Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)).

GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.

Centrally acting alpha 1-adrenoceptor agonists based on hexahydronaphth[2,3-b]-1,4-oxazines and octahydrobenzo[g]quinolines.

Centrally acting alpha 1-agonists may be of therapeutic value in dementias and other CNS disorders characterized by symptoms of noradrenergic insufficiency. Therefore, on the basis of known peripherally acting alpha 1-agonists two new groups of centrally acting alpha 1-agonists with improved lipophilicity, the hexahydronaphth[2,3-b]-1,4-oxazines type A and the octahydrobenzo[g]quinolines type B were designed. The N-methylated derivatives 14 and 33 demonstrate potent, direct agonistic activity at postjunctional alpha 1-receptors. Ring substituent alterations in compounds of type A and B change the potency of compounds on the rabbit ear artery by over 3 orders of magnitude (pD2 = 5.35-8.40). The efficacy of these compounds varies from 42 to 110%. Those alpha 1-agonists which were selective in the pithed rat increase vigilance in rats. Compound 14 was found to be a centrally acting alpha 1-agonist with good tolerability in different animal species and in healthy volunteers. Furthermore, 14 selectively stimulates the breakdown of phosphatidylinositol in rat cerebral cortex slices. In vivo, the compound reverses behavioral deficits in animals which received noradrenergic lesions following DDC or DPS4 treatment. Oxazine 14 and its close derivatives are by far more lipophilic than commonly known alpha 1-agonists. This is demonstrated in a ClogP-PROBIS plot.

Cognitive slowing in Parkinson's disease fails to respond to levodopa treatment: the 15-objects test.

To evaluate clinically the slowing of cognitive processing in Parkinson's disease, we used a visual discrimination task consisting of 15 superimposed images of objects. The time needed to identify 12 objects increased by 58% in 70 patients withdrawn from levodopa treatment compared with 20 controls matched for age and education. Perceptual, motor, and psycholinguistic factors, as well as mood, only partially accounted for the slowness of performance. The 15-objects test scores of the parkinsonian patients correlated significantly with both their intellectual impairment and the severity of their parkinsonian disability, but not with the duration of the disease. The scores did not correlate with depression. Levodopa had no effect on the score, although the parkinsonian motor disability score was improved by 54%. The results indicate a cognitive slowing in Parkinson's disease which is probably related to abnormalities of nondopaminergic neuronal systems in the brain.

Dopamine D1- and D2-receptor interaction in turning behaviour induced by dopamine agonists in 6-hydroxydopamine-lesioned rats.

The selective dopamine D2-antagonist sulpiride potentiated contralateral circling behaviour induced by the D1-agonist CY 208-243 in rats with unilateral lesions of substantia nigra, but reduced the effects of the selective D2-agonist bromocriptine. Similarly, the D1-antagonist SCH 23390 tended to increase the effects of bromocriptine but markedly inhibited CY 208-243 induced turning. The mixed D1/D2-antagonist fluphenazine was effective in reducing circling behaviour induced by either agonist, whereas pimozide (D1/D2) inhibited only the actions of bromocriptine. These results indicate that the actions of CY 208-243 and bromocriptine are mediated via distinct but interacting receptor subtypes.

A new semisynthetic ergot peptide alkaloid: DCN 203-922.

We report the synthesis, stereochemistry and preliminary pharmacological evaluation of DCN 203-922, a novel ergot alkaloid of the cyclol type, which contains in its peptide moiety the uncommon amino acid L-allo-isoleucine.

Biochemical, behavioural, and endocrine effects of CK 204-933, a novel 8 beta-ergolene.

CK 204-933 displaces [3H]dopamine and [3H]spiperone with high affinity from D-1 and D-2 recognition sites in membranes of calf caudate. Results from functional in vitro tests suggest that it is a partial agonist at D-1 receptors and an antagonist at D-2 receptors. These opposite effects at dopamine receptor subtypes are also expressed in vivo. For instance, in 6-hydroxydopamine lesioned rats, CK 204-933 induces contralateral rotations which are antagonised by SCH 23390 but not by sulpiride. On the other hand, CK 204-933 induces a long lasting increase of dopamine turnover in rat striatum and antagonises apomorphine-induced gnawing behaviour in rats. CK 204-933 increases prolactin serum levels in rats after subcutaneous administration, whereas after oral administration a moderate decrease of prolactin serum levels was seen. The latter effect is probably due to the formation of active metabolites. CK 204-933 exhibits also a high affinity to [3H]prazosin binding sites and antagonises serotonin-mediated stimulation of adenylate cyclase in rat hippocampus. On the other hand, CK 204-933 has no effect of only very weak effects on noradrenaline and serotonin release from rat cerebral cortex slices, which is consistent with its weak effects on noradrenaline- and serotonin-turnover in rat brain. Based on these properties it is suggested that CK 204-933 could be of therapeutic value in brain diseases associated with disturbances of monoaminergic neurotransmission.

Structure-activity relationships of dopaminergic 5-hydroxy-2-aminotetralin derivatives with functionalized N-alkyl substituents.

5-Hydroxy-2-aminotetralin derivatives in which one N-alkyl substituent carries a functional group have been prepared and their dopaminergic activities compared with those of 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) and known ergolines. Several members of the series demonstrated high affinities in dopamine (DA) receptor binding and DA agonist properties in the rotational behavior model in the range of known potent ergolines. The results suggest that the accessory binding site for the larger N-alkyl substituent of the 5-hydroxy-2-aminotetralins can accommodate various neutral and bulky functionalities and is probably identical with the site(s) to which the 8-substituents of the ergolines bind.

Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist.

The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by gamma-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for 3H-dopamine and 3H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs.

Effects of Hydergine and its components on Lashley maze acquisition in rats.

Rats were trained in 4 consecutive trials to obtain a liquid reward in a labyrinth system. Drugs were given s.c. 2-4 hours before each trial, and starting time (ST), running time (RT) and number of errors (NE) were recorded on the fourth trial. Hydergine reduced NE independently of its effect on ST and RT. Dihydroergocristine and dihydroergocornine prolonged ST, dihydro-alpha-ergokryptine reduced NE whilst dihydro-beta-ergokryptine did not induce any significant effect on the three parameters. These results demonstrated that none of the Hydergine components exerts a similar effect to that of Hydergine in this model. It is also known that Hydergine influences neurotransmitters like serotonin, dopamine, noradrenaline and acetylcholine in vivo and in vitro. Therefore, the effects of Hydergine on cognitive functions in rats appear to be the consequence of its different actions on the cerebral transmission.

[Involvement of serotoninergic mechanisms in the circling behaviour induced by apomorphine and LSD 25 in rats (author's transl)]. / Implications de mécanismes sérotoninergiques dans le comportement de rotations induit par le LSD 25 et l'apomorphine chez le rat.

Studies with selective lesions of cerebral structures have revealed the involvement of serotonin in sleep and wakefulness. However, the mechanisms underlying the role of serotonin remain obscure. An appreciation of the interrelationships between serotonin and other transmitter systems might lead to a better understanding of the functions subserved by serotonin. A serotoninergic projection from the median raphé nucleus to dopamine neurons in the substantia nigra has been reported. We have therefore investigated the possible influence of the raphé system on the nigro striatal dopamine pathway in the rat using the "turning" model described by UNGERSTEDT (1971). An unilateral lesion in the median raphé nucleus induces contralateral turning similar to that observed following apomorphine administration to rats with a unilaterally degenerated nigro striatal pathway. Similarly, unilateral application of 2.5 micrograms of LSD 25 to the median raphé nucleus of normal rats also provokes contralateral turning. On the other hand, unilateral injection of LSD 25 into the zona compacta of the substantia nigra induces turning ipsilateral to the site of injection. The above results, and also those from several experiments in which apomorphine or LSD 25 was applied systematically, suggest that serotonin neurons in the median raphé nucleus exert an inhibitory influence on the dopaminergic nigro striatal system. These studies demonstrate that the serotoninergic median raphé system, in addition to its involvement in sleep and wakefulness, also exerts an important influence on motor functions.

Central dopamine receptors.

Experimental results with various dopaminomimetic drugs, in particular ergot derivatives, imply the existence in the brain of various subgroups of dopamine (DA) receptors with differing properties. This review focuses on the prolactin cell and on different types of DA receptors in the nigro-striatal system. Some of the apparent complexity of central DA receptors may be due to the particular experimental approaches used (behavioural, biochemical, biophysical) which reveal different functional aspects of the action of DA. Central DA receptors are seen not as a static component of the brain, but their numbers may vary and the functional results of their stimulation may depend on regulatory factors.

Ergot alkaloids. New ergolines as selective dopaminergic stimulants.

A new two-step sequence for the epimerization of methyl dihydrolysergate (5) at C-8 leading to methyl dihydroisolysergate (7) is presented. The latter compound was used as a starting material for the synthesis of various ergolines, of which (5R,8R,10R)-8-(cyanomethyl)-6-methylergoline (4) is a very strong and long-lasting central dopaminergic agent. Furthermore, it was found that some 8-(arylthiomethyl)-6-methyler-golenes are not able to induce apomorphine-like stereotyped behavior in normal rats but exhibit a remarkable activity in rats unilaterally lesioned by 6-OH-DA in the nigrostriatal region. Compound 4 and (5R,8R)-8-[(2-pyridyl)thiomethyl]-6-methylergolene (9) were further tested for their ability to inhibit ovum implantation and to depress serum prolactin levels in rats. Their potency was evaluated in comparison with (5R,8S,10R)-8-(cyanomethyl)-6-methylergolines (2a and 2b) and 2-bromo-alpha-ergocryptine (1) as standards.

Inhibition of reserpine-induced PGO waves in the cat by ergot derivatives.

The number of reserpine-induced PGO waves in the cat is decreased by administration of ergot derivatives. The inhibition is dose-dependent and the various ergot derivatives show differing potencies. The action of the ergot derivatives may result from stimulation of central serotonin receptors. In addition, possible involvement of dopaminergic systems is discussed.

Neurochemical and neuropharmacological investigations with four ergot derivatives: bromocriptine, dihydroergotoxine, CF 25-397 and CM 29-712.

Neurochemical and neuropharmacological investigations with four ergot derivatives reveal differential pharmacodynamic effects of these compounds. Bromocriptine and CM 29-712 showed actions typical of postsynaptic dopamine receptor stimulants, in particular in the extrapyramidal system. CM 29-712 proved to be more potent than bromocriptine, with an early onset of action. CF 25-397 and dihydroergotoxine, while not showing all actions typical of central dopamine agonists, appeared to exert some of their effects by means of a stimulation of central serotoninergic sites. In the rat sleep-wakefulness cycles and in reserpine-induced ponto-geniculooccipital waves in the cat, they mimicked the effects of 5-hydroxytryptophan. In the latter test, CF 25-397 proved to be particularly potent. In addition, bromocriptine, dihydroergotoxine and CM 29-712 showed neurochemical effects consistent with central alpha-adrenergic blockade or an enhanced impulse flow in central noradrenergic neurons.