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1.  VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse 
The monoaminergic neuron, in particular the dopaminergic neuron, is central to mediating the hedonic and addictive properties of drugs of abuse. The effects of amphetamine (AMPH) and cocaine (COC), for example, depend on the ability to increase dopamine in the synapse, by effects on either the plasma membrane transporter DAT or the vesicular transporter for monoamine storage, VMAT2. The potential role of DAT as a target for AMPH and COC has been reviewed extensively. Here, we present VMAT2 as a target that enables the rewarding and addictive actions of these drugs, based on imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence. The presence of VMAT2 in noradrenergic, serotoninergic, histaminergic, and potentially trace aminergic neurons invites consideration of a wider role for aminergic neurotransmission in AMPH and COC abuse and addiction.
PMCID: PMC4183197  PMID: 21272013
VMAT2; amphetamine; cocaine; addiction; monoamines; vesicular transporter
2.  PACAP: A master regulator of neuroendocrine stress circuits and the cellular stress response 
The neuropeptide PACAP is an informational molecule released from stress-transducing neurons. It exerts post-synaptic effects required to complete hypothalamo-pituitary-adrenocortical (HPA) and hypothalamo-splanchnico-adrenomedullary (HSA) circuits activated by psychogenic and metabolic stressors. PACAP-responsive (in cell culture models) and PACAP-dependent (in vivo) transcriptomic responses in the adrenal gland, hypothalamus, and pituitary upon activation of these circuits have been identified. Gene products produced in response circuits during stress include additional neuropeptides and neurotransmitter biosynthetic enzymes and neuroprotective factors. Major portions of HPA and HSA stress responses are abolished in PACAP-deficient mice. This deficit occurs at the level of both the adrenal medulla (HSA axis) and the hypothalamus (HPA axis). PACAP-dependent transcriptional stress responses are conveyed through non-canonical cyclic AMP- and calcium-initiated signaling pathways within the HSA circuit. PACAP transcriptional regulation of the HPA axis, in the hypothalamus, is likely to be mediated via canonical cyclic AMP (cAMP) signaling through protein kinase A.
PMCID: PMC3078626  PMID: 21388403
PACAP; stress; HPA axis
3.  Discovery of Pituitary Adenylate Cyclase-Activating Polypeptide-Regulated Genes through Microarray Analyses in Cell Culture and In Vivo 
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an evolutionarily well conserved neuropeptide with multiple functions in the nervous, endocrine, and immune systems. PACAP provides neuroprotection from ischemia and toxin exposure, is anti-inflammatory in gastric inflammatory disease and sepsis, controls proliferative signaling pathways involved in neural cell transformation, and modulates glucohomeostasis. PACAP-based, disease-targeted therapeutics might thus be both effective and benign, enhancing homeostatic responses to behavioral, metabolic, oncogenic, and inflammatory stressors. PACAP signal transduction employs synergistic regulation of calcium and cyclic adenosine monophosphate (cAMP), and noncanonical activation of both calcium- and cAMP-dependent processes. Pharmacological activation of PACAP signaling should consequently have highly specific effects even in vivo. Here, a combined cellular biochemical, pharmacologic, transcriptomic, and bioinformatic approach to understanding PACAP signal transduction by identifying PACAP target genes with oligonucleotide- and cDNA-based microarray is described. Calcium- and cAMP-dependent PACAP signaling pathways for regulation of genes encoding proteins required for neuritogenesis, changes in cell morphology, and cell survival have been traced in PC12 cells. Pharmacological experiments have linked gene expression to cell physiological responses in this system, in which gene silencing can also be employed to confirm the functional significance of induction of specific transcripts. Differential transcriptional responses to metabolic, ischemic, and other stressors in wild type compared to PACAP-deficient mice establish in principle which PACAP-responsive transcripts in culture are PACAP-dependent in vivo. Bioinformatic approaches aid in creating a pipeline for identifying neuropeptide-regulated genes, validating their cellular functions, and defining their expression in the context of neuropeptide signaling physiology, required for discovery of new targets for drug action.
PMCID: PMC2933652  PMID: 19076358
bioinformatics; gene discovery; microarray; neuropeptide; neuroprotection; PACAP; PC12; pituitary adenylate cyclase-activating polypeptide; signal transduction; stress response

Results 1-3 (3)