In Huntington's disease (HD), neuronal loss is most prominent in the striatum leading to emotional, cognitive and progressive motor dysfunction. The R6/2 mice, transgenic for exon 1 of the HD gene, develop a neurological phenotype with similarities to these features of HD. In striatal tissue, electrically evoked release of tritiated acetylcholine (ACh) and dopamine (DA) were compared in wild-type (WT) and R6/2 mice. In R6/2 mice, the evoked release of ACh, its M2 autoreceptor-mediated maximum inhibition and its dopamine D2 heteroreceptormediated maximum inhibition was diminished to 51%, 74% and 87% of controls, respectively. Also, the activities of choline acetyltransferase and of synaptosomal high-affinity choline uptake decreased progressively with age in these mice. In the DA release model, however, electrical stimulation elicited equal amounts of [ 3 H]-DA both in WT and R6/2 mice. Moreover, high-affinity DA uptake into striatal slices was similar in WT and R6/2 mice. In order to confirm these findings in vivo, intrastriatal levels of extracellular DA were measured by intracerebral microdialysis in freely moving mice: striatal DA levels were found to be equal in WT and R6/2 mice. In conclusion, in the transgenic R6/2 mice changes occur mainly in striatal cholinergic neurones and their pre-synaptic modulation, but not in the dopaminergic afferent terminals. Whether similar events also contribute to the pathogenesis of HD in humans has to be established. Keywords: acetylcholine, dopamine, Huntington's disease, microdialysis, striatum, transgenic mice. Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder. It is caused by an unstable expanded CAG nucleotide repeat greater than 37 in the 5¢-coding region within the huntingtin gene on chromosome 4 (Huntington's Disease Collaborative Research Group 1993). The primary brain region affected in HD is the striatum, where selective degeneration of GABAergic projection neurones takes place. HD begins at about the age of 40 and is characterized by depression, dementia and progressive motor dysfunction, such as hyperkinesia. Currently, HD patients can only be treated symptomatically, as there is no causal therapy. Medication mainly consists of the dopamine (DA) antagonists haloperidole and tiapride to alleviate hyperkinesis, and of sulpiride to treat depression .The first transgenic HD mouse model, developed by G. Bates, is expressing exon 1 of the mutated human HD gene with a CAG repeat length of 141-157. These mice (line R6/2) display a progressive neuronal disorder (Mangiarini et al. 1996;Carter et al. 1999). At the age of 9-11 weeks they develop stereotypic and epileptic movements, irregular gait and resting tremor. Their mean lifetime is about 100 days. Histologically, no selective neurodegeneration Received October 1, 2002; revised manuscript received December 17, 2002; accepted January 16, 2003. Address correspondence and reprint requests to Jan M. Vetter, Sektion Klinische Neuropharmakologie der Neurologischen Univers...

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.

B. reports being the chair of the European Huntington's Disease Network Executive Committee at the time of the execution of this work. F.C. reports no disclosures. D.O.C. reports no conflicts. G.B.L. has provided consulting services, advisory board functions, clinical trial services, and/or lectures for

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