Katalin Horvath

Anxiolytic 2,3-benzodiazepines, their specific binding to the basal ganglia.

Over the past 20 years, several members of the 2,3-benzodiazepine family have been synthesized. Some of these compounds--tofisopam (Grandaxin), girisopam, nerisopam--exert significant anxiolytic and antipsychotic activities. Sites where actions of 2,3-benzodiazepines are mediated differ from those of 1,4-benzodiazepines. Binding of 2,3-benzodiazepines to neuronal cells in the central nervous system shows a unique and specific distribution pattern: their binding sites are located exclusively to the basal ganglia. Chemical lesioning of the striato-pallido-nigral system, surgical transections of the striato nigral pathway and the activation of c-fos expression in the basal ganglia after application of 2,3-benzodiazepines suggest that these compounds mainly bind to projecting neurons of the striatum. The binding sites are transported from the striatum to the substantia nigra and the entopeduncular nucleus. Recent studies on mechanism of action of 2,3-benzodiazepines indicate their possible role in opioid signal transduction since 2,3-benzodiazepines augment the agonist potency of morphine to induce catalepsy and analgesia, and their action is diminished in morphine tolerant animals. The possible biochemical target of 2,3-benzodiazepines is an alteration in the phosphorylation of protein(s) important in the signal transduction process. Agents affecting emotional responses evoked by endogenous opioids without danger of tolerance and dependence may represent a new therapeutic tool in the treatment of addiction and affective disorders.

Effect of adrenalectomy and dexamethasone treatment on prolactin secretion of lactating rats

The contribution of corticosteroids to the control of prolactin secretion in lactating rats was investigated. The prolactin response to domperidone (20 microg/kg b.w., i.v.), a dopamine receptor antagonist and to domperidone plus formalin stress was tested in adrenalectomized and/or dexamethasone-treated continuously nursing rats. Animals were adrenalectomized on the 3rd day of lactation and tested on the 7th day of lactation. Dexamethasone was injected s.c. 24 h before testing (400 microg/kg b.w.) and on the day of testing (200 microg/kg b.w.). Domperidone caused a significant rise in plasma prolactin levels. The prolactin response to domperidone was twice as high in solely adrenalectomized dams and in solely dexamethasone-treated rats compared to controls. In adrenalectomized animals treated with dexamethasone, the prolactin response to domperidone was like in controls. Formalin injection to either adrenalectomized plus domperidone-treated animals or to animals injected with dexamethasone plus domperidone, resulted in a statistically significant depletion of plasma prolactin. In controls and in adrenalectomized animals receiving dexamethasone and domperidone, the prolactin response to formalin was very similar, i.e., plasma prolactin levels did not change after the administration of formalin. The present findings suggest that in lactating rats, corticosteroids are involved in the prolactin response to domperidone and to formalin stress.

INHIBITION OF PROTEIN PHOSPHATASE 2A (PP2A) MIMICS SUCKLING-INDUCED SENSITIZATION OF MAMMOTROPES : INVOLVEMENT OF A PERTUSSIS TOXIN (PTX) SENSITIVE G- PROTEIN AND THE ADENYLATE CYCLASE (AC)

In lactating rats, suckling renders mammotropes more responsive to prolactin (PRL)-releasing stimuli and less responsive to PRL-inhibiting secretagogues. We have previously shown that a decrease in the activity of protein phosphatase 2A (PP2A) may be responsible for the decrease in responsiveness to the inhibitory secretagogue dopamine (DA). In our present experiments, we have studied the involvement of the adenylate cyclase (AC), stimulatory and inhibitory GTP-binding proteins and also the role of PP2A in the sensitization phenomenon. Pituitary cells obtained from mother rats separated from their pups for 4 h prior to dispersion (non-suckled), suckled for 10 or 30 min after the separation period (suckled) and without separation (continual suckling) were incubated in the presence of different doses of forskolin to activate AC and DA. In a further study, pituitary cells of non-suckled rats were pretreated with cholera toxin (CTX) or pertussis toxin (PTX) and tested for the stimulatory action of forskolin or TRH on PRL release. Ocadaic acid (OA) pretreatment has been used to investigate the involvement of PP2A. Hormone secretion was measured by the reverse hemolytic plaque assay (RHPA). Our results have shown that cells from non-suckled rats were unresponsive to forskolin. A 10-min suckling stimulus sensitizes pituitary mammotropes to respond with a PRL release to a dose-dependent activation of AC by forskolin. This sensitization of AC becomes a permanent feature of the cells when suckling continues for an additional 20 min. We have also found that pituitary mammotropes from non-suckled dams respond to forskolin or TRH with PRL release when they were preincubated with either PTX or the PP2A inhibitor OA. It clearly indicates that the non-responsive pituitary can be shifted to the responsive stage by uncoupling of inhibitory G-protein from its receptor as well as by inhibition of PP2A. This latter finding, consonant with our previous results, suggests that suckling may cause selective changes in the function of G(i) of mammotropes due to a rapid phosphorylation which can remove tonic, GTP-dependent inhibitory function.

A novel approach to the treatment of benign prostatic hyperplasia

To assess the clinical efficacy and safety of the combined α1‐ and postsynaptic α2‐blocker GYKI‐16084 compared to placebo during a 28‐day active treatment of patients with benign prostatic hyperplasia (BPH).

Suckling-induced increase in cyclic AMP exclusively in the central region of the rat adenohypophysis.

Investigating the cellular events in the pituitary gland, the intracellular cyclic AMP (cAMP) of the neural lobe (NL), intermediate lobe (IL), the inner (IZ-AL) and outer zone (OZ-AL) of the anterior lobe (AL) have been measured during the suckling stimulus. Ten-minutes suckling, parallel to the elevation of plasma PRL, induced a significant increase of cAMP concentration in the IZ-AL. In contrast, 10- and 30-min suckling resulted in a decrease of cAMP level in the NL. Changes in cAMP of the OZ-AL and the IL as well as in the plasma level of alpha-MSH could not be detected. These region-specific changes of cAMP in the pituitary gland during suckling stimulus seems to be related to interacting neuroendocrine signals delivered concomitantly from the hypothalamus and from the NIL to the IZ-AL.