“…Major ascending 5-HT fiber systems have been described, including a transtegmental system which innervates the VTA (originating mainly from the dorsal raphe nucleus and the median raphe, to the dorsal raphe nucleus). Iontophoretically administered 5-HT produced a slight inhibition of the firing of DA neurons in the SN and electrical stimulation of the raphe nucleus has been reported to inhibit and excite SN neurons as well (Dray et al, 1978). In fact, a majority of the ascending 5-HT fibers and terminals in the SN appear to be collaterals arising from the dorsal raphe nucleus (Parent et al,198 1).…”
Positron emission tomography and in vivo microdialysis were used to study serotonin's role in modulating striatal dopamine. Serial PET studies were performed in adult female baboons at baseline and following drug treatment, using the dopamine (D2) selective radiotracer, 11C-raclopride. The serotonergic system was manipulated by administration of the selective 5-HT reuptake inhibitor, citalopram, or by serotonergic (5-HT2) receptor blockade (using altanserin, a 5-HT2 antagonist). 11C-Raclopride time-activity data from striatum and cerebellum were combined with plasma arterial input functions and analyzed by calculating a distribution volume as described previously (Logan et al., 1990). Additionally, in vivo microdialysis studies were performed in awake freely moving rats using similar pharmacologic challenges plus SR 46349B, a new highly selective 5-HT2 receptor antagonist. Altanserin and SR 46349B increased extracellular striatal dopamine concentrations (35% and 910%, respectively) while altanserin decreased striatal 11C-raclopride binding (37%). Citalopram, however, decreased extracellular striatal dopamine concentrations (50%) and increased 11C-raclopride binding (33%). These data demonstrate that 5- HT-selective drugs produce changes in striatal dopamine that can be measured noninvasively with PET. Furthermore, the PET data obtained from anesthetized baboons is consistent with in vivo microdialysis data obtained from awake and freely moving rats. Finally, these studies have implications for understanding the therapeutic efficacy of atypical neuroleptics and their utility for treating schizophrenia and affective disorders.
“…Major ascending 5-HT fiber systems have been described, including a transtegmental system which innervates the VTA (originating mainly from the dorsal raphe nucleus and the median raphe, to the dorsal raphe nucleus). Iontophoretically administered 5-HT produced a slight inhibition of the firing of DA neurons in the SN and electrical stimulation of the raphe nucleus has been reported to inhibit and excite SN neurons as well (Dray et al, 1978). In fact, a majority of the ascending 5-HT fibers and terminals in the SN appear to be collaterals arising from the dorsal raphe nucleus (Parent et al,198 1).…”
Positron emission tomography and in vivo microdialysis were used to study serotonin's role in modulating striatal dopamine. Serial PET studies were performed in adult female baboons at baseline and following drug treatment, using the dopamine (D2) selective radiotracer, 11C-raclopride. The serotonergic system was manipulated by administration of the selective 5-HT reuptake inhibitor, citalopram, or by serotonergic (5-HT2) receptor blockade (using altanserin, a 5-HT2 antagonist). 11C-Raclopride time-activity data from striatum and cerebellum were combined with plasma arterial input functions and analyzed by calculating a distribution volume as described previously (Logan et al., 1990). Additionally, in vivo microdialysis studies were performed in awake freely moving rats using similar pharmacologic challenges plus SR 46349B, a new highly selective 5-HT2 receptor antagonist. Altanserin and SR 46349B increased extracellular striatal dopamine concentrations (35% and 910%, respectively) while altanserin decreased striatal 11C-raclopride binding (37%). Citalopram, however, decreased extracellular striatal dopamine concentrations (50%) and increased 11C-raclopride binding (33%). These data demonstrate that 5- HT-selective drugs produce changes in striatal dopamine that can be measured noninvasively with PET. Furthermore, the PET data obtained from anesthetized baboons is consistent with in vivo microdialysis data obtained from awake and freely moving rats. Finally, these studies have implications for understanding the therapeutic efficacy of atypical neuroleptics and their utility for treating schizophrenia and affective disorders.
“…In mouse and rat, the densest afferent 5-HT innervation is present in the substantia nigra pars compacta (SNc) and pars reticulata (SNr)-both integral parts of the basal ganglia (BG) (Miller et al, 1975;Dray et al, 1978;Imai et al, 1986;Vertes, 1991;Moukhles et al, 1997). The SNc DAergic neurons project to the striatum and provide DAergic modulatory input into the direct and indirect pathways of the BG.…”
Serotonin (5-HT)-selective reuptake inhibitors (SSRIs) are widely administered for the treatment of depression, anxiety, and other neuropsychiatric disorders, but response rates are low, and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs inhibit dopaminergic activity, but mechanistic insight remains scarce. Here we show that in mice, chronic 5-HT transporter (5-HTT) blockade during adulthood but not during development impairs basal ganglia-dependent behaviors in a dose-dependent and reversible fashion. Furthermore, chronic 5-HTT blockade reduces striatal dopamine (DA) content and metabolism. A causal relationship between reduced DA signaling and impaired basal ganglia-dependent behavior is indicated by the reversal of behavioral deficits through L-DOPA administration. Our data suggest that augmentation of DA signaling would reduce side effects and increase efficacies of SSRIbased therapy.
“…In what manner this regulation is achieved is at present a matter of conjecture. It may be that the afferent 5-HT-ergic innervation to the substantia nigra from both medial and dorsal raphe nuclei (Dray, Gonye, Oakley & Tanner, 1976;Dray et al, 1978) may regulate the release of GABA from the terminals of the striato-nigral GABA-ergic pathway which in turn affect ascending dopaminergic neurones. In vitro release studies are now being undertaken in an attempt to resolve this possibility.…”
Section: Discussionmentioning
confidence: 99%
“…substance P, (Dray & Straughan, 1976;Cuello, Emson, Del Fiacco, Gale, Iversen, Jessell, Kanazawa, Paxinos & Quik, 1978) and 5-hydroxytryptamine (5-HT) (Fibiger & Miller, 1977;Dray, Davies, Oakley, Tongroach & Velucci, 1978) being amongst the best documented.…”
1 a-Flupenthixol (a-FPT)-induced catalepsy in the rat was potentiated by diaminobutyric acid (DABA), an inhibitor of the neuronal high affinity uptake of y-aminobutyric acid (GABA). 2 The depletion of 5-hydroxytryptamine (5-HT) with p-chlorophenylalanine (PCPA) abolished the DABA potentiation of a-FPT-induced catalepsy; this response was restored with 5-hydroxytryptophan. 3 Potentiation of a-FPT-induced catalepsy by clonazepam was significantly reduced by methysergide. Conversely, the potentiation of catalepsy by clomipramine was significantly reduced by picrotoxin. 4 These results are interpreted as evidence supporting a role for 5-HT in modifying the GABAergic inhibition of dopaminergic pathways, possibly by regulating the release of GABA.
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