Serotonin synthesis inhibition or receptor antagonism reduces pregnancy-induced nocturnal prolactin secretion

During early pregnancy, two surges of prolactin (PRL) designated as nocturnal (N) and diurnal (D) are displayed by the rat. We previously reported the positive influence of serotonin (5-HT) in regulating the D surge. Its role in the N surge remained inconclusive due to the contradictory results obtained with the 5-HT synthesis inhibitor parachlorophenylalanine (PCPA) and 5-HT2 receptor antagonists. This study further characterizes the involvement of 5-HT in regulating the N surge. The effectiveness of different doses of ketanserin (KET), a 5-HT2 receptor antagonist, to reduce plasma PRL levels during the surge was established. Sub-threshold (1 mg/kg BW) or just maximally effective (10 mg/kg BW) doses of KET were administered to rats that had been pre-treated with PCPA (250 mg/kg BW) for 24h. The lower dose of KET was ineffective in reducing the N surge even though less 5-HT was available due to PCPA treatment 24h earlier. The higher dose was effective in blocking the surge. Subsequently, the effect of one compared to two injections of PCPA 24 hours apart on plasma PRL levels and concentrations of 5-HT, dopamine (DA) and their respective metabolites 5-hydroxy-indoleacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC) in the medial basal hypothalamus (MBH) and the medial dorsal hypothalamus (MDH) was studied. Two injections of PCPA but not one abolished the N PRL surge. Levels of 5-HT and 5-HIAA were significantly (p less than .005) reduced following either one or two injections of PCPA. Nevertheless, there was a greater (50 fold) decrease in 5-HIAA following 2 injections compared to one injection (10 fold), resulting in lower 5-HT turnover as indicated by lower 5-HIAA/5-HT ratios. Levels of DA in the MBH were reduced significantly only following two injections of PCPA, suggesting that the lack of effect of PCPA after one injection on the N surge was not due to a decrease in DA.     

Replacement of progesterone restores the nocturnal surge of prolactin following suppression with a gonadotropin-releasing hormone agonist during early pregnancy in the rat

Continuous administration of a GnRH agonist (GnRH-Ag) at a dose of 5 micrograms/day, commencing on day 7 of pregnancy resulted in the suppression of daily nocturnal surges of prolactin (PRL) on day 8, and serum progesterone (P4) levels with subsequent termination of pregnancy. Replacement with dydrogesterone, a synthetic analog of P4 at a dose of 4 mg/day s.c. restored the magnitude of nocturnal PRL surges. These data suggest that GnRH-Ag may act either at the level of the brain to suppress the nocturnal PRL surge, resulting in a fall in serum P4 levels or at the level of the corpus luteum itself or at both sites simultaneously to terminate pregnancy.     

Suppression of the prolactin surges in the pseudopregnant rat by urethane anesthesia

In pseudopregnancy of the rat prolactin (PRL) is released in the form of twice daily surges (nocturnal and diurnal surges). An attempt was made to examine the effects of urethane anesthesia on PRL surges during pseudopregnancy of the rat. In a preliminary study, using the continuous blood sampling method, the nocturnal PRL surge was completely blocked when urethane (1.0g/kg BW) was administered at 0:00 hr. Urethane (1.0g/kg BW) was injected at 0:00 or 12:00 hr, and serum and pituitary PRL concentrations were measured at 6:00 or 18:00 hr, respectively, to study the effects of urethane on nocturnal or diurnal PRL surges. There were no serum PRL surges during either the nocturnal or diurnal periods following urethane injection. The experiment examining pituitary PRL concentration at 6:00 or 18:00 hr confirmed that urethane (1.0g/kg) anesthesia suppressed the release of PRL surge from the pituitary.     

The serotonin 5-HT2 receptor system, but not the alpha 1-adrenergic receptor system, is involved in the estrogen-induced afternoon prolactin surge in the rat

Ketanserin (Ket), a new serotonergic (5-HT2) antagonist, has recently been shown to block the estrogen-induced afternoon PRL surge (Endocrinology 120: 2070-2077, 1987). It is not certain, however, whether the effect of Ket was due to its serotonergic or adrenergic receptor antagonistic property. Another 5-HT2 receptor antagonist, LY53857, which possesses no alpha 1-adrenergic receptor affinity, as well as an alpha 1-adrenergic receptor antagonist, prazosin, were used in this study to further clarify the mechanism of 5-HT in the control of PRL secretion. Adult female Sprague-Dawley rats ovariectomized for 2-3 weeks and given a single injection of polyestradiol phosphate were studied 6 days later. Ket, LY53857 and prazosin were examined singly or in combination and animals were injected twice on the sampling day at 1200 and 1300h, respectively. The dosages were as follows: Ket and LY53857, 3 mg/kg BW, ip and 2 mg/kg BW, sc; prazosin, 1 mg/kg BW, ip and 0.7 mg/kg BW, sc. Blood samples were drawn from indwelling intraatrial catheters throughout the afternoon PRL surge.     

