Tools are inadequate to investigate ACh-DA controversy

TiPS - October 1989 IVol. IO] 1983) presents 65 pages of pharmacokinetic constants, roughly a quarter of which are racemates although this is not indicated. Almost without exception the constants have been derived from plasma levels determined with non-chiral assays. These constants will therefore be fiction anyway;

395

addition of correct prefixes (e.g. SIGNS) will only make this nonsense more sophisticated. Elimination of the invalid data is required. A final point is: should we not restrict ourselves to SIGNS for racemates, rut- or (RS), and mixtures of geometric isomers, E/Z?

Diastereomers racemates.

are in fact sets of E. J. ARIiiNS

6524 TP Nijmegen, The Netherlands.

Reference 1 Simonyi.M.. Gal,I. and

Testa, B. (1989) Trends Phormacol. Sd. 10,349-354

The acetylcholine-dopamine interaction: in-vivo microdialysis data are equivocal

Tools are inadequate to investigate AC&DA controversy In their recent TiPS article (July, 1989)’ Westerink and Damsma justifiably point out that the oft quoted antagonism between acetylcholine and dopamine has never been adequately demonstrated in vim. Their scepticism appeared to be substantiated by their own studies. They monitored acetylcholine and dopaminp in microdialysis perfusates G! rat striatum using HPLC with electrochemical detection and gave sensible systemic doses of drJgs which modify the actions of these neurotransmitters. Their conclusion, that changes in acetylcholine and dopamine release are quite independent, may be totally valid but their data lose impact by failure to give n values, standard errors and measures of significance, and in particular by their use of normalization. The importar.
reduced the activity of the elevated acetylcholine and so leave dopamine release apparently unaltered. Similarly, oxotremorine might decrease acetylcholine release (as demonstrated) by activating autoreceptors but at the same time compensate by directly activating its postsynaptic receptors and so keeping dopamine efflux constant. Again, in their study with apomorphine and haloperidol which modify dopamine function (they stimulate and block dopamine autoreceptors, respectively), these drugs produced the expected decrease and increase in dopamine efflux. However, any effect this might have had on acetylrholine release could have been negated by the postsynaptic actions of such drugs (e.g. apomorphine directly dccreasiilg acetylcholine release despite reducing the level of synaptic dopamine). Thus until

Nicotinic involvement in ACh-DA interaction? Westerink and Damsma (TiPS,July 1989)l purport that brain microdialysis fails to detect a dopamineacetylcholine interaction in the basal ganglia. The comments and cautions offered by the authors with regard to the interpretation of in-vitro data are very wise, and the elegant technique of brain dialysis is a welcome tool in the quest to understand brain function. However, the authors’ dismissal of a dopamine-acetylcholine interaction ignores some relevant data

drugs are available that affect preand postsynaptic dopamine and acetylcholine receptors specifically it will be difficlllt to resolve the issue of whether acetvlcholine and -_dopamine have oppoiing effects in the stiatum. Certainlv any dif_-ference between the _ effeits of drugs on transmitter release in vim and in vitro will not depend only on the loss of neuronal feedback circuits in vitro, as suggested by Westerink and Damsma. Of equal importance are differences in the actual synaptic level of neurotransmitters as determined by ongoing synaptic activity, which will be quite different in viva from in vitro, and in the presence or otherwise of drugs affecting the metabolism of the neurotransmitters. R. A. WEBSTER Deparhm?nt of Pharmacology, College London, Cower WClE 6BT. UK.

Street,

University London.

Reference 1 Westerink,

8. H. C. and Damsma, G. (1989) Trends Pharmacol. Sci. 10,26X263

using this methodology, including some of their own work. In the TiPS article they point out that neither muscarinic agonists nor antagonists modulate dopamine release, but Damsma et al.’ and others3s4 have shown that nicotine given peripherally, or the nicotinic agonist lobeline administered directly into the striatum, can stimulate dopamine release from this tissue. This effect can be attributed to presynaptic nicotinic cholinergic receptors that exist on the dopaminergic nerve terminals5*‘. Of course stimulation of these receptors by exogenous drugs does not tell us that modulation by endogenous acety!choline will occur by this route. Administration of an anticholinesterase to augment synaptic