Effects of adrenergic and serotonergic agonists in the amygdala on the hypothalamo-pituitary-adrenocortical axis

The effect of direct administration of adrenergic and serotonergic (5-HT) agonists into the central nucleus of the amygdala (AMG) on the hypothalamo-pituitary-adrenal (HPA) axis have been studied in intact male rats and in animals with 6-hydroxydopamine (6-OHDA) or 5, 7-dihydroxytryptamine (5,7-DHT) neurotoxic lesions in the paraventricular nucleus of the hypothalamus (PVN). In intact animals, the administration of phenylephrine, an alpha1 adrenergic agonist or 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) a 5-HT(1A) agonist caused depletion of median eminence corticotropin releasing hormone and a rise in serum adrenocorticotrophic hormone (ACTH) and corticosterone (CS) levels. Isoproterenol a beta agonist was more effective than phenylephrine and a 5-HT(1B) agonist CP-93, 129 was less effective than 8-OH-DPAT on the adrenocortical activity. The 6-OHDA or 5,7-DHT hypothalamic lesions prevented the stimulatory effects of phenylephrine and 8-OH-DPAT, respectively, which where injected into the AMG, on serum ACTH and CS levels. In view of our previous studies on the effects of the adrenergic and 5-HT antagonists in the AMG and the present data, it is suggested that norepinephrine and 5-HT play an important role in the stimulatory effect of the AMG on the HPA axis. These effects depend on the presence of these excitatory neurotransmitters in the PVN.     

Effect of 6-hydroxydopamine and 5,7-dihydroxytryptamine on tissue uptake and cell nuclear retention of corticosterone in the rat hypothalamus

Previous studies have shown that norepinephrine and serotonin can modulate the glucocorticoid (GC) binding capacity in the hippocampus. The aim of the present study was to evaluate the role of these neurotransmitters in regulating GC receptors in the hypothalamus. Injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the ventral noradrenergic bundle (VNAB) and 5,7-dihydroxytryptamine (5,7-DHT) into the raphe nuclei caused a marked depletion in norepinephrine and serotonin, respectively, in the paraventricular nucleus (PVN) and mediobasal hypothalamus (MBH). The injection of these neurotoxins did not change the basal levels of ACTH and corticosterone. Injection of 6-OHDA into the VNAB caused a significant reduction in the cell nuclear binding of corticosterone in the PVN but not in the MBH. Conversely, injection of 5,7-DHT into the raphe nuclei caused a significant reduction in cell nuclear binding of corticosterone in the MBH but did not affect binding in the PVN. These results demonstrate that at least part of the nuclear corticosteroid receptors in the PVN and MBH are differentially regulated by the noradrenergic and serotonergic systems.     

Paraventricular nucleus serotonin mediates neurally stimulated adrenocortical secretion

The purpose of this study was to further elucidate the role of serotonin (5-HT) in adrenocortical regulation. The effects of stimulating the frontal cortex and extrahypothalamic limbic structures, on plasma corticosterone (CS) responses, were studied in rats with vehicle or 5,7-dihydroxytryptamine (5,7-DHT) injection into the midbrain raphe nuclei. In another group of rats the neurotoxin was injected locally into the paraventricular nucleus (PVN) in view of its importance in adrenocortical regulation, and the effects of photic and dorsal hippocampal stimulation on plasma CS were studied. 5,7-DHT caused a significant depletion of hypothalamic 5-HT and blocked the rise in plasma CS following the stimulation of the above neural modalities. These studies suggest that the PVN 5-HT mediates the adrenocortical responses following afferent neural stimuli.     

Effects of intracisternal vs. intrahypothalamic 5,7-DHT on feeding elicited by hypothalamic infusion of NE.

