The cholinergic system exerts an important modulatory effect on hippocampal functions. Presynaptic inhibition of hippocampal and neocortical acetylcholine (ACh) release by serotonin (5-HT) has been reported in both rat and human brain. There is some controversy, however, concerning the 5-HT receptor which mediates the inhibitory effects of 5-HT. Using slices of the hippocampal formation of rat prelabelled with [3HI-choline, superfused and depolarized electrically (2 rain, 3 Hz, 2 ms, 24 mA) or by K ÷ (20 raM) we observed that 5-HT inhibits hippocampal and entorhinal [3H]-overflow ([3H]-ACh release) by 5-HT~B receptors located on cholinergic terminals. However, this inhibition requires the functional elimination of substance P/7-aminobutyric acid (SP/ GABA) intemeurons which express 5-HTaA receptors as shown by in situ hybridisation histochemistry. Activation of these somadendritically located 5-HT2A receptors facilitates SP release. SP, in turn, stimulates hippocampal [3H]-ACh release through NKa receptors present on cholinergic terminals. These findings suggest close links between cholinergic afferents, SP interueurons and 5-HT2 receptors. A loss of cholinergic afferents and 5-HT2 receptors, along with a reduction in substance P-immunoreactive neurons, have been observed in the brains of patients suffering from Alzheimer's disease, suggesting the concept that these three alterations reflect a disruption of a functional unit. The present findings might help to explain early pathological changes in Alzheimer's disease.

The effects of various opioid receptor agonists and antagonists on evoked acetylcholine release were studied in slices of human neocortex prelabelled with [3H]-choline, superfused and depolarized electrically (2 rain, 3 Hz, 2 ms, 24 mA) or by K + (20 raM). The 6-opioid receptor agonist DPDPE and the K-opioid receptor agonist U50488 reduced the evoked [3H]-overflow (acetylcholine release) in a concentration-dependent fashion; the cLopioid receptor antagonist naltrindole and the the ~c-opioid receptor antagonist norbinaltorphimine, respectively, antagonized these effects. Application of the g-opioid receptor agonist DAGO also resulted in an inhibition of acetylcholine release; however, both 6-and tc-opioid receptor antagonists were able to block this effect. The g-opioid receptor agonists morphine and (+)-nortilidine had no effect. These results indicate that acetylcholine release in human neocortex is inhibited through ~-and K-opioid receptors, but not through g-opioid receptors.Acetylcholine release was significantly increased by the cLopioid receptor antagonist naltrindole in the presence of a mixture of peptidase inhibitors providing evidence for a cLopioid receptor-mediated inhibition of acetylcholine release by endogenous enkephalin.K+-evoked acetylcholine release in the presence of TTX was inhibited by U50488, but not by DPDPE, suggesting the presence of ~c-opioid receptors on cholinergic terminals and the localization of c~-receptors on cortical interneurons. Therefore, the potent effect of DPDPE on acetylcholine release is likely to be indirect, by modulation of intrinsic cortical neurons. These interneurons probably do T.J. Feuerstein ([5~) • O. Gleichauf -D. Peckys not use GABA as neurotransmitter since both GABAA and GABAB receptor agonists (muscimol and baclofen, respectively) were without effect on acetylcholine release.

Influence of dopamine-agonists on the pharmacokinetics and pharmacodynamics of levodopaBackground: Despite the broad clinical use of levodopa and dopamine-agonists and their well established clinical efficacy in parkinsonian patients, little is known about the exact pharmacodynamics of both substances and their pharmaeodynamic interactions. However, exact knowledge of pharmacodynarrdcs is essentially for the optimization of therapeutic regimens and maximal clinical efficacy especially in fluctuating patients.Methods: An oral single dose challenge using 100 mg levodopa 25 mg benserazide was performed under standardized conditions in 10 parkinsonian patients with clear-cut wearing-off fluctuations. A continuous s.c. infusion of apomorphine in a clinical subthreshold dosage was coadmimstered to the levodopa challenge under double blind conditions vs. NaC1 in each patient. Levodopa serum-concentrations (LSC) and the actual motor disability (AMD) as the efficacy parameter were measured in 15 rain intervalls over 4 h. AMD was semiquantitatively measured by Columbia-University-Rating-Scale (CURS) sum-scoring, LSC was measured by HPLC. Calculation of main pharmacodynamic parameters (LPC-effect analysis) was performed individually using a semiparametric approach. Data were fitted by an Emax model.Results: Levodopa pharmacokinetics were not significantly influenced by the coadministration of apomorphine with exception of a slight increase of AUC. Pharmacodynamics were significantly altered by apomorphine. Starting from a similar level of basic disability Emax (19.9 _+ 7.7 vs. 19.7 -+ 7.7 pts.) was similar under both regimen but clear differences were seen in Teq (26-+ 8 vs. 19 + 10 min), MRTe (1.9 + 0.5 vs. 3.0 + 0.9 h) and EC50 (430 _+ 163 vs. 315 + 123 ng/ml). The slope factor N showed some decrease under apomorphine but remained still on a high level (17 vs. 7). Our data have shown that the "all or nothing" character of the motor response to levodopa ist preserved under coadministration of a dopamine-agonist and that the mnplitude of motor improvement remains unchanged whereas the duration of the on phase is clearly increased.