One of the current strategies of new drug development consists in designing receptor specific compounds with respect to different transmitter systems. However, the biological consequences in terms of changes of neuronal activity and behaviour can not be predicted easily. A method for characterization of these changes on an intermediate biological level can be seen in recording of field potentials from four brain regions in the freely moving rat. Field potentials contain information on the balance of neurotransmitter activity induced by interaction of compounds with transmitter receptors like the 5-HT1 or dopamine D2 receptor and so forth after activating particular configuration of ion conductances within single cells. These local electrical activity changes in the presence of a compound are called an electropharmacogram (EPG, for example see page 2). The relation of these EPG`s to clinical practice has been proven for nearly any category of drug action in the past on the base of 30 000 hours of recording under identical conditions. After feeding these EPG`s into a discriminant analysis and its six dimensional documentation a newly developed compound can be classified with high probability. An overview on 23 compounds having an influence on the balance of neurotransmission is given below.

Compounds acting on the level of neurotransmission are easily separated from each other by discriminant analysis of the electropharmacogram on the base of 24 variables (4 brain regions X 6 frequency ranges) and coding the first three discriminant axes into the additive colour mixture of red, green and blue and the next three into 3 spatial dimensions (spherical projection is used). Drugs having an identical mechanism of action show similar colour (i.e. 8-OH-DPAT, ipsapirone, gepirone). Dosage, time of recording and transmitter involved are given in the next table .

 

Example of an electropharmacogram induced by fentanyl (i.p.) and its antagonism by naloxone. Bar graphs indicate decreases in spectral frequency power within the delta (red), theta (orange), alpha1 (yellow), alpha 2 (green), beta 1 (light blue) and beta 2 power (dark blue). Delta changes seem to represent cholinergic, theta noradrenergic, alpha 1 serotonergic, alpha 2 dopaminergic, beta 1 glutamatergic and beta 2 GABA-ergic transmission.

 

This example clearly shows that the whole orchestra of neurotransmitter activity which was modulated in a stable reproducible way by the presence of fentanyl is silenced by antagonism of one receptor occupied by naloxone. Please remark that this effect is transient as could be predicted from the well known short action of naloxone. In summary this animal model reflects the consequences of net balance changes of local neurotransmission and therefore also predicts clinical use of new compounds (Dimpfel, 2003).

 

Dimpfel W (2003) Preclinical data base of pharmaco-specific rat EEG fingerprints (Tele-Stereo-EEG) Eur J Med Res 8: 199-207