A variety of evidence has led to suggestions that brain serotonin (5-HT) and norepinephrine (NE) interact within the medial hypothalamus to control food intake. To test the possibility that chronic decrements in 5-HT might enhance NE-induced feeding, adult male rats were prepared with permanently indwelling cannulae aimed at the paraventricular nucleus (PVN), then received either intracisternal (IC) or PVN injections of the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) vs. its vehicle, 1% ascorbic acid. Over a 4-week period, IC-5,7-DHT rats showed no signs of enhanced daily feeding or drinking. However, in 40-min intake tests, feeding but not drinking was enhanced by injecting 20 nmol NE into the PVN commencing 2 weeks after neurotoxin treatment. Terminal monoamine assays confirmed that IC-5,7-DHT produced large (80-90%) depletions of brain regional 5-HT. A functional index of 5-HT terminal damage was also implied by the impaired short-term feeding responses IC-5,7-DHT rats showed to the systemic administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) when tested between 3 and 4 weeks after IC treatment. Over a comparable 4-week period, PVN-5,7-DHT rats also showed no tendencies to overeat or overdrink on a daily basis. However, in contrast to IC-5,7-DHT rats, they also showed no differences in their feeding or drinking responses to NE injections into the PVN. This was so despite reliable depletions of 5-HT in the hypothalamus (-28%) and hippocampus (-71%). These results support earlier work showing that neither widespread nor localized hypothalamic damage to brain 5-HT neurons produce chronic overeating. However, the data suggest that phasic enhancements of PVN NE activity may trigger enhanced feeding when there is widespread damage to brain 5-HT neurons, although the PVN does not appear to be the brain site mediating this effect.     

5,7-DHT facilitated lordosis: effects of 5-HT agonists.

The role of 5-HT (serotonin) in regulating lordosis was investigated by combining peripheral administration of the 5-HT agonists 8-OH-DPAT (8-hydroxy-2-[di-N-propylamino]tetralin) or TFMPP (1-[m-trifluoromethylphenyl]piperazine), with intrahypothalamic application of the 5-HT neurotoxin 5,7-DHT (5,7-dihydroxytryptamine). The 5-HT1A agonist, 8-OH-DPAT, significantly inhibited lordosis in 5,7-DHT-treated and non-treated rats. TFMPP, an agonist at 5-HT1B and 5-HT1C receptors, significantly facilitated lordosis in 5,7-DHT-treated and non-treated rats. Our results show that both inhibitory and facilitatory influences of hypothalamic 5-HT on lordosis, are modulated via postsynaptic receptors.     

Depletion of hypothalamic norepinephrine and serotonin enhances the dexamethasone negative feedback effect on adrenocortical secretion.

The role of norepinephrine (NE) and serotonin (5-HT) in the negative feedback effect of dexamethasone (DEX) on the adrenocortical response to ether stress was investigated. Injection of the catecholamine neurotoxin, 6-hydroxydopamine, into the ventral noradrenergic bundle or the paraventricular nucleus of the hypothalamus (PVN) which produced a very significant depletion in hypothalamic NE content enhanced the negative feedback effect of DEX. Injection of the 5-HT neurotoxin, 5,7-dihydroxytryptamine, into the raphé nuclei or PVN, which caused a depletion of hypothalamic 5-HT, produced a similar effect on the adrenocortical response to DEX. The degree of negative feedback may be viewed as a balance of neural stimulatory and glucocorticoid influences of the hypothalamus. Thus the removal of the stimulatory effects of NE and 5-HT on adrenocortical secretion, by the neurotoxic lesions, enhanced the inhibitory influence of DEX.     

Identification of and interactions between noradrenergic and serotonergic neurites in the myenteric plexus

Interactions between enteric noradrenergic and serotonergic neurites in the myenteric plexus were examined. The influence of exogenous norepinephrine (NE) and endogenously released NE on the release of 3H-serotonin (3H-5-HT) from electrically stimulated, everted segments of guinea pig small intestine were analyzed. In addition, methods were employed to permit the ultrastructural identification of enteric serotonergic and noradrenergic neurites. These included electron microscopic radioautographic localization of 3H-5-HT in gut from animals treated with 6-hydroxydopamine (6-HD; 100 mg/kg) and examination of NaMnO4-fixed tissue from animals given desmethylimipramine and the indolic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Exogenous NE antagonized the stimulated release of 3H-5-HT; this action was mediated through alpha adrenoceptors. Evidence was obtained, however, that endogenous NE liberated from sympathetic postganglionic nerve terminals had a different action on the stimulated release of 3H-5-HT from that of exogenous NE. Endogenous NE appeared to facilitate 3H-5-HT release through an action on beta adrenoceptors. Terminals identified as probably serotonergic by radioautographic labeling with 3H-5-HT or by loading with 5,7-DHT were most often found to end on neuronal somata or proximal dendrites. Synaptic specializations were found by radioautography in these locations. Terminals, dendrites, and cell bodies that took up 5,7-DHT could be identified in NaMnO4-fixed material that also permitted the simultaneous recognition of noradrenergic varicosities. Apparent noradrenergic-serotonergic axoaxonic contacts were found by means of this double-labeling technique. Together with the results of the experiments on the release of 3H-5-HT, these anatomical observations suggest that noradrenergic axons form facilitatory axoaxonic synapses with enteric serotonergic neurons.     