Turnover rates of hypothalamic dopamine associated with the two types of prolactin surges during pseudopregnancy in rats.

Two surges of prolactin (PRL) are observed daily during pseudopregnancy (PSP) in the rat: the nocturnal (N) surge at dawn and the diurnal (D) surge in the evening. In order to clarify differences in the controlling mechanisms of the two types of PRL surges, we attempted to examine the turnover rates of dopamine (DA) and norepinephrine (NE) in the preoptic-anterior hypothalamus (PAH) and mid-posterior hypothalamus (MPH) on day 5-6 of PSP. The turnover rates of DA in the hypothalamus were inversely correlated with the serum PRL levels at the D surge when a significant increase in serum PRL was accompanied by not only a marked decrease in turnover rates of DA in the PAH, but also a slight decrease in turnover rates of the amine in the MPH. Contrarily, no significant decrease occurred in the turnover rates of DA in the hypothalamus at the N surge. There was no obvious correlation between the turnover rates of NE in the hypothalamus and the serum PRL levels at either PRL surge. These findings suggest that decreased turnover rates of DA in the hypothalamus are involved in the D surge, and it is most probable that the N PRL surge occurs under the control of another factor such as the hypothalamic PRL-releasing factor.     

Pituitary prolactin concentrations associated with daily prolactin surges in pseudopregnant rats

During pseudopregnancy (PSP) two surges of prolactin (PRL) secretion from the pituitary are observed, the nocturnal surge at dawn and the diurnal surge in the evening. An attempt was made to clarify the correlation between changes in serum and pituitary PRL concentrations on day 5-6 of PSP. During the nocturnal surge, pituitary PRL concentration decreased significantly from 0000 hr to 0300-0600 hr. On the other hand, the high pituitary PRL concentration remained unchanged during the diurnal surge from 1200 hr to 1800 hr. These findings suggest that the nocturnal and diurnal PRL surges are regulated by separate controlling mechanisms.     

Effects of naloxone on basal and stress-induced prolactin secretion,in intact,hypothalamic deafferentated,adrenalectomized, and dexamethasone-pretreated male rats

The effects of naloxone (Nal) on basal and stress-induced PRL secretion were investigated in intact (N) adult male rats, as were its effects in rats with complete hypothalamic deafferentiation (CHD), in adrenalectomized (adrenX) rats, and in rats pretreated with dexamethasone (dex). Forty-five minutes subsequent to Nal administration (5mg/kg, BW, IP) basal serum levels of PRL were reduced by approximately 25% (p<0.05), in both N and CHD groups. PRL secretory responses to acute exposure to both photic and acoustic stress were markedly attenuated in Nal-injected, as compared to vehicle-injected animals. Basal serum PRL concentrations were elevated by 40% in adrenX rats (p<0.05), as compared to controls. In (p<0.05) in dex-treated rats, as compared to controls. In both these experimental groups, Nal administration caused significant reductions in serum PRL. This study demonstrates that stress-induced, as well as basal PRL secretion, is attenuated by Nal, and points to a hypothalamic site of action in this regard. Furthermore, these Nal effects are independent of glucocorticoid interactions with the CNS.     

Effects of ketanserin on DOI-, MCPP- and TRH-induced prolactin secretion in estrogen-treated rats.

The effects of ketanserin (Ket), a serotonin (5-HT2) receptor antagonist, on DOI- and mCPP-, two 5-HT agonists, and TRH-induced PRL secretion were studied. Adult female Sprague-Dawley rats ovariectomized for two weeks and treated with a long-acting estrogen, polyestradiol phosphate for one week were used. Drug administration and serial blood sampling were accomplished through indwelling intraatrial catheters which were implanted two days before the experiment. Both DOI (0.5 mg/kg BW) and mCPP (1 mg/kg BW) stimulated prolactin secretion within 10 min after iv injection and the effects were diminished by 30 min. In animals pretreated with Ket (5 mg/kg BW, sc), the effect of DOI was blocked, while that of mCPP was augmented. Co-administration of Ket (1 mg/kg BW, iv) with DOI or mCPP produced similar effect. Pretreatment with Ket, similar to sulpiride (Sulp), a dopamine antagonist, potentiated the TRH-induced prolactin secretion. Co-administration of Ket and Sulp further potentiated the TRH action. It is concluded that Ket not only acts as a 5-HT2 receptor antagonist that blocks the action of DOI, but may also act on dopamine receptor(s) with lower sensitivity to Sulp.     

