Neuroleptics neurotransmitters

Dailey, JW (1992) Typical and atypical neuroleptic drug effects on dopamine and other neurotransmitter functions in rodents. PhD thesis, University of London, p. 125. 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

Schulz, E., Fleischhaker, C., and Remschmidt, H. (1996) Correlated changes in symptoms and neurotransmitter indices during maintenance treatment with clozapine or conventional neuroleptics in adolescence and young adulthood schizophrenia. / Child Adolesc Psychopharmacol 6 119-131. 

Hsiao JK, Colison J, Bartko JJ, et al Monoamine neurotransmitter interactions in drug-free and neuroleptic-treated schizophrenics. Arch Gen Psychiatry 50 606-614, 1993... 

Richelson E, Nelson A Antagonism by neuroleptics of neurotransmitter receptors of normal brain in vitro. Eur J Pharmacol 103 197-204, 1984 Rickels K, Schweizer E The treatment of generalized anxiety disorder in patients with depressive symptomatology. J Clin Psychiatry 54 [suppl) 20-23, 1993 Rickels K, Weisman K, Norstad N, et al Buspirone and diazepam in anxiety a controlled study. J Chn Psychiatry 43(12 pt 2) 81-86, 1982 Rickels K, Feighner JP, Smith WT Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. Arch Gen Psychiatry 42 134-141, 1985 Rickels K, Schweizer E, Weiss S, et al Maintenance drug treatment for panic disorder, 11 short- and long-term outcome after drug taper. Arch Gen Psychiatry 50 61-68, 1993... 

The first psychotropics of the modern era (e.g., lithium, neuroleptic antipsychotics, tricyclic and monoamine oxidase inhibitor antidepressants) were discovered serendipitously. These agents were not engineered to have selective actions, but instead produce a wide range of central biochemical effects and generally affect more than one neurotransmitter system simultaneously, resulting in multiple repercussions ... 

All clinically effective antipsychotics block DA receptor activity. Further, stimulation of this neurotransmitter can induce psychotic symptoms de novo or exacerbate an existing psychotic disorder. Atypical agents have differential impacts on other systems (e.g., 5-HT) in comparison with the earlier neuroleptic agents. They also selectively target specific DA tracts that may mediate the pathological condition, while sparing those tracts that mediate the unwanted adverse effects (e.g., EPS, TD). 

Dopamine is a major neurotransmitter which acts on multiple receptors. It can activate both a and 3 adrenoceptors in addition to acting on specific dopamine receptors. These are widely distributed throughout the CNS and are also present in the renal tubules and renal and mesentric blood vessels, and many dopaminergic drugs are used in the treatment of Parkinson s disease, psychiatric disorders, as antiemetics, and for renal protection. Neuroleptic drugs, such as haloperidol and droperidol, are dopamine receptor antagonists. 

Theories about the causes of mental disease are just that - theories. Various areas of the brain are involved in integrating "normal" behaviour patterns. DA, NE and 5-HT are believed to be key neurotransmitters in these systems. An overactivity in dopaminergic or adrenergic neurons may bring on a hyperagitated state. The neuroleptics were introduced into treatment in... 

Schizophrenia is usually treated with a class of medications called antipsychotics, or neuroleptics, that act to reduce the activity of the neurotransmitter dopamine, which may be overactive in the brains of schizophrenics. Commonly used antipsychotic medications include risperidone (Risperdal ),... 

A principal interest in our laboratory is the molecular characterization of CNS receptor sites of the neurotransmitter dopamine (DA, 5). These sites are strongly implicated in the biochemical etiology of schizophrenia and Parkinson s Disease, as well as other diseases of the CNS (50,51). Thus, the rank order of clinical potency of antipsychotic drugs (neuroleptics) correlates with the affinity of these drugs for dopaminergic sites (52,53), It is also well established that Parkinson s disease is directly related to deterioration in dopaminergic neurotransmission in the corpus striatum, which is a brain region rich in dopamine receptor sites (54). The use of L-DOPA, the biosynthetic precursor of dopamine, in treatment of patients with Parkinson s disease is one of the best examples of biochemically directed medical treatment. 

The most frequently cited possible cause of mental illnesses is an abnormal hyperactivity of the dopamine neurotransmitter system in the brain. Neuroleptics inhibit dopamine nerve transmission in the frontal lobes and in the limbic system—the emotion-regulating brain structures. Inhibiting this portion of the brain causes diffuse CNS depression and disrupts an individual s behavior entirely—reducing psychotic thoughts, perceptions, and agitation. 

Neuroleptics are sometimes placed into two categories, typical and atypical. The typical neuroleptics are those that were marketed before 1990. The atypical or new generation neuroleptics work on different neurotransmitters than the older medications. The most common typical or conventional neuroleptic drugs include ... 

It is well known that typical neuroleptics, all of which have a high affinity for dopamine receptors (particularly D2 receptors), do not effectively treat all schizophrenic patients and have only limited beneficial effects on the negative symptoms of the illness. Furthermore, neither typical nor atypical neuroleptics have an immediate effect on the positive symptoms even though it can be shown by both experimental studies in animals and by imaging methods in schizophrenic patients that neuroleptics rapidly bind to dopamine receptors. Thus factors other than an overactive dopaminergic system are probably operative in this disorder. The question is which of the numerous neurotransmitters and modulatory neuropeptides are responsible for both the negative symptoms and the delay in onset of the therapeutic effects of neuroleptics on the positive symptoms ... 

Effects of neuroleptics on dopaminergic and other neurotransmitter systems... 

In addition to their affinity for dopamine receptors, which appears to be essential for their therapeutic activity, all neuroleptics in current clinical use have affinities for other types of neurotransmitter receptor. Mention has already been made of the side effects of the weaker neuroleptics such as chlorpromazine for histamine-1, muscarinic and alpha-1 adrenoceptors. However, it is now apparent that many of the newer, atypical, neuroleptics have an affinity for subtypes of 5-HT (particularly 5-HT2A) receptors which may be beneficial in reducing the frequency of extrapyramidal side effects. Thus neuroleptics may now be broadly classified into those which are selective antagonists of D2 receptors, those that are D2 and D3 receptor antagonists, those blocking both D and D2 receptors and, a most important group of novel neuroleptics, those that are antagonists of 5-HT2 and D2 receptors. 

Action of neuroleptics on different types of neurotransmitter receptor relevance to side effects... 

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