1- like receptors stimulates cAMP/PKA signaling via Gs mediated activation of adenylyl cyclase. In contrast, activation of D2-like receptors inhibits cAMP/PKA signaling by Gi inhibition of adenylyl cyclase. In the brain, dopamine signaling is tightly regulated by cyclic nucleotide phosphodiesterases (PDEs). PDEs are a family of enzymes that selectively degrade cAMP and cGMP. There are 11 different families of PDEs that vary in their substrate specificity, kinetic properties, mode of regulation, intracellular localization, and tissue expression patterns. A number of PDE families are highly expressed in the striatum including PDE1, PDE2, PDE4, and PDE10. There is a growing amount of evidence to suggest that these enzymes play a critical role in modulating dopamine signaling and selective inhibitors of these enzymes are currently being explored as novel therapeutics to treat schizophrenia, Huntington’s disease, cognitive disorders and Parkinson’s disease. The aim of this review is to summarize the distinct roles of different PDEs in regulating dopamine signaling in the striatum. In addition, we will briefly review the therapeutic potential of selective PDE inhibitors to treat neurological and psychiatric disorders associated with abnormal striatal function.

The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of estradiol on motivated behaviors. Dopamine acting in the nucleus accumbens is thought to be important for the attribution of incentive motivational properties to cues that predict reward delivery, while dopamine in the striatum is associated with the expression of repetitive or stereotyped behaviors. Elevated concentrations of estradiol are associated with increased motivation for sex or cues associated with access to a mate, while simultaneously attenuating motivation for food. This shift in motivational salience is important for adaptive choice behavior in the natural environment. Additionally, estradiol’s adaptive effects on motivation can be maladaptive when increasing motivation for non-natural reinforcers, such as drugs of abuse. Here we discuss the effect of estradiol on mesotelencephalic dopamine transmission and subsequent effects on motivated behaviors.

Pediatric brain tumors (BT) represent a broad group of malignancies that affect children, displaying different degrees of aggressiveness and prognosis. Current studies demonstrate a crosslink between genetic and epigenetic changes within these tumors. Histone modifications are key elements in the pathogenesis of cancer in general and in brain tumors in particular. It is well documented that at least two classes of enzymes control acetylation of histones: histone acetyltransferases (HATs) and histone deacetylase (HDACs). Transformed HAT or HDAC action was identified in a number of human tumors. It has been hypothesized that HDACs regulate gene expression by deacetylating important genes for cell maintenance. Several HDACs inhibitors have been characterized in the last years and have been shown to promote growth blockage, differentiation and apoptosis in various types of tumors, including glioblastomas, medulloblastomas, neuroblastomas, melanomas, and leukemias. Some of these inhibitors are currently under clinical investigation for different cancer treatments. This review summarizes important mechanisms of histone modifications and discusses recent discoveries with impact on the pre-clinical and clinical field of pediatric brain tumor treatment.

Serotonin receptors (5-HTRs) are implicated in the pathophysiology of a variety of neuropsychiatric and neurodegenerative disorders and are also targets for drug therapy. In the CNS, most of these receptors are expressed in high abundance in specific brain regions reflecting their role in brain functions. Quantifying binding to 5-HTRs in vivo may permit assessment of physiologic and pathologic conditions, and monitoring disease progression, evaluating treatment response, and for investigating new treatment modalities. Positron emission tomography (PET) molecular imaging has the sensitivity to quantify binding of 5-HTRs in CNS disorders and to measure drug occupancy as part of a process of new drug development. Although research on PET imaging of 5-HTRs have been performed more than two decades, the successful radiotracers so far developed for human studies are limited to 5-HT1AR, 5-HT1BR, 5-HT2AR, 5-HT4R and 5-HT6R. Herein we review the development and application of radioligands for PET imaging of 5-HTRs in living brain.

Objectives: Alzheimer’s disease (AD) is the main cause of gradual cognitive impairment in elderly individuals. This highlights the need of obtaining biomarkers to identify features that are different among mild cognitive impairment (MCI), AD and cognitively normal (CN) individuals. Design and methods: Ultra-performance liquid chromatography (UPLC)/mass spectrometry (MS) was employed to find the metabolic changes in plasma samples obtained from AD, MCI and CN individuals. Based on principal component analysis (PCA), the metabolic differences among AD, MCI and CN subjects were identified. Results: The PCA of UPLC/MS spectra indicated metabolic differences among AD, MCI and CN subjects. The peak intensities of progesterone, lysophos- phatidylcholines (LPCs), tryptophan, L-phenylalanine, dihydrosphingosine and phytosphingosine in the plasma of the MCI and AD subjects were significantly different from the CN subjects. Furthermore, the peak intensities of tryptophan, LPCs, dihydrosphingosine in the plasma of the AD subjects were significantly lower compared to the MCI subjects. Conclusion: Our data provide a link between metabolite imbalance and AD, and suggest that metabolomics can be used to reveal the early disease mechanisms occurred in the progression from CN to MCI and AD.