Intrahypothalamic 5,7-dihydroxytryptamine: Temporal analysis of effects on 5-hydroxytryptamine content in brain nuclei and on facilitated lordosis behavior

The long-term relationship between serotonin (5-HT) levels in discrete hypothalamic nuclei and female rat sexual behavior, the lordosis response, was examined following intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). One week following 5,7-DHT injection, 5-HT levels in the ventromedial hypothalamic nucleus, dorsomedial nucleus, anterior hypothalamic nucleus and the medial preoptic nucleus were approximately 90% depleted as compared to sham animals. Other hypothalamic and preoptic areas including the arcuate-median eminence, vertical nucleus of diagonal band and lateral septal nucleus showed smaller reductions in 5-HT, from 40 to 70% of sham values. At this time estrogen-dependent lordosis behavior in the lesioned group was facilitated. Behavioral facilitation was greatest at 4 weeks post lesion when depletion of 5-HT in the VMN was maximal. 5-HT levels increased at 57 days after 5,7-DHT treatment in most areas, and by 71 days post lesion, no significant differences in 5-HT levels were found between sham and 5,7-DHT-treated groups. Concomitant with the increases in 5-HT, facilitated lordosis behavior gradually decreased. Loss of behavioral facilitation appeared to be most closely related to increases in content of 5-HT in the ventromedial nucleus. These results further support the hypothesis that 5-HT endings in the hypothalamus exert tonic inhibitory regulation over hormone-dependent lordosis in the female rat. They also indicate that regenerating 5-HT fibers in the hypothalamus can reinstate a normal pattern of hormone-dependent behavioral function.     

Effects of 6-hydroxydopamine and the PNMT inhibitor LY134046 on pressor responses to stimulation of the subretrofacial nucleus in anaesthetized stroke-prone spontaneously hypertensive rats

The subretrofacial nucleus of the rostral ventrolateral medulla is an important site for the control of sympathetic vasomotor tone and is the location of the C1 PNMT-containing cell bodies. In the present study the involvement of central monoaminergic neurons in the pressor responses evoked by chemical or electrical stimulation of this nucleus was examined in urethane-anaesthetized stroke-prone spontaneously hypertensive rats (SHRSP). Vehicle-treated rats were compared to animals treated with the PNMT inhibitor LY134046, the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) or a combination of 6-OHDA and the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). LY134046 caused a 43% depletion of adrenaline content in the hypothalamus and medulla but not in the spinal cord but had no effect on the pressor responses to stimulation of the subretrofacial nucleus. However, intraventricular administration of 6-OHDA reduced the pressor responses to subretrofacial nucleus stimulation by 50%. 6-OHDA caused profound depletion of noradrenaline in the brain and spinal cord, and adrenaline in the hypothalamus. Combined treatment with 6-OHDA and 5,7-DHT caused the additional depletion of serotonin to 34% and 13% in the hypothalamus and spinal cord, respectively, but caused no further reduction of pressor responses than with 6-OHDA alone. These results suggest that the pressor responses elicited by subretrofacial nucleus stimulation involve a 6-OHDA-sensitive pathway (presumably catecholaminergic) other than the bulbospinal adrenaline pathway but that serotonergic mechanisms do not contribute.     

Neural and hormonal consequences of neonatal 5,7-dihydroxytryptamine may not be associated with serotonin depletion

The neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) is often used in neonatal rats to induce specific, rapid, and permanent depletion of brain serotonin (5-HT). One assumed benefit of using this drug in neonates is that it is well-tolerated, with pups exhibiting few side effects normally attributed to 5-HT depletion. Here, we present evidence that 5,7-DHT administered neonatally induces seizure-like behavior, decreases weight gain, and increases plasma corticosterone without depletion of brain 5-HT.     