Effects of (-)-trans- delta 9-tetrahydrocannabinol on serum prolactin in the pseudopregnant rat

Groups of pseudopregnant rats were injected intravenously with (-)-trans- delta 9-tetrahydrocannabinol (THC) to determine its effects on serum prolactin (PRL) and the maintenance of pseudopregnancy. A single injection of 4 mg THC/kg BW at 2400 h on the first day of leukocytic vaginal smears of pseudopregnancy (D-1) delayed the ensuing nocturnal PRL surge for approximately one hour. When THC (1.0 mg/kg BW) was administered hourly from 2400 h on D-1 through 1700 h on D-2, the nocturnal surge was blocked and serum PRL levels were suppressed until 0600 h on D-2, but not thereafter. Neither treatment altered the duration of pseudopregnancy. These results indicate that the nocturnal surge secretion of PRL during early pseudopregnancy in the rat is sensitive to THC suppression, but that this suppression is not adequate to influence the duration of pseudopregnancy. The mechanism through which THC exerts this action remains unknown.     

Effects of serotonin depletion byp-chlorophenylalanine,p-chloroamphetamine or 5,7-dihydroxytryptamine on central dopaminergic neurons: Focus on tuberoinfundibular dopaminergic neurons and serum prolactin

Three serotonin (5-HT) neurotoxins,p-chlorophenylalanine (PCPA, 125 and 250 mg/kg, i.p.),p-chloroamphetamine (PCA, 10 mg/kg, i.p.) and 5,7-dihydroxytryptamine (5,7-DHT, 200 µg/rat, i.c.v.) were used to examine whether depletion of central 5-HT has an effect on central dopaminergic (DA) neuronal activities or on prolactin (PRL) secretion. Adult ovariectomized Sprague-Dawley rats primed with estrogen (polyestradiol phosphate, 0.1 mg/rat, s.c.) were treated with one of three neurotoxins and then decapitated in the morning after 3–7 days. Blood sample and brain tissues were collected. The acute effect of PCA (from 30 to 180 min) was also determined. The concentrations of 5-HT, DA and their metabolites, 5-hydroxyindoleacetic acid and 3,4-dihydroxyphenylacetic acid, in the median eminence, striatum and nucleus accumbens were determined by HPLC-electrochemical detection. All three toxins significantly depleted central 5-HT stores by 11–20%. Except for PCPA, neither PCA nor 5,7-DHT had any significant effect on basal DA neuronal activities or PRL secretion. PCA also exhibited an acute effect on the release and reuptake of 5-HT and DA. In summary, depletion of central 5-HT stores to a significant extent for 3–7 days did not seem to affect basal DA neuronal activity and PRL secretion.     

Male copulatory behavior triggers nightly prolactin surges resulting in successful pregnancy in rats

A positive correlation between the number of preejaculatory intromissions that a female receives during copulation and the probability of successful pregnancy has been demonstrated previously. In the present investigation the nocturnal secretion of prolactin (PRL) was followed for 4 days after mating in female rats receiving either 3–5 intromissions before ejaculation (low intromission group) or 15–18 intromissions (high intromission group). Nightly PRL surges occurred in most of the females (9/12) in the high intromission group and the same 9 females became pregnant. Only 2/9 females in the low intromission group exhibited nightly PRL surges and again only these 2 females became pregnant. This study demonstrates that the stimulation which the female receives from multiple intromissions during mating is effective in setting off nightly PRL surges. We propose that the so-called pregnancy-inducing neuroendocrine reflex which is triggered in this manner is expressed in a characteristic pattern of nightly surges of prolactin, the hormone known to be essential for the activation of the corpora lutea and their secretion of progesterone.     

