Central nervous system schizophrenia

The last 20 years have seen severe mental illness treated far better by medication than by psychological treatment many otherwise hopeless cases have been able to return to their homes, and to employment, on maintenance doses of new drugs. More and more, biochemical research on mental illness is suggesting that many cases are caused by purely biochemical changes in the central nervous system (schizophrenia by over-methylation, for example). Hence the hope for more specific drug-based treatments is very bright. 

Histamine produces its pharmacological actions by three subtypes of receptors the postsynaptic Hi and H2 receptors and the presynaptic H3 receptor. The H3 receptor is mainly located in the central nervous system (CNS), where it acts as an inhibitory autoreceptor in the central histaminergic neuronal pathways [176]. A number of therapeutic applications have been proposed for selective H3 receptor antagonists, including several CNS disorders such as Alzheimer s disease. Attention Deficit Hyperactivity Disorder, Schizophrenia, or for enhancing memory or obesity control. 

Dean, B., Bradbury, R., and Copolov, D.L., Cannabis-sensitive dopaminergic markers in postmortem central nervous system changes in schizophrenia, Biol. Psychiatry, 53, 585, 2003. 

Schizophrenia is a chronic, complex psychiatric disorder affecting approximately 1% of the population worldwide. The chronic nature of the illness, in addition to the early age of onset, results in direct and indirect health care expenditures in the U.S., which amount to approximately 30 to 64 billion dollars per year [4]. It is perhaps the most devastating of psychiatric disorders, with approximately 10% of patients committing suicide. The dopamine hypothesis of schizophrenia postulates that overactivity at dopaminergic synapses in the central nervous system (CNS), particularly the mesolimbic system, causes the psychotic symptoms (hallucinations and delusions) of schizophrenia. Roth and Meltzer [5] have provided a review of the literature and have concluded a role for serotonin as well in the pathophysiology and treatment of schizophrenia. The basic premise of their work stems from the known interaction between the serotonergic and dopaminergic systems. 

Substance P, an undecapeptide, is abundant both in the periphery and in the central nervous system. It is usually co-localized with one of the classical neurotransmitters, most commonly serotonin. Substance P is thought to have a role in the regulation of pain, asthma, psoriasis, inflammatory bowel disease and, in the CNS, emesis, migraine, schizophrenia, depression and anxiety. The substance-P-preferring receptor neurokinin-1 has been focused on most intensively in drug development, and existing... 

In this rapidly evolving field, the detection of PDE enzymes in the central nervous system (CNS) has stimulated interest in exploring potential applications of PDE inhibitors for treating CNS disorders such as Alzheimer s disease and other cognitive malfunctions, depression, anxiety, and schizophrenia. This review will focus on these therapeutic opportunities as well as new developments in the medicinal chemistry and biology associated with selected members of the PDE family, in particular PDEs 2, 4, 9, and 10. There have been a number of other reviews in this field in the past year that have covered selected individual PDE enzymes and potential pharmacologic applications of PDE inhibitors in CNS disorders [3,7,8]. 

Dopamine is a major catecholamine neurotransmitter in the central nervous system (37) that is involved in the neuroregulation of locomotor activity, emotion, and neuroendocrine secretion (38,39). Clinically, dopaminergic drugs are used to treat Parkinson s disease and schizophrenia by activating or blocking dopamine receptors, respectively (40). 

As with research on drugs for the treatment of disease, an understanding of the mechanism by which mind-altering drugs operate is fundamental to the development of new chemicals to treat mental disorders, such as Parkinson s disease, schizophrenia, and depression. Scientists now understand that many abnormal mental conditions are the result ofbiochemical imbalances— an excess or deficiency of essential chemicals in the central nervous system—that can be ameliorated or cured by treatment with natural or synthetic drugs. 

Neuroleptic drugs are used in the treatment of psychosis, such as schizophrenia they are generally antagonist ligands of dopamine at the central nervous system level. " Indications and therapeutic effects of the various families of neuroleptics result from two factors. The first one is the specifity of the ligand toward the different types of dopaminergic receptors, which are unequally distributed in the... 

Ohouha DC, Hyde TM, Kleinman JE The role of serotonin in schizophrenia an overview of the nomenclature, distribution and alterations of serotonin receptors in the central nervous system. Psychopharmacology 112 S5-S15, 1993... 

In the central nervous system, there are close associations between NT and dopamine systems, and NT may be involved in clinical disorders involving dopamine pathways such as schizophrenia, Parkinson s disease, and drug abuse. Consistent with this, it has been shown that central administration of NT produces effects in rodents similar to those produced by antipsychotic drugs. 

Chlorpromazine Blockade of D2 receptors >> 5 2 receptors .-Receptor blockade (fluphenazine least) muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) Hx-receptor blockade (chlorpromazine, thiothixene) t central nervous system (CNS) depression (sedation) t decreased seizure threshold t QT prolongation (thioridazine) Psychiatric schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) nonpsychiatric antiemesis, preoperative sedation (promethazine) pruritus Oral and parenteral forms, long half-lives with metabolism-dependent elimination Toxicity Extensions of effects on a - and M- receptors blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardivedyskinesia, and hyperprolactinemia... 

The co-3 fatty acids have numerous important functions, especially in the brain. Accordingly, a deficiency of DHA and EPA may cause dysfunction of the central nervous system and probably also the retina, thereby resulting in impaired vision. In addition, there is a variety of neurological and psychiatric disorders that have been associated with decreased levels of especially DHA and AA, such as, for example, schizophrenia and depression [3], post-traumatic stress syndrome, autism and attention deficit hyperactivity disorder. Since no primary inherited defect of essential fatty acid interconversion has yet been described, no specific explanations for the essential fatty acid concentration changes are readily available. 

Cholecystokinin. Cholecystokinin (CCK) is also colocalized with dopaminergic neurons and has two receptor subtypes, CCK-A being predominantly outside of and CCK-B within the central nervous system. Studies of CCK agonists and antagonists to date have not given clear clues as to their potential for therapeutic actions in schizophrenia. 

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