5,7-Dihydroxytryptamine injections increase glial fibrillary acidic protein in the hypothalamus of adult rats

The distribution and levels of glial fibrillary acidic protein (GFAP) were determined in the adult rat hypothalamus following axotomy of serotonin (5-HT) neurons. Seven days after unilateral intrahypothalamic injection of the 5-HT neurotoxin, 5,7-dihydroxytryptamine, there was a marked increase in the number of GFAP-labelled astrocytes in the ipsilateral hypothalamus of 5,7-DHT-treated as compared to sham-treated rats. In addition, levels of GFAP were significantly increased 7 days after 5,7-DHT injection.     

Temporal effects of intrahypothalamic 5,7-dihydroxytryptamine: relationship between serotonin levels and [3H]serotonin binding

The relationship between serotonin (5-HT) levels and [3H]5-HT binding in discrete hypothalamic areas was examined in separate groups of animals at various times, following unilateral intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). Seven days post-5,7-DHT lesion, 5-HT levels were significantly decreased in both the ipsilateral and contralateral ventromedial and dorsomedial hypothalamic nuclei (VMN, DMN). In the lateral hypothalamic area (LHA), 5-HT levels were significantly decreased only ipsilaterally. Fifty days postlesion, 5-HT levels in the ipsilateral VMN remained significantly below sham, while the DMN and LHA returned to sham values. Seven days after 5,7-DHT there was a significant increase in [3H]5-HT labeling densities in the ipsilateral and contralateral ventromedial hypothalamic area as well as in the ipsilateral LHA. In contrast, in the dorsomedial hypothalamic area there was no increase in [3H]5-HT binding. Fifty days postlesion, no significant differences in [3H]5-HT binding between 5,7-DHT and sham were observed in any areas examined. This data provides further evidence for the regeneration of 5-HT fibers in the hypothalamus and demonstrates that the relationship between [3H]5-HT binding and 5-HT levels varies from one hypothalamic area to another.     

Temporal effects of intrahypothalamic 5,7-dihydroxytryptamine: relationship between serotonin levels and [H]serotonin binding

The relationship between serotonin (5-HT) levels and [³H]5-HT binding in discrete hypothalamic areas was examined in separate groups of animals at various times, following unilateral intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). Seven days post-5,7-DHT lesion, 5-HT levels were significantly decreased in both the ipsilateral and contralateral ventromedial and dorsomedial hypothalamic nuclei (VMN, DMN). In the lateral hypothalamic area (LHA), 5-HT levels were significantly decreased only ipsilaterally. Fifty days postlesion, 5-HT levels in the ipsilateral VMN remained significantly below sham, while the DMN and LHA returned to sham values. Seven days after 5,7-DHT there was a significant increase in [³H]5-HT labeling densities in the ipsilateral and contralateral ventromedial hypothalamic area as well as in the ipsilateral LHA. In contrast, in the dorsomedial hypothalamic area there was no increase in [³H]5-HT binding. Fifty days postlesion, no significant differences in [³H]5-HT binding between 5,7-DHT and sham were observed in any areas examined. This data provides further evidence for the regeneration of 5-HT fibers in the hypothalamus and demonstrates that the relationship between [³H]5-HT binding and 5-HT levels varies from one hypothalamic area to another.     

Noradrenergic innervation of serotonergic neurons in the dorsal raphe: demonstration by electron microscopic autoradiography

In this study, noradrenergic (NE) terminals in the dorsal raphe were identified by [3H]NE electron microscopic (EM) autoradiography. Lesioning of NE terminals by treatment with the selective catecholamine neurotoxin, 6-hydroxydopamine produced a marked decrease in NE-labelled terminals. [3H]5-HT EM autoradiography of the dorsal raphe produced labelling of cell bodies, dendrites and axons but labelled terminals with synaptic junctions were not observed. Serotonergic (5-HT) neurons were identified at an early stage of degeneration following treatment with the selective 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). When both [3H]NE autoradiography and 5,7-DHT lesioning were combined, a majority of NE-labelled terminals, which formed synaptic specializations, innervated degenerating dendrites. These findings suggest that NE terminals directly innervate 5-HT cells in the dorsal raphe.     

