nitrophenols and Schizophrenia

Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.

Topics: Alleles; Animals; Anxiety; Benzophenones; Benzoxazines; Biogenic Monoamines; Cannabinoid Receptor Agonists; Cannabinoids; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Chromatography, High Pressure Liquid; Cyclohexanols; Enzyme Inhibitors; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Naphthalenes; Nitrophenols; Pain Measurement; Phenotype; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Social Behavior; Swimming; Tolcapone

Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.

Topics: Animals; Antipsychotic Agents; Benzophenones; Biomarkers; Blotting, Western; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cell Membrane; Dopamine; Enzyme Inhibitors; Humans; Isoenzymes; Male; Matrix Metalloproteinases; Membrane Potential, Mitochondrial; Nitrophenols; Rats; Rats, Sprague-Dawley; Rats, Wistar; Recombinant Proteins; Schizophrenia; Substrate Specificity; Tolcapone

It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available antipsychotics fail to improve cognitive and negative symptoms originating from this deficit. Evidence from basic science has revealed the importance of prefrontal dopamine signaling for optimal prefrontal function. This article describes succinctly the progress made so far, taking into account the mechanisms involved in catechol-O-methyltransferase (COMT)-induced modulation of prefrontal dopamine signaling, the impact of COMT on cognitive function and the role of COMT gene polymorphisms. The potential role of the COMT inhibitor tolcapone to improve cognitive function in health and disease is also presented here. It will soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotype-specific, targeted treatments of cognitive and negative symptoms of schizophrenia.

Topics: Antipsychotic Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cognition Disorders; Dopamine; Genetic Predisposition to Disease; Genotype; Humans; Nitrophenols; Polymorphism, Genetic; Schizophrenia; Schizophrenic Psychology; Signal Transduction; Tolcapone

Topics: Benzophenones; Bipolar Disorder; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cognition Disorders; Comorbidity; Diagnosis, Differential; Enzyme Inhibitors; Gene Expression; Genotype; Humans; Nitrophenols; Pharmacogenetics; Schizophrenia; Telecommunications; Tolcapone

The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene affects activity of the enzyme and influences performance and efficiency of the prefrontal cortex (PFC); however, although catecholaminergic neurotransmission is implicated, the underlying mechanisms remain elusive because studies of the role of COMT in PFC function are sparse. This study investigated the effect of tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set shifting, which is dependent on catecholamines and the medial PFC (mPFC). Additionally, we investigated the effect of tolcapone on extracellular catecholamines in the mPFC using microdialysis in awake rats. Tolcapone significantly and specifically improved extradimensional (ED) set shifting. Tolcapone did not affect basal extracellular catecholamines, but significantly potentiated the increase in extracellular dopamine (DA) elicited by either local administration of the depolarizing agent potassium chloride or systemic administration of the antipsychotic agent clozapine. Although extracellular norepinephrine (NE) was also elevated by local depolarization and clozapine, the increase was not enhanced by tolcapone. We conclude that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission. These data suggest that the links between COMT activity and PFC function can be modeled in rats and may be specifically mediated by DA. The interaction between clozapine and tolcapone may have implications for the treatment of schizophrenia.

Topics: Animals; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catecholamines; Clozapine; Dopamine; Enzyme Inhibitors; Microdialysis; Nitrophenols; Norepinephrine; Prefrontal Cortex; Rats; Schizophrenia; Serotonin Antagonists; Synaptic Transmission; Tolcapone