In Vivo Neurochemical Evaluation of Striatal Serotonergic Hyperinnervation in Rats Depleted of Dopamine at Infancy

Abstract

Destruction of nigrostriatal dopamine (DA) neurons with 6-hydroxydopamine (6-OHDA) early in development results in hyperinnervation of striatum by the serotonergic afferents deriving from the dorsal raphe nucleus. We have used in vivo microdialysis to investigate the degree to which serotonergic neurotransmission in striatum is altered by this increase in the density of serotonin (5-HT) terminals. The effects of several manipulations known to influence 5-HT function on extracellular 5-HT and 5-hydroxyindoleacetic acid in striatum were compared in adult rats treated neonatally with 6-OHDA and in intact adult rats. Basal levels of 5-HT in extracellular fluid (ECF) of striatum were similar in neonatally DA-depleted rats and in intact rats. Perfusion with the 5-HT reuptake blocker, fluoxetine (100 microM), increased 5-HT in striatal ECF of neonatally DA-depleted rats to levels that were threefold greater than those achieved in intact rats. Likewise, K(+)-depolarization of the 5-HT terminals (100 mM in perfusate) or systemic administration of the 5-HT releaser, (+/-)-fenfluramine (10 mg/kg i.p.), increased the concentration of 5-HT in striatal ECF of neonatally DA-depleted rats to levels approximately threefold greater than those observed in striatum of intact rats. These findings indicate that the 5-HT hyperinnervation of striatum that takes place in rats depleted of DA at infancy is associated with an increased capacity for neurotransmitter release in this system. Concomitant increased in high-affinity 5-HT uptake may prevent the occurrence of any measurable changes in the resting concentration of 5-HT in striatal ECF.

Alterations in the Postnatal Development of Striatal Preprotachykinin but Not Preproenkephalin mRNA Expression in the Serotonin-Depleted Rat

“…Interestingly, these lesions have also been reported to result in the sprouting of 5-HT terminals [49][50][51][52]. Therefore, it is possible that increased 5-HT neurotransmission in the developing striatum may elicit more drastic effects on neuropeptide gene expression as compared to the present study in which 5-HT was removed.…”

Basal and stimulated extracellular serotonin concentration in the brain of rats with altered serotonin uptake

“…Because dialysate 5-HT is representative of the equilibrium between release and reuptake, inhibition of the latter resulted in lower increments of the 5-HT concentration in lesioned rats. An opposite situation (i.e., hyperinnervation of the striatum by 5-HT terminals in dopamine-depleted rats at infancy) also results in unchanged baseline 5-HT values but greater increments after blockade of the 5-HT reuptake (Jackson and Abercrombie, 1992). Hence, it appears that changes in the brain extracellular fraction of 5-HT take place only after the disruption of the balance between release and reuptake (e.g., by axonal depolarization or inactivation of the 5-HT transporter), despite the existence of an extensive lesion of the serotonergic system.…”

“…Previous studies indicated that, in absence of pharmacological interventions, the extracellular concentration of 5-HT in different areas of the rat brain is confined within a relatively narrow range and does not reflect that present in brain tissue Jackson and Abercrombie, 1992). In experiments involving destruction of the serotonergic system with 5,7-DHT, Daszuta et al (1989) reported a very severe reduction of basal dialysate 5-HT values in the VHPC of lesioned rats, whereas Kirby et al (1995) found unaltered dialysate 5-HT values even after an almost complete (Ͼ90%) lesion of the striatal 5-HT system.…”

“…In rats lesioned with 6-hydroxydopamine at infancy, a condition resulting in a large serotonergic hyperinnervation of the caudate-putamen, the baseline concentration of 5-HT in striatal dialysates is unchanged compared to control rats (Jackson and Abercrombie, 1992). In contrast, regional dialysate 5-HIAA concentrations parallel the amount of 5-HT and 5-HIAA in brain tissue .…”

Genetically engineered neural transmission

“…Therefore, the phenoNeonatal cell death of nigrostriatal dopaminergic neurons produced by 6-hydroxydopamine administration type of transgenic mouse models could be a mere consequence of developmental abnormality, instead of resulted in serotonergic hyperinnervation of striatum from the dorsal raphe nucleus. 35 The serotonergic hypthe physiological role of a targeted gene product per se. Recent development of molecular genetic techniques erinnervation increased the capacity of 5-HT release by 3-fold in the striatum of the neonatally dopaminemakes it possible to circumvent this problem by spatiotemporal regulation of a gene-targeting or transgene depleted rat.…”