Serotonergic function of aging hippocampal CA3 pyramidal neurons: Electrophysiological assessment following administration of 5,7-dihydroxytryptamine in the fimbria-fornix and cingulum bundle

Serotonergic (5-hydroxytryptamine; 5-HT) neuro-transmission has been implicated in the regulation of cognitive function and this neurotransmitter system may underlie selective neuronal degeneration found in the aging hippocampus. Age-dependent changes in 5-HT function of hippocampal CA3 subfield pyramidal neurons were evaluated in female Fischer 344 rats (2 and 17 months) following denervation of the serotonergic afferents to the dorsal hippocampus using the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Vehicle (ascorbic saline) or 5,7-DHT was administered bilaterally in the fimbria-fornix/cingulum bundle and dorsal pyramidal cell responses to microiontophoretic application of 5-HT, the 5-HT_1A agonist (±)-8-hydroxy-2-(di-N-propylamino) tetralin, the 5-HT_1A antagonist WAY 100,135 and N-methyl-D-aspartate were recorded at 3 weeks post-lesion. Independent of changes in sensitivity to the inhibitory effects of 5-HT with aging, the time to recovery of cell firing following application of 5-HT was significantly increased in the 18 month 5,7-DHT group compared to the 18 month Vehicle and 3 month 5,7-DHT groups (3.3- and 2.6-fold, respectively). These results demonstrate that serotonergic neurotransmission is altered with aging following a selective neurotoxic insult to the hippocampus. J. Neurosci. Res. 47:58–67, 1997. © 1997 Wiley-Liss, Inc.     

Effects of indolic neurotoxins on enteric serotonergic neurons

The effects of the indolic neurotoxins 5,6- and 5,7-dihydroxytryptamine (5,6-DHT; 5,7-DHT) on the enteric nervous system were examined. 5,6-DHT, in moderate dosage, 40 mg/kg, decreased uptake of tritiated 5-hydroxytryptamine (³H-5-HT) but not that of tritiated norepinephrine (³H-NE). However, selectivity of the neurotoxins for enteric serotonergic rather than adrenergic axons was enhanced by pretreating animals with desmethylimipramine to inhibit the catecholamine uptake mechanism. When this was done, 5,7-DHT was found to prevent the development of 5-HT histofluorescence (following injection of L-tryptophan) without affecting histofluorescence of NE. In contrast, 6-hydroxydopamine virtually abolished NE histofluorescence and uptake of ³H-NE without affecting development of 5-HT histofluorescence or uptake of ³H-5-HT. Electron microscopy revealed that 5,7-DHT induced dose-dependent lesions of axonal varicosities in the enteric nervous system. Early lesions, 1–4 hours following injection, resembled cytolysosomes and consisted of membrane enclosed regions of opaque cytoplasm containing synaptic vesicles. Affected varicosities contained a mixed population of large dense cored (～120nm) and small lucent vesicles (～70nm) but none exhibited pre- or postsynaptic membrane specializations. After 24 hours terminals degenerated and were engulfed by surrounding supporting cells. It is concluded that peripheral serotonergic neurons resemble central serotonergic neurons in susceptibility to the toxic effects of indolic neurotoxins. These neurotoxins are useful anatomical markers of serotonergic terminal varicosities.     

The effect of intracerebral injections of 5,7-dihydroxytryptamine and 6-hydroxydopamine on the serotonin-immunoreactive cell bodies and fibers in the adult rat hypothalamus

The effect of intracerebral injections of 5,7-dihydroxytryptamine (5,7-DHT) and 6-hydroxydopamine (6-OHDA) on the serotonin (5-HT)-immunoreactive (IR) cell bodies ¹¹ and fibers in the adult rat hypothalamus was studied with 5-HT immunocytochemistry. In rats pretreated with pargyline and l-tryptophan, 5-HT-IR cells were seen in the ventromedial part of the dorsomedial nucleus (DMN) and 5-HT-IR fibers in all hypothalamic areas. In the ventrolateral part of the DMN the 5-HT-IR fibers were of a much finer type than those seen in other hypothalamic areas. Five days after unilateral injection of 5,7-DHT into the dorsolateral hypothalamus, the 5-HT-IR cells were absent from the DMN, and there was a decrease in the number of 5-HT-IR fibers throughout the hypothalamus ipsilateral to the injection. Contralateral to the injection there was evidence of selective 5-HT fiber degeneration but the 5-HT-IR cells and the group of fine fibers in the ventrolateral DMN remained. Unilateral injection of 6-OHDA into the dorsolateral hypothalamus had no effect on the 5-HT-IR fibers or cell bodies in the hypothalamus.Twelve days after unilateral injection of 5,7-DHT into the rostral midbrain, the majority of 5-HT-IR fibers in the ipsilateral hypothalamus had disappeared. The 5-HT-IR cell bodies in the DMN and the group of fine 5-HT-IR fibers in the ventrolateral DMN remained on both sides of the hypothalamus. These results support our previous finding of a group of 5-HT-IR cell bodies in the ventromedial DMN of the hypothalamus, and suggest that these cells innervate the ventrolateral part of the same nucleus. Evidence that these cells constitute a new 5-HT cell group, B-10, is discussed.     

