For the past 20 years the most enduring explanation for schizophrenia has been the dopamine hypothesis, which proposes that the dopaminergic system is overactive in this widespread disease. Classically, the D2 receptor formed the core of the dopamine hypothesis since there was considerable evidence for elevations of D2 receptor levels in the brains of schizophrenic patients, and because these receptors served as the primary target in mediating antipsychotic effects of most neuroleptics. However, the dopamine D4 receptor has recently received particular attention in this context. This is because the atypical antipsychotic, clozapine, which is effective in treating refractory schizophrenics without the side-effect profile of typical neuroleptics, displays a 10-fold higher affinity for D4 compared to D2 or D3 receptors. Furthermore, the concentration in plasma water of clinical doses ofclozapine correlates well with its in vitro binding affinity for D4, but not D2 or D3 receptors, suggesting that D4 is a potential target in mediating clozapine's antipsychotic effects. As well, marked elevations in the level of a D4-like site (not identical to the D4 receptor) has been seen in the striatum of postmortem schizophrenic brains, but not in control brains. Finally, the most interesting feature of the D4 receptor is perhaps the array of polymorphisms associated with it, creating structural diversity in this receptor that supercedes all other known catecholamine receptors. The existence of these D4 polymorphisms raises the possibility that structural variations of this receptor may be associated with an increased susceptibility to schizophrenia, or observed variations in individual response to clozapine treatment. However, several studies aimed at investigating these hypotheses could not establish a direct role of D4 in schizophrenia. Furthermore, no association was evident between the polymorphic forms of D4 and susceptibility to schizophrenia, or variable clozapine response. Nevertheless, investigations surrounding this receptor has been far from futile. The observations which support the idea that D4 might serve as a target for clozapine have significantly modified and extended our understanding of mechanisms underlying atypical antipsychotic treatment of schizophrenia, as well as the dopamine hypothesis for schizophrenia. Further characterization of this receptor may prove to be crucial in designing highly effective antipsychotic drugs with minimal contraindications.

Antipsychotic Agents↗

PubMedDate not supplied

Antispermatogenic effect of aspirin and its prevention by prostaglandin E2.

Aspirin treatment causes a decrease in Leydig cell function, change in Sertoli cell morphology and a subsequent decrease in Spermatid count. Administration of Prostaglandin E2 prevents the effect of Aspirin on the Sertoli cell morphology and Spermatid degeneration without significant improvement of the Leydig cell function. On the basis of these findings, a possible relationship between Prostaglandin and testicular spermatogenesis has been discussed.

Animals↗

PubMedDate not supplied

In vitro studies on histochemical localization of testicular delta5-3beta-hydroxysteroid dehydrogenase activity from indomethacin pretreated rats--effect of prostaglandins and luteinizing hormone.

In vitro studies on the effect of LH and prostaglandins on delta5 3beta-hydroxysteroid dehydrogenase activity using indomethacin pre-treated testis as the experimental model, revealed a greater stimulation of the enzyme activity when the incubation medium contained LH and PGE2 both at a concentration of 1 microgram/ml in comparison to the effect produced by 1 microgram LH/ml alone, but the augmentory effect of PGE2 on testicular response to LH was not evidenced as the LH: PGE2 ratio became 1 : 10. Neither PGE2 nor PGF2A produced any stimulation of the enzyme activity at concentrations of 1, 10, or 20 microgram/ml in the incubating medium. PGF2A at concentrations of 1 or 10 microgram/ml did not appear to interfere with LH action on this steroidogenic enzyme. On the contrary, prostaglandins, both PGE2 and PGF2A, at concentrations of 20 microgram/ml, antagonized LH action over testicular delta5-3beta-hydroxysteroid dehydrogenase activity. On the basis of these findings, it appears that prostaglandin E2 in some way, is necessary for manifestation of the steroidogenic action of LH in testis.

3-Hydroxysteroid Dehydrogenases↗

PubMedDate not supplied

Andrenogonadal interactions in nicotine-induced alteration of steroidogenesis in male rat.

Chronic nicotine administration in larger doses inhibits steroidogenesis in testis. This inhibition is possibly secondary to increased adrenomedullary norepinephrine activity, since the anti-steroidogenic effect of nicotine can be prevented by alpha-adrenergic blocker like phentolamine. In vitro incubation of testicular slices with nicotine failed to elicit any appreciable effect on delta 5-3 beta-hydroxysteroid dehydrogenase activity indicating lack of direct action of nicotine on testicular steroidogenesis.

3-Hydroxysteroid Dehydrogenases↗

PubMedDate not supplied

Possible alpha-adrenergic involvement in nicotine induced alteration of spermatogenesis in rat.

Nicotine caused a fall in primary spermatocyte number together with a retardation of spermatocyte to spermatid conversions process. These effects of nicotine were possibly secondary to increased activity of adrenomedullary catecholamines, since the antispermatogenic effect of nicotine was prevented by phentolamine, a known blocker of catecholamine action at the alpha-receptor level.

Animals↗

PubMedDate not supplied

Transpectoral anterior approach to the axilla for lymph node dissection in association with mastectomy preserving both pectoral muscles and their neurovascular bundles.

In Patey's mastectomy, which is still the most common operation for breast cancer, axillary node dissection (AND) is performed through the base of the axilla after retracting the pectoralis major muscle and excising the pectoralis minor muscle (some surgeons preserve the latter). This has the disadvantage of inadequate exposure of the axilla and the risk of damage to the neurovascular bundles supplying the pectoral muscles, which in the long run may lead to atrophy of these muscles. A transpectoral anterior approach to the axilla for AND in association with mastectomy was attempted in 115 cases to obviate the above-mentioned disadvantages. The approach included: 1) splitting of the pectoralis major between the clavicular and sternal fibers; 2) mobilization and swinging of the pectoralis minor into different directions by means of a sling to facilitate AND at selected levels. The major advantages of this approach were: 1) total preservation of both pectoral muscles with their neurovascular bundles maintained the normal anatomy and function of the shoulder; 2) the axilla was directly approached through the anterior wall instead of through the base; in this way the axillary contents were exposed almost at surface level; 3) the dissection plane could be limited to anterior to and below the axillary vein and the risk of postoperative lymphedema could thus be minimized; 4) change of position of the ipsilateral arm was not necessary; 5) the duration of surgery was reduced. Monoblock ablation of significant and suspected tissues, maintaining the normal anatomy and function of the shoulder, could be easily accomplished with this approach.

Adult↗

PubMedDate not supplied

Augmentation of luteinizing hormone action by prostaglandin E2 in the prevention of antispermatogenic effect of indomethacin. Indomethacin & spermatogenesis.

Administration of indomethacin exhibited antigonadal action by inhibiting the Leydig cells, sex-accessories and spermatocyte-spermatid conversion process. Administration of PGE2 or PGF2 alpha had no effect on Leydig cell nuclear volume or accessory organ weights, but PGE2 had a restorative effect on the efficiency of meiosis, although at a statistical non-significant level. Administration of LH to indomethacin treated rats restored the accessories fully with a non-significant effect on the yield of step-7 spermatids from meiosis. Simultaneous administration of indomethacin, LH and PGE2 (but not PGF2 alpha) restored both sex-accessories and spermatid number to the level of vehicle injected controls.

Animals↗