.1. SEROTONIN (5-HT) WITHIN DOPAMINE REWARD CIRCUITS SIGNALS OPEN-FIELD BEHAVIOR .2. BASIS FOR 5-HT-DA INTERACTION IN COCAINE DYSFUNCTIONALBEHAVIOR

Light microscopic immunocytochemical studies, using a sensitive silver intensification procedure, show that dopamine (DA) and serotonin (5-H T) axons terminate on neurons in the nucleus accumbens (NAcc) (A(10)) terminals and also in dorsal striatum (DSTr) (A(9)) terminals. The dat a demonstrate a prominent endogenous anatomic interaction at these dis tal presynaptic sites between the neurotransmitters 5-HT and DA; the p attern of the 5-HT-DA interaction differs between A(10) and A(9) termi nals. Moreover, in distinction to the variance shown anatomically betw een 5-HT-DA interactions at distal A(9) and A(10) sites, the 5-HT-DA i nteractions at the level of DA somatodendrites, the proximal site, are similar, i.e. 5-HT terminals in the midbrain tegmentum are profuse an d have a massive overlap with DA neurons in both ventral tegmental are a (VTA) and substantia nigra pars compacta (SNpc). We suggest with ref erence to the DA neurons of A(10) and A(9) pathways, inclusive of soma todendrites (sites of proximal presynaptic interactions in the midbrai n) and axons (sites of distal presynaptic interactions), that 5-HT-DA interactions in A(10) terminals are more likely to exceed those in the DStr arrangement. Furthermore, our neuroanatomic data show that axona lly released DA at A(10) terminals may originate from proximal 5-HT so matodendrites, i.e. dorsal raphe (DR) or the proximal DA somatodendrit es, VTA. In vivo microvoltammetric studies were done with highly sensi tive temporal and spatial resolution; the studies demonstrate basal (e ndogenous) real time 5-HT release at distal A(10) and distal A(9) term inal fields and real time 5-HT release at proximal A(10) VTA somatoden drites. In vivo microvoltammetric studies were performed concurrently and on line with studies of DA release, also at distal A(10) and dista l A(9) terminal fields and at proximal A(10) somatodendrites. Serotoni n release was detected in a separate voltammetric peak from the DA vol tammetric peak. The electrochemical signal for 5-HT release was detect ed within 10-12 s and that for DA release within 12-15 s, after each b iogenic amine diffused through the synaptic environment onto the micro electrode surface. The electrochemical signal for 5-HT and a separate electrochemical signal for DA are detected on the same voltammogram wi thin 22-27 s; each electrochemical signal represents current changes i n picoamperes, within seconds of detection time. The amplitude of each electrochemical signal reflects the changes in diffusion of each biog enic amine to the microelectrode surface. Each neurotransmitter has a distinct potential at which oxidation occurs; this results in a record ing which has a distinct peak for a specific neurotransmitter. The con centration of each neurotransmitter within the synaptic environment is directly related to the electrochemical signal detected via the Cottr ell equation. Voltammograms were recorded every 5 min. At the time tha t basal 5-HT release and basal DA release were recorded within same an imal control, open-field behavioral studies were performed, also concu rrently, by infrared photocell beams. The frequency of each behavioral parameter was monitored every 100 ms; the number of behavioral events , were summated every 5 min during the time course of study. Thus, the detection of neurotransmitters occurs in real time, while simultaneou sly monitoring the animal's behavior by infrared photocell beams. The results from the in vivo microvoltammetric and behavioral data from th is study show that basal 5-HT release at distal A(10) and A(9) termina ls dramatically increased with DA release. Moreover, each increase in basal 5-HT release, at both A(10) and at A(9) terminal fields occurred consistently and at the same One as each increase in open-field locom otion and stereotypy occurred naturally during the animal's exploratio n in a novel chamber. Thus, the terminology 'synchronous and simultane ous' describes aptly the correlation between 5-HT release at distal A( 10) and A(9) terminal fields and open-field locomotion and stereotypic behavior. Increases in rearing behavior occurred in a temporally sync hronous and simultaneous pattern, with the observed increases in 5-HT release at A(9) terminal fields; however, at A(10) terminal fields, 5- HT release and rearing behavior were separated by a temporal gap of mi nutes. Thus, the latter type of correlation between 5-HT release and o pen-field behavior is aptly described as synchronous and yet temporall y juxtaposed. In striking contrast to the correlation we observed betw een 5-HT release at distal A(10) and A(9) DA terminal fields and open- field locomotion and stereotypic behavior, the correlation between 5-H T release at proximal A(10) somatodendrites, VTA, and open-field locom otion and stereotypic behavior, was, although temporally synchronous, also temporally juxtaposed. There was a distinct time gap of minutes b etween 5-HT release at A(10) somatodendrites and open-field behavior. This temporal juxtaposition occurred between 5-HT release and each par ameter of open-field behavior. In this paper we present 5-HT-DA intera ctions in DA neural circuits and 5-HT release relationships with open- held behavior as the physiological skeleton on which the drug of abuse , cocaine, exerts its mechanism of action, In this context, we present abundant empirical evidence for profound colocalized interactions bet ween 5-HT and DA in A(10) and A(9) neural circuits which are a rationa le for the potent neurochemical and behavioral effects of cocaine. The data demonstrate by in vivo microvoltammetric neurochemical studies t hat following cocaine administration, 5-HT and DA release are increase d at distal presynaptic A(10) and A(9) terminals, as well as at proxim al A(10) somatodendrites, VTA. In each neuroanatomic site studied, the effect of cocaine on the release of 5-HT and DA is colocalized. The p attern of 5-HT release differs between distal A(10) to terminals and p roximal A(10) somatodendrites and the pattern of 5-HT release also dif fers between distal A(10) and A(9) terminals. Moreover, the data demon strate that, in the presence of cocaine, the pattern of 5-HT which is released at distal and proximal A(10) and A(9) sites no longer exhibit s a correlation with exploratory open-field behavior which is synchron ous, either in a temporally simultaneous or in a temporally juxtaposed manner. The effect of neurochemical and behavioral dissonance after c ocaine administration appears to be more pronounced at the p