Light microscopic immunocytochemical studies, using a sensitive silver intensification procedure, show that dopamine (DA) and serotonin (5-HT) axons terminate on neurons in the nucleus accumbens (NAcc) (A(10)) terminals and also in dorsal striatum (DSTr) (A(9)) terminals. The data demonstrate a prominent endogenous anatomic interaction at these distal presynaptic sites between the neurotransmitters 5-HT and DA; the pattern of the 5-HT-DA interaction differs between A(10) and A(9) terminals. Moreover, in distinction to the variance shown anatomically between 5-HT-DA interactions at distal A(9) and A(10) sites, the 5-HT-DA interactions at the level of DA somatodendrites, the proximal site, are similar, i.e. 5-HT terminals in the midbrain tegmentum are profuse and have a massive overlap with DA neurons in both ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). We suggest with reference to the DA neurons of A(10) and A(9) pathways, inclusive of somatodendrites (sites of proximal presynaptic interactions in the midbrain) 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 axonally released DA at A(10) terminals may originate from proximal 5-HT somatodendrites, i.e. dorsal raphe (DR) or the proximal DA somatodendrites, VTA. In vivo microvoltammetric studies were done with highly sensitive temporal and spatial resolution; the studies demonstrate basal (endogenous) real time 5-HT release at distal A(10) and distal A(9) terminal fields and real time 5-HT release at proximal A(10) VTA somatodendrites. In vivo microvoltammetric studies were performed concurrently and on line with studies of DA release, also at distal A(10) and distal A(9) terminal fields and at proximal A(10) somatodendrites. Serotonin release was detected in a separate voltammetric peak from the DA voltammetric peak. The electrochemical signal for 5-HT release was detected within 10-12 s and that for DA release within 12-15 s, after each biogenic amine diffused through the synaptic environment onto the microelectrode surface. The electrochemical signal for 5-HT and a separate electrochemical signal for DA are detected on the same voltammogram within 22-27 s; each electrochemical signal represents current changes in picoamperes, within seconds of detection time. The amplitude of each electrochemical signal reflects the changes in diffusion of each biogenic amine to the microelectrode surface. Each neurotransmitter has a distinct potential at which oxidation occurs; this results in a recording which has a distinct peak for a specific neurotransmitter. The concentration of each neurotransmitter within the synaptic environment is directly related to the electrochemical signal detected via the Cottrell equation. Voltammograms were recorded every 5 min. At the time that basal 5-HT release and basal DA release were recorded within same animal control, open-field behavioral studies were performed, also concurrently, 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 simultaneously monitoring the animal's behavior by infrared photocell beams. The results from the in vivo microvoltammetric and behavioral data from this study show that basal 5-HT release at distal A(10) and A(9) terminals 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 locomotion and stereotypy occurred naturally during the animal's exploration in a novel chamber. Thus, the terminology 'synchronous and simultaneous' 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 synchronous 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 minutes. Thus, the latter type of correlation between 5-HT release and open-field behavior is aptly described as synchronous and yet temporally juxtaposed. In striking contrast to the correlation we observed between 5-HT release at distal A(10) and A(9) DA terminal fields and open-field locomotion and stereotypic behavior, the correlation between 5-HT release at proximal A(10) somatodendrites, VTA, and open-field locomotion and stereotypic behavior, was, although temporally synchronous, also temporally juxtaposed. There was a distinct time gap of minutes between 5-HT release at A(10) somatodendrites and open-field behavior. This temporal juxtaposition occurred between 5-HT release and each parameter of open-field behavior. In this paper we present 5-HT-DA interactions in DA neural circuits and 5-HT release relationships with open-field 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 between 5-HT and DA in A(10) and A(9) neural circuits which are a rationale for the potent neurochemical and behavioral effects of cocaine. The data demonstrate by in vivo microvoltammetric neurochemical studies that following cocaine administration, 5-HT and DA release are increased at distal presynaptic A(10) and A(9) terminals, as well as at proximal A(10) somatodendrites, VTA. In each neuroanatomic site studied, the effect of cocaine on the release of 5-HT and DA is colocalized. The pattern of 5-HT release differs between distal A(10) to terminals and proximal A(10) somatodendrites and the pattern of 5-HT release also differs between distal A(10) and A(9) terminals. Moreover, the data demonstrate 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 exhibits a correlation with exploratory open-field behavior which is synchronous, either in a temporally simultaneous or in a temporally juxtaposed manner. The effect of neurochemical and behavioral dissonance after cocaine administration appears to be more pronounced at the proximal interaction site, VTA. We conclude that the 5-HT-DA interaction at the proximal presynaptic site is excitatory and that 5-HT release facilitates DA release at both distal A(10) terminals and proximal A(10) somatodendrites. We also conclude that this basal 5-HT-DA interaction is intricately related to natural open-field behavior. We further conclude that in the presence of cocaine, this 5-HT-DA interaction at A(10) terminal fields exaggerates DA release at the distal site and may subsequently synergize DA release at A(10) somatodendrites at the proximal site. This is in spite of the known cocaine-induced suppression of cell firing at DA somatodendrites, VTA, and also in spite of the known cocaine-induced suppression of cell firing at 5-HT somatodendrites, DR. We suggest that the final outcome of this cocaine-manipulated 5-HT-DA interaction within A(10) neural circuits, is cocaine-induced temporal dysregulation of behavior. Copyright (C) 1997 Elsevier Science Ltd.
