PubMed Health⌕ Search

Biomedical subjects

P Worms

Publications and source records attributed to P Worms.

At least 37 records · Page 2Linked to original sources
PubMed1986

Evidence for dopaminomimetic effect of intrastriatally injected cholecystokinin octapeptide in mice.

The behavioural effect of intrastriatally injected cholecystokinin sulphated octapeptide (CCK-8S), and its interactions with the antagonists Z-CCK-(27-32)NH2 and proglumide, were investigated in mice. When injected into the right striatum, CCK-8S (0.05-1 ng) induced contralateral rotations, as did the dopamine agonist apomorphine. Non-sulphated CCK-8 was inactive and sulphated desamino-CCK-7 was only weakly active in this respect. CCK-8S-induced turning was antagonized by co-injected Z-CCK-(27-32)NH2 (0.01-10 ng) or proglumide (0.1-1 micrograms), as well as by intraperitoneal injection of the neuroleptic drug haloperidol. These data suggest that CCK-8S may, in these conditions, stimulate dopamine-mediated neurotransmission, and that Z-CCK-(27-32)NH2, in addition to its peripheral effect, is also a very potent CCK antagonist at the striatal level.

Animals↗
PubMed1986

Dopamine-like activities of an aminopyridazine derivative, CM 30366: a behavioural study.

The behavioural effects of CM 30366, an aminopyridazine derivative, on dopamine-mediated neurotransmissions, have been studied in mice and rats. CM 30366 induced stereotyped behaviour and antagonized haloperidol-induced catalepsy in rats, after parenteral and oral administration. In 6-hydroxy dopamine (6-OHDA)-lesioned mice, CM 30366 induced contralateral rotations and, when injected before 6-OHDA, protected mice against its neurotoxicity. CM 30366 also provoked contralateral rotations when injected directly into the mouse right striatum. After parenteral injection, CM 30366 slightly increased motility in mice, at least at low doses. The stereotypies and rotations (after intrastriatal injection) induced by CM 30366 were antagonized by haloperidol, alpha-methyl-p-tyrosine and reserpine. The effects of CM 30366 were compared to those of direct and indirect dopamine-like drugs. Bromocriptine induced a behavioural profile, which in most aspects, was qualitatively and quantitatively similar to that of CM 30366. Apomorphine was found slightly more potent than CM 30366, but in contrast to the latter, apomorphine-induced stereotypies were insensitive to alpha-methyl-p-tyrosine or reserpine. (+)-Amphetamine and nomifensine were less potent than CM 30366, and unlike CM 30366, induced ipsilateral rotations in 6-OHDA-lesioned mice. These results indicate that CM 30366 is a potent atypical dopamine-like drug of potential therapeutic usefulness.

Animals↗
PubMed1985

The effect of different types of cortical lesions on drug-induced catalepsy in rats: a pharmacological analysis.

The effect of bilateral lesions of various cortical areas on neuroleptic- and non-neuroleptic-induced catalepsy was studied in the rat. Ablation of the frontal or parietal cortex led to a marked decrease in haloperidol catalepsy, whereas lesions of the occipital cortex, or of the olfactory bulbs did not affect catalepsy, when measured 3 weeks post lesion in all cases. The frontal cortex lesions also diminished the cataleptic state induced by cis-flupenthixol, (+)-butaclamol and chlorpromazine, but failed to affect that induced by reserpine, tetrabenazine or morphine. Four months after the frontal lesions, haloperidol catalepsy was at control values, and a rebound phenomenon was observed at 10 months post lesion. The homeostatic mechanisms seem to have stabilized at 18 months post lesion when haloperidol catalepsy had returned to control levels.

Animals↗
PubMed1985

Minaprine, a new drug with antidepressant properties.

Minaprine is a new psychotropic drug which has recently proved to be effective in the treatment of various depressive states. In rodents, minaprine exhibits an atypical spectrum of antidepressant and dopaminomimetic activities. Thus in mice minaprine antagonizes the effects of reserpine, decreases immobility time in the behavioural despair test and potentiates the effects of 5-HTP; in rats it antagonizes muricidal behaviour (blocked by PCPA or raphectomy). However, minaprine does not affect yohimbine lethality and does not induce anticholinergic effects in mice. Minaprine also activates central dopaminergic transmission. Thus at low doses the drug antagonizes neuroleptic-induced catalepsy and induces stereotypies in rats. These stereotypies are blocked by neuroleptics. In addition, minaprine (like apomorphine) induces contralateral turning in mice with a unilateral lesion of the striatum, whereas d-amphetamine induces ipsilateral rotations. Unlike classical dopaminomimetic drugs, minaprine does not stimulate locomotor activity in rats. The mechanisms by which minaprine exerts its effects are still unclear, since in vitro minaprine does not affect monoamine uptake or release and does not interact with monoamine receptors. In vivo, minaprine (acute doses) increases 5-HT, decreases 5-HIAA levels in various brain areas and weakly and reversibly inhibits type A MAO; subacute treatments lead to a decrease in the number of 5-HT1 and 5-HT2 receptors. In addition, in the striatum the drug decreases HVA and DOPAC, and increases 3-MT levels, without affecting DA levels. Minaprine also weakly displaces (3H)-spiperone from striatal D2 receptors and increases striatal ACh levels. Finally, minaprine fails to affect brain NA or MHPG levels in acute doses and does not modify beta receptor density in subacute treatment. Thus minaprine appears to be a chemically and pharmacologically original antidepressant drug which activates both 5-HT- and DA-mediated transmission but which is devoid of NAergic and anticholinergic effects. This latter statement is confirmed by the good cardiovascular tolerance of minaprine in dog, monkey and humans, and by the lack of "tricyclic-like" anticholinergic side-effects in man.

