Pharmacology

There is abundant evidence that dopamine plays a key role in the aetiology of psychosis and the action of antipsychotic drugs. Studies with drugs such as amphetamine and methamphetamine that exacerbate delusions and hallucinations in schizophrenics, and can produce them with chronic administration in non-schizophrenics as well, have established the importance of dopamine in their aetiology. Stimulation of a subgroup of dopamine receptors, the D 2 receptors, which are negatively coupled to the second messenger adenyl cyclase in the mesolimbic system is a key factor in the aetiology of psychotic symptoms. (1 29) The mesolimbic dopamine neurones reside in the ventral tegmentum, the so-called A10 area, and have terminals in the nucleus accumbens, stria terminalis, and olfactory tubercle. The outflow of these regions to the thalamus and the cortex is believed to mediate psychotic symptoms. The firing rate of the mesolimbic dopaminergic neurones are subject to multiple influences, including serotonergic input from the median raphe. (21) The antipsychotic action of the atypical antipsychotic drugs is highly correlated with their affinities for D2 receptors.(19) The origin of the dopamine neurones that terminate on cholinergic neurones in the basal ganglia is the substantia nigra, the so-called A9 region.(l9) Blockade of striatal D2 receptors leads to the extrapyramidal side-effects produced by antipsychotic agents. A group of ventral tegmental dopamine neurones project to various regions of the cortex and comprise the mesocortical dopamine system. There is extensive evidence that these neurones are important for cognition, especially working memory.(22) The prefrontal cortex has relatively low concentrations of D 2 receptors and has a higher density of D3 and D4 dopamine receptors.(20) Despite this, drugs which selectively block D4 receptors have not been found to have an antipsychotic effect.(23) There are no relevant clinical data yet on the antipsychotic action of drugs which are selective for the D 3 receptor. Both agonists and antagonists of D3 receptors are of potential interest as antipsychotic agents. Neuroleptic drugs occupy 80 to 95 per cent of striatal D 2 receptors in patients with schizophrenia at clinically effective doses, with extrapyramidal side-effects occurring above 80 per cent occupancy of these receptors. (24) Blockade of D2 receptors in the anterior pituitary gland is the basis for their ability to stimulate prolactin secretion.(!Z)

The typical antipsychotic drugs vary in their in vitro and in vivc affinities for receptors such as the dopamine D1, histamine H^ muscarinic, a^-adrenergic, and serotonergic receptors, which modulate their effects on arousal, extrapyramidal, cognitive, cardiovascular, gastrointestinal, and genitourinary function. Thioridazine is a relatively potent antimuscarinic agent. Most of the low-potency antipsychotic agents are potent a 1 and H antagonists. The specific receptor profile of each atypical antipsychotic is of special interest because it may account for the difference among these compounds. Clozapine has high affinities for the 5-HT 2A, 5-HT2C, 5-HT6,

5-HTZ, a1, muscarinic, and H1 receptors.(2 ,26) Risperidone has high affinities for the 5-HT2A, 5-HT3, D2, D3, D4, H1, a1, and a2 receptors, and weak affinities for the 5-HT2C, 5-HT6, and muscarinic receptors.(2,26> Olanzapine has high affinities for the 5-HT2A, 5-HT2C, D1, D2, D4, a1, H1, and M1 and M2 muscarinic receptors. It is also a potent 5-HT6 and a weak 5-HTZ antagonist/2,26) Quetiapine has weaker affinities for receptors than the other atypical antipsychotic but among those receptors for which it has its highest affinities are the 5-HT2A, 5-HTZ, D2, 5-HT 1A, and a1. It is a weak 5-HT2C and 5-HT6 antagonist.( , ) Ziprasidone has high affinities for the 5-HT2A, 5-HT2C, 5-HT1, 5-HT6, 5-HTz, D2, D3, a1, and H1 receptors and moderate affinity for the D1 receptor.(25,2Z> Ziprasidone is also a partial agonist at the 5-HT 1A receptors.(27> Iloperidone has a high affinity for the 5-HT2A, 5-HT6, 5-HTZ, D2, D3, D4, a1, and H1 receptors. It is a relatively weak 5-HT2C antagonist.(9)

All of the above compounds are more potent 5-HT2A than D2 receptor antagonists. This is the most consistent way yet discovered to produce a separation between antipsychotic action and interference with motor function. This principle arose from examining the pharmacology of clozapine, the prototypical atypical antipsychotic drug, and a series of other antipsychotic compounds which had typical or atypical properties. (28> These studies suggested that the low potential for extrapyramidal side-effects of clozapine, olanzapine, quetiapine, risperidone, iloperidone, and ziprasidone are due, in part, to their 5-HT 2 antagonist and weak D2 antagonist properties. Several agents which have only 5-HT 2A-receptor blocking properties, and which lack D2-receptor antagonism are in testing at the current time, for example

SR43469B and M100907.(2!> They are active in animal models as antipsychotics. However, M10090Z was reported to be less effective than haloperidol, but more so than placebo, in treating acutely psychotic patients. There are no data on SR43469B as yet. It is likely that if such compounds are effective, they will require concomitant treatment with low doses of typical antipsychotics to block D2 receptors.

The atypical antipsychotic agents have the ability to increase prefrontal cortical dopaminergic activity compared with subcortical and cortical dopaminergic activity. (29> The ability to increase the release of dopamine in the prefrontal cortex may be important for atypical antipsychotic agents to improve cognition and negative symptoms. It may also contribute to decreasing the release of dopamine in the mesolimbic region, because prefrontal dopamine neurones modulate the activity of corticolimbic glutamatergic neurones that influence the release of dopamine from nerve terminals in the limbic region. (22) The atypical antipsychotics also increase the expression of the early intermediate gene c-fos, in the prefrontal cortex and the shell of the nucleus accumbens, while sparing the core of the latter region and the striatum. Typical neuroleptic drugs have the opposite effect on c- fos expression. Sparing the dorsal striatum is believed to be related to the low potential for extrapyramidal side-effects of these agents. (22I) Clozapine and some of the other atypical antipsychotic drugs also produces marked increases in prefrontal cortical acetylcholine efflux. (39 This may be related to their ability to improve cognitive function. All of the atypical agents also produce marked increase in noradrenaline efflux in the prefrontal cortex which is correlated in time and magnitude with the increase in extracellular dopamine. (31> The basis for and significance of this combined increase in dopamine and noradrenaline in the prefrontal region is unknown. Clozapine, olanzapine, risperidone, and quetiapine are able to block the interference in prepulse inhibition produced by D-amphetamine, apomorphine, or phencyclidine at doses that do not interfere with locomotor function. Clozapine and M10090Z, a highly selective 5-HT2A antagonist, are able to block the effects of phencyclidine, an M-methyl-D-aspartate receptor antagonist, on locomotor activity in rodents. This suggests the ability of rat 5-HT2A-receptor blockade to block some of the effects of phencyclidine which is one of the more important models for schizophrenia. (22!'

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Do Not Panic

Do Not Panic

This guide Don't Panic has tips and additional information on what you should do when you are experiencing an anxiety or panic attack. With so much going on in the world today with taking care of your family, working full time, dealing with office politics and other things, you could experience a serious meltdown. All of these things could at one point cause you to stress out and snap.

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