Neurotransmitter atypical

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

There are, of course, several other theories as to how the atypical antipsychotics work. These focus on other neurotransmitters, including the neuropeptide neurotensin and the amino acid glutamate, and on a variety of other complex receptor activities. In the final analysis, we are still not sure just what makes the atypical antipsychotics work so well, but we are glad that they do. 

Probably the greatest advances in psychiatric medications of the last 15 years have involved the neurotransmitter serotonin. First was the arrival of serotonin-specific antidepressants with fewer side effects and greater safety than their predecessors. More recently, atypical antipsychotics have highlighted the importance of serotonin-dopamine interactions in the optimal treatment of schizophrenia and other psychotic disorders. While these are indeed significant advances, medications that alter serotonin activity are not without their own side effect burden. 

Examples of monoamine oxidase inhibitors are phenelzine, tranylcypromine, isocarboxazid and mo-clobemide. They are indicated for atypical depression. Changes in the neurotransmitter levels are seen in several days but the clinical effect may lag by several weeks. Phenelzine is a non-selective hydrazine-type monoamine oxidase inhibitor while the also non-selective inhibitor tranylcypromine is of the non-hydrazine-type. Phenelzine, tranylcypromine and isocarboxazid are irreversible inhibitors. Phenelzine is partly metabolized by acetylation and slow acetylators are more prone to toxicity. It has anxiolytic properties and superior efficiacy in treating severe anxiety. 

Popoli M, Zanotti S, RadaeUi R, Gaggianesi C, Verona M, Brunello N, Racagni G (1997b) The neurotransmitter release machinery as a site of action for psychotropic drugs effect of typical and atypical antidepressants. Soc Neurosci Abstr 2325 Prast H, Philippu A (2001) Nitric oxide as modulator of neuronal function. Prog Neurobiol 64 51-68... 

Nitric oxide (NO) and carbon monoxide are atypical neurotransmitters. They are not stored in synaptic vesicles, are not released in by exocytosis, and do not act at postsynaptic membrane receptor proteins. NO is generated in a single step from the amino acid arginine through the action of the NO synthase (NOS). The form of NOS initially purified was designated nNOS (neuronal NOS), the macrophage form is termed inducible NOS (iNOS), and the endothelial from is called eNOS. 

Atypical antidepressants such as Wellbutrin simultaneously target the neurotransmitters dopamine and norepinephrine. 

Synaptic communication between neurons does not only involve the classical neurotransmitter systems reviewed in this chapter. Two other classes of neurotransmitters are also known to affect brain function neuropeptides and atypical neurotransmitters, such as nitric oxide and carbon monoxide. These neurotransmitters are not stored in vesicles, are not released by exocytosis, and do not bind to postsynaptic receptors. We have chosen not to review these neurotransmitters here, since they do not yet have implications for the current practice of neuropsychopharmacology. They are, however, promising targets for the development of new treatment strategies, and the interested reader is referred to other articles for review (Hokfelt, 1991 Snyder and Ferris, 2000). 

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). 

Current research is directed toward discovering atypical antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or have effects on central neurotransmitter receptors—such as those for acetylcholine and excitatory amino acids—that have been proposed as new targets for antipsychotic action. 

L-type calcium channels are the primary trigger for excitation-contraction (EC) coupling in cardiac, skeletal, and smooth muscles (Bean, 1989). They are also found in most central and peripheral neurons where they in part control calcium-dependent gene expression, as well as in endocrine cells and many types of non-excitable cells where they contribute to a variety of processes including exocytotic release. Unlike most synapses in the brain and spinal cord that rely on P/Q- and N-type calcium channels for neurotransmitter release, (Wheeler et al., 1994), the presynaptic terminals in photoreceptor cells rely on the Cav1.4 (a1F) L-type calcium channel for mediating glutamate release (Tachibana et al., 1993 Nachman-Clewner et al., 1999). Photoreceptor neurotransmission is atypical first,... 

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 ... 

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. 

Cl dependence has been chiefly associated with amino acids which are not typical amino acids. These include taurine, -alanine, y-amino butyric acid (GABA), and betaine (Schon and Kelly, 1975 Kanner, 1978 Chesney, 1985 Turner, 1986 Kanner and Bendahan, 1990 Tiruppathi et al., 1992 Yamauchi et al., 1992). To a significant extent, some of these atypical amino acids (as well as glycine) are also neurotransmitters, although NaCl-coupled cotransport of these atypical amino acids also occurs outside the nervous system. The specificity for chloride is high. Of the anions tested (Cl-, Br-, I-, NO3, and glucuronate) as replacements, only sulphate has proved an effective substitute in a nominal way (25-50% of the activity in chloride see Turner, 1986). 

Much is also made of the observation that the newer atypical neuroleptics impact on a greater variety of neurotransmitter systems than the older ones (e.g., Lieberman et al., 2005b). However, there is no reason to suspect that impacting on multiple neurotransmitter systems would improve either safety or efficacy. To the contrary, it would seem bound to increase the spectrum of adverse effects. But even in regard to their impact on multiple neurotransmitter systems, the atypicals are not unique. All of the older neuroleptics affect at least three neurotransmitter systems, such as serotonin and histamine, and several affect four or five of them. For example, old-fashioned thioridazine (Mellaril) impacts at least five neurotransmitter systems. 

These selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and, most recently, escitalopram (Lexapro see the appendix). These drugs block the removal of the neurotransmitter serotonin from the synaptic cleft. A number of other antidepressants are potent nonselective serotonin reuptake inhibitors (NSRIs). These include the atypical venlafaxine (Effexor) and the tricyclic clomipramine (Anafra-nil). Nefazodone (Serzone) has been withdrawn from the market due to liver damage. 

The pharmacology, efficacy, and safety of quetiapine, an atypical neuroleptic drug, have been extensively reviewed (1). Quetiapine interacts with a broad range of neurotransmitter receptors and has a higher affinity for serotonin... 

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