Experimentally induced supersensitivity of neocortical neurons to microiontophoretically administered serotonin

Central serotonergic fiber systems of the rat were selectively lesioned by intraventricular injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At various times thereafter, the sensitivity of rostral cortical neurons to microiontophoretically administered serotonin (5-HT) was compared in groups of lesioned and sham-operated animals pretreated with the 5-HT uptake inhibitor CGP 6085. Twenty-four hours after the injection of 5,7-DHT, at which time the cortical 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were both reduced by 40%, there was no significant difference in the sensitivity of cortical neurons to 5-HT. However, 3 days after such treatment, when the cortical 5-HT and 5-HIAA levels were reduced by 52% and 53% respectively, pronounced supersensitivity to 5-HT was noted. The depressant action of 5-HT on neuronal firing was potentiated with regard to both maximal firing depression and duration of the firing inhibition. A similar potentiation of the 5-HT responses was observed 7 days after lesioning. Supersensitivity thus appears to develop between 1 and 3 days after the injection of 5,7-DHT. Seven days after lesioning, the sensitivity of rostral cortical neurons to gamma-aminobutyric acid was unchanged compared to that observed in sham-operated animals.     

The functional significance of neonatal 5,7-dihydroxytryptamine lesions in the rat: response to selective 5-HT1A and 5-HT2,1C agonists

To study the involvement of serotonin (5-HT) receptor subtypes in behavioral supersensitivity following neonatal 5,7-dihydroxytryptamine (5,7-DHT) lesions, we measured acute behavioral responses to a single dose of selective 5-HT1A (8-OH-DPAT) or 5-HT2,1C (DOI) agonist compared to 5-hydroxytryptophan (5-HTP) in rats injected with 5,7-DHT intraperitoneally or intracisternally 14 weeks earlier. Only intraperitoneal 5,7-DHT injection resulted in brainstem 5-HT hyperinnervation, but cortical 5-HT depletions were also less. Effects of DOI, such as shaking behavior and forepaw myoclonus, were enhanced by 5,7-DHT lesions made intracisternally not intraperitoneally, whereas 8-OH-DPAT-evoked behaviors, such as forepaw myoclonus and head weaving, were enhanced more by the intraperitoneal route. The main consequence of intraperitoneal compared to intracisternal 5,7-DHT injection on supersensitivity to 5-HT agonists was increased presynaptic 5-HT1A responses and decreased 5-HT2,1C responses. In contrast, 5-HTP evoked more shaking behavior and less of the serotonin syndrome with the intraperitoneal compared to the intracisternal route of 5,7-DHT injection. Behavioral supersensitivity to 5-HTP, which was attributable to 5-HT1A, 5-HT2,1C, and possibly to other 5-HT receptors, was orders of magnitude greater than that elicited by direct receptor agonists and more clearly differentiated between rats with 5,7-DHT lesions and their controls, and between routes of 5,7-DHT injections, than responses to 5-HT agonists at the dose studied. 5,7-DHT induced dysregulation of 5-HT receptors, including both presynaptic and postsynaptic changes and altered interactions between receptor subtypes, better explains these data than postsynaptic changes alone.     

Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats

The effect of L-dihydroxyphenylalanine (L-DOPA) on extracellular dopamine (DA) in the striatum was determined by microdialysis in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with and without the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At the same time the intensity of L-DOPA-induced rotational behavior was assessed. In 6-OHDA-lesioned rats treated with 5,7-DHT, L-DOPA (50 mg/kg, i.p.) increased extracellular DA only to 20% of that measured in animals not treated with 5,7-DHT. Likewise, 6-OHDA-lesioned rats treated with 5,7-DHT exhibited a significantly lower number of L-DOPA-induced rotations. These results suggest that serotonergic terminals in the striatum can convert exogenously administered L-DOPA into DA that can be released into the extracellular space.