Acetylcholine↗
PubMed1983

The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials.

Progabide, a new antiepileptic GABA agonist of moderate affinity for GABA receptors, has been studied in a number of psychiatric disorders and the results compared with the action of this drug in animal models. In an animal model for anxiety (the aversive response to periaqueductal grey stimulation in the rat) progabide had a similar action to that of diazepam. However in clinical trials to date the effect of the GABA agonist was inferior to that of benzodiazepines. As progabide diminishes both the nigrostriatal dopamine neuron activity and the effects of striatal dopamine receptor activation, a trial in schizophrenic patients was undertaken. Progabide was devoid of any evident antipsychotic action. However a certain improvement in responsiveness to the environment and in social interactions was noticed in hebephrenic and schizoaffective syndromes. This lack of antipsychotic effect of progabide may be a reflection of the weak activity of GABA agonists on limbic dopamine neurons. In these various clinical trials a definite improvement of affect and mood was noted in those patients receiving progabide. In clinical trials in depressed patients progabide produces a significant reduction in depressive symptoms, an action similar to that of imipramine both for the global clinical rating and the HRSD. This antidepressant activity is reflected by the action of progabide in behavioural models of depression such as olfactory bulbectomy, learned helplessness and the sleep-wake cycle.

Adjustment Disorders↗
PubMed1983

Enhanced effect of haloperidol and apomorphine after hypophysectomy: pharmacokinetic considerations.

The behavioural effects of both apomorphine (stereotypies) and haloperidol (catalepsy and reversal of stereotypies) were significantly enhanced in hypophysectomized rats compared with sham-operated rats. Both the efficacy and duration of action were increased Hypophysectomized animals had significantly greater brain haloperidol concentrations than did sham-operated animals. The data suggest that changes in brain drug concentrations following hypophysectomy at least partially explain the behavioural alterations seen in this test situation.

Animals↗
PubMed1983

Neurochemical and neuropharmacological indications for the involvement of GABA and glycine receptors in neuropsychiatric disorders.

From binding studies using 3H-GABA and 3H-strychnine in dissected human brain material, inhibitory amino acid neurotransmitter receptors have a widespread distribution in the human CNS. Generally GABA receptors are predominant in the forebrain and upper brainstem whereas glycine receptors are more localized in the lower brainstem and spinal cord. Some areas (eg. the substantia nigra) have appreciable quantities of both receptors. Although glycine receptors are altered in some pathological conditions (eg. in Parkinson's disease, in the substantia nigra) the neuropharmacology of the glycine system is still poorly understood. On the other hand the GABA system has been intensively studied. Dysfunction of GABA receptors occurs in various neurological states, as epilepsy, Parkinson's disease and Huntington's chorea. Furthermore GABA agonists are active in animal models for dyskinesia, epilepsy and depression, amongst others. Clinical studies with progabide confirm these findings in animal models, and suggest that low-medium affinity GABA agonists are more appropriate clinical agents than are high or very high affinity GABA agonists. From these and many other findings there appears to be a very large potential for creating new pharmacological agents for different neuropsychiatric disorders based on agonist activity at inhibitory amino-acid receptors. From the example of progabide these compounds can be made not only specific for the receptor involved, but also to have a lower incidence of neurotoxic effects than presently available drugs.

Central Nervous System↗
PubMed1983

Pharmacological and therapeutic actions of GABA receptor agonists.

GABA receptor agonists, e.g. progabide, modify the activity of several brain neuronal systems which are implicated in the pathogenesis of some neuropsychiatric disorders. Thus, alterations in noradrenergic and serotoninergic transmissions induced by progabide may be a mechanism involved in the antidepressant action of this drug in the clinic. The antagonism of the neuroleptic-induced increase in dopamine receptor sensitivity and the decrease in dopamine synthesis and release may be responsible for the effectiveness of the GABA receptor agonists in the treatment of neuroleptic- and L-DOPA-induced dyskinesia. This action of GABA receptor agonists also suggests their therapeutic potential in mania. Finally, decrease in cellular excitability induced by GABA receptor agonists, e.g. progabide, accounts for their efficacy in epilepsy.

