ABSTRACT
Prostatic acid phosphatase (PAP), the first diagnostic marker and present therapeutic target for prostate cancer, modulates nociception at the dorsal root ganglia (DRG), but its function in the central nervous system has remained unknown. We studied expression and function of TMPAP (the transmembrane isoform of PAP) in the brain by utilizing mice deficient in TMPAP (PAP-/- mice). Here we report that TMPAP is expressed in a subpopulation of cerebral GABAergic neurons, and mice deficient in TMPAP show multiple behavioral and neurochemical features linked to hyperdopaminergic dysregulation and altered GABAergic transmission. In addition to increased anxiety, disturbed prepulse inhibition, increased synthesis of striatal dopamine, and augmented response to amphetamine, PAP-deficient mice have enlarged lateral ventricles, reduced diazepam-induced loss of righting reflex, and increased GABAergic tone in the hippocampus. TMPAP in the mouse brain is localized presynaptically, and colocalized with SNARE-associated protein snapin, a protein involved in synaptic vesicle docking and fusion, and PAP-deficient mice display altered subcellular distribution of snapin. We have previously shown TMPAP to reside in prostatic exosomes and we propose that TMPAP is involved in the control of GABAergic tone in the brain also through exocytosis, and that PAP deficiency produces a distinct neurological phenotype.
Subject(s)
Brain/metabolism , Brain/physiopathology , Cell Membrane/metabolism , GABAergic Neurons/metabolism , Protein Tyrosine Phosphatases/deficiency , Synaptic Transmission/genetics , Acid Phosphatase , Animals , Brain/pathology , Dopamine/biosynthesis , Glutamate Decarboxylase/metabolism , Hippocampus/metabolism , Hippocampus/physiopathology , Isoenzymes , Lateral Ventricles/pathology , Magnetic Resonance Imaging , Male , Mice , Mice, Knockout , Protein Binding , Protein Transport , Protein Tyrosine Phosphatases/geneticsABSTRACT
Neuronal changes induced by chronic nicotine in the brain dopaminergic circuits are thought to lead to compulsive nicotine use. When nicotine is given to mice chronically in their drinking water, its intake and effects mimic human smoking. Previously, we have reported that this treatment in mice induces several neurochemical and behavioural changes that are associated with nicotine addiction. Here we studied the effects of chronic oral nicotine treatment and nicotine treatment cessation on two well-characterised markers of neuronal plasticity, brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element-binding protein (pCREB), in several dopaminergic brain areas. BDNF levels were not altered by chronic nicotine treatment, but they were significantly increased in the nucleus accumbens (NAc) after 24h and 29 days of nicotine abstinence and in the ventral tegmental area (VTA) and substantia nigra after 29 days of nicotine abstinence. These findings suggest that nicotine abstinence promotes long-lasting neuroadaptations in dopaminergic neurocircuits by inducing BDNF production. Withdrawal from chronic nicotine treatment oppositely affected pCREB levels in the NAc and in the VTA. Thus, in the NAc, the pCREB levels were significantly elevated and in the VTA significantly decreased as compared with the pCREB levels during the nicotine treatment. These alterations could be compensatory and related to increased dopaminergic signalling during nicotine treatment. In conclusion, the current results suggest the involvement of BDNF- and CREB-related neuronal processes in nicotine-induced neurochemical, behavioural, and neuroplastic changes in dopaminergic neurocircuits.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Brain/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Nicotine/administration & dosage , Substance Withdrawal Syndrome/metabolism , Tobacco Use Disorder/metabolism , Administration, Oral , Animals , Brain/metabolism , Dopamine/metabolism , Enzyme-Linked Immunosorbent Assay , Immunohistochemistry , Male , Mice , Neuronal Plasticity/drug effects , Nicotinic Agonists/administration & dosage , PhosphorylationABSTRACT
Besides alcohol, alcohol-preferring AA and alcohol-avoiding ANA rats differ also with respect to other abused drugs. To study the molecular basis of these differences, we examined the expression of two transcription factors implicated in addiction, DeltaFosB and pCREB, in brain dopaminergic regions of AA and ANA rats. The effects of morphine and nicotine were studied to relate the behavioral and molecular changes induced by these drugs. Baseline FosB/DeltaFosB immunoreactivity (IR) in the nucleus accumbens core and pCREB IR in the prefrontal cortex (PFC) were elevated in AA rats. Morphine increased DeltaFosB-like IR more readily in the caudate-putamen of AA rats than in ANA rats. In the PFC morphine decreased pCREB IR in AA rats, but increased it in ANA rats. In addition to enhanced locomotor response, the development of place preference to morphine was enhanced in AA rats. The enhanced nicotine-induced locomotor sensitization found in AA compared with ANA rats seems to depend in addition to dopamine and DeltaFosB on other mechanisms. These findings suggest that enhanced sensitivity of AA rats to morphine is related to augmented morphine-induced expression of FosB/DeltaFosB and morphine-induced reduction of pCREB levels. Moreover, altered innate expression of FosB/DeltaFosB and pCREB in AA rats is likely to affect the sensitivity of these rats to abused drugs.