Bipolar Disorder↗
PubMed1983

Indications for the use of gamma-aminobutyric acid (GABA)-agonists in convulsant disorders.

From studies using pharmacological models of convulsive disorders and also from the neurochemical analysis of epileptogenic tissue removed during neurosurgical resection (cortectomy), there is strong evidence that at least a subgroup of epileptic disorders may be linked (among other things) to a deficit in GABAergic neurotransmissions. This deficit may be found at the level of GABA synthesis or at the GABA-recognition site; whether these GABA neurons are lost or are dysfunctional is not yet answered. This suggests that GABA-agonists will be of potential use in epilepsy. GABA-agonists (progabide, SL 75102, muscimol, THIP) for the classical GABA-recognition sites as well as other compounds active at sites in the GABA-receptor macromolecular complex (eg, diazepam and phenobarbital) exhibit a wide range of anticonvulsant effects in different animal models and species. However, for some of these compounds (eg, muscimol) secondary central effects occur at the same dose level as the anticonvulsant actions, and for others (eg, THIP) such secondary effects may limit the use to certain types of seizures. This problem may be related to the high affinity of such compounds for the GABA recognition site as compounds with a more moderate affinity (eg, progabide, SL 75102) have a wider margin between anticonvulsant and secondary central effects in rodents. Clinical results using progabide suggests that the GABA hypothesis of convulsive disorders has indeed a rational foundation as a significant percent of refractory or unresponsive epileptic patients with different types of seizures (eg, complex partial or primary generalized) have a significant clinical improvement with this GABA-agonist.

Animals↗
PubMed1982

Cortical modulation of striatal function.

The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decarboxylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decarboxylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [3H]acetylcholine release in striatal slices preloaded with [3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which--in behavioral terms--is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decarboxylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Action of progabide in the photosensitive baboon, Papio papio.

Progabide is a GABA agonist which is nontoxic and crosses the blood-brain barrier. Progabide was tested in naturally and allylglycine-induced photosensitive baboons (Papio papio). Intravenous injection of various doses (30 to 100 mg/kg) of progabide induced a protective effect against intermittent light stimulation (25 Hz) in both test situations. This protection lasted 10 to 120 min. This duration was dose-dependent and was generally shorter in allylglycine-treated than in naturally photosensitive baboons. At all doses, progabide reinforced rhythmic activities in the frontorolandic and occipital regions. At doses greater than 50 mg/kg, progabide produced a mild sedation with somnolence and myorelaxation, all effects which could be reversed by sensory stimulation. These data confirm the anticonvulsant properties of progabide in another animal model.

Allylglycine↗
PubMed1982

gamma-Aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra.

Progabide (4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)-methylene]amino) butanamide) is a gamma-aminobutyric acid (GABA) receptor agonist which readily enters the brain. In the body, progabide is metabolized to three active metabolites: SL 75102, gabamide and GABA. Progabide and SL 75102 readily enter the brain and GABA and gabamide are also formed within this organ. Both progabide and SL 75102 exhibit a broad spectrum of anticonvulsant activities against seizures which involve GABA-mediated events (bicuculline, picrotoxinin and pentylenetetrazol) or which are apparently independent of GABAergic mechanisms (penicillin, strychnine, electroshock and audiogenic seizures). These data support the hypothesis that direct GABA receptor stimulation is an effective means of controlling convulsions of various origins. Progabide and SL 75102 have relatively minor secondary effects in comparison to commonly used antiepileptics. Myorelaxation occurs, but only at doses higher than the ED50 values in convulsant tests. Furthermore, these compounds are not sedative. Finally, these GABA agonists have a complex action in the extrapyramidal system. Anticonvulsant doses are antagonistic to dopamine receptor-mediated behaviors, whereas much lower doses seem to facilitate the effects of dopaminergic transmission.

Animals↗
PubMed1981

Neuropharmacological actions of GABA agonists: predictability for their clinical usefulness.

From the data presented and the clinical studies reviewed, it would appear that the tests presently used to forecast the clinical effects of GABA agonists are rather accurate in their predictability. Thus, these tests are positive for antiepileptic, antispastic and antidyskinetic potential; they are negative for schizophrenia and are at best equivocal for Huntington's disease. This is parallelled in a surprisingly close matter by the antidyskinetic, anticonvulsant and antispastic effects of at least one GABA agonist (progabide) in preliminary clinical testing. It is concluded the non-toxic GABA agonists will be useful in a variety of neurological disorders without precipatating incapacitating side effects.

Antipsychotic Agents↗