Effects of estradiol on the prolactin surges and the feedback mechanisms of gonadotropins in pseudopregnant rats

The influences of estradiol on the prolactin (PRL) surges and on the secretion of gonadotropins (LH and FSH) were investigated in the pseudopregnancy (PSP) of acutely ovariectomized rats. The four following experimental groups were prepared: 1) intact PSP as a control, 2) ovariectomy was performed on day 0 of PSP (OVX), 3) a Silastic tube containing estradiol was implanted for day 1-4 into the OVX rats (OVX-E 1-4), and 4) the Silastic tube was implanted for day 5-8 by the same manner into the OVX rats (OVX-E 5-8). In the OVX group nocturnal (N) PRL surges were observed at 0500 h on days 4, 8 and 12 examined, and increased secretions of LH and FSH were noted. In the OVX-E 1-4 group, the N PRL surge was suppressed on day 4, and the suppressed N PRL surge did not occur on day 8, after the removal of the implanted tubes. Diurnal (D) PRL surges with LH surges were observed at 1700 h on day 4 in these rats. Similarly, more remarkable results were obtained on days 8 and 12 in the OVX-E 5-8 group than in the OVX-E 1-4.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolactin secretory rhythm of mated rats induced by a single injection of oxytocin

Mating or vaginocervical stimulation [copulatory stimulus (CS)] induces two daily surges of the hormone prolactin (PRL) in rats. This unique secretory pattern of PRL surges is characteristic for the first half of pregnancy and is also present in ovariectomized (OVX) rats. Studies have shown that CS additionally provokes an acute release of the hormone oxytocin (OT). In this study, we tested whether a single injection of OT (iv) is sufficient to initiate the PRL secretion pattern of OVX/CS rats. Furthermore, we measured the 24-h profile of dopamine (DA) content in the anterior lobe of the pituitary gland, because DA is the major inhibitory factor of PRL secretion. The results indicated that a single injection of OT induces a PRL secretory rhythm and a DA release pattern similar to that initiated by CS. Immunocytochemical investigation showed that particular OTergic neurons in the hypothalamus express receptors for PRL, as well as for vasoactive intestinal polypeptide, which indicates an involvement in generating the PRL rhythm and entraining it to the ambient photoperiod. On the basis of this study, we suggest that the PRL-DA inhibitory feedback loop between lactotrophs and DAergic neurons plays a crucial role in generating the oscillatory PRL secretion pattern in CS rats. A timing signal, likely provided by the hypothalamic suprachiasmatic nucleus, entrains the autonomous PRL oscillation to a particular time of day. Mathematical modeling was used to illustrate the proposed network function. The experimental results further suggest an additional feedback mechanism in which certain hypothalamic OTergic neurons are influenced by PRL.     

人参茎叶皂甙对大鼠垂体催乳素分泌的影响及其机制的探讨

本实验观察了人参茎叶皂甙(GSLS)对雄性大鼠血浆催乳素水平、垂体催乳素细胞超微结构和下丘脑中枢神经递质的影响。结果表明:5～100mg/kg的GSLS可刺激催乳素的释放,剂量加大反而无效;GSLS还可拮抗急性饥饿所致的大鼠垂体催乳素细胞超微结构的损伤;GSLS能分别使大鼠下丘脑中多巴胺和5-羟色胺含量增高和降低。结果表明,GSLS有刺激垂体催乳素分泌的作用,其机制可能与其直接作用于垂体细胞和/或经下丘脑中多巴胺和5-羟色胺含量的变化有关。     

Extrahypothalamic control of daily surges of prolactin secretion in pseudopregnant rat

The role of the limbic forebrain structures in controlling twice daily surges of prolactin (PRL) induced by cervical stimulation was investigated after acute or chronic deafferentation of the limbic forebrain afferents to the hypothalamus in rats. The preoptic area-roof section (POA-RS), which interrupted the rostral limbic afferents at the dorsal level of the anterior commissure, induced pseudopregnancy (PSP) and initiated the same nocturnal PRL surges as those initiated by the cervical stimulation. Diurnal PRL surges, however, did not occur following this procedure. The nocturnal PRL surge by POA-RS also occurred in ovariectomized rats. Deafferentation between the diagonal band of Broca and the medial preoptic area (F2-cut) initiated PSP in 37 % of the rats and induced an apparent but small nocturnal PRL surge. The rats with POA-RS or F2-cut showed restoration of their regular estrous cyclicities. Cervical stimulation after POA-RS did not affect the initiation of nocturnal PRL surge induced by POA-RS alone. POA-RS after cervical stimulation also did not affect the initiation of nocturnal PRL surge induced by cervical stimulation, though a diurnal PRL surge was initiated in these rats. The cut made just before the diagonal band of Broca after cervical stimulation did not inhibit the occurrence of either surge. Nocturnal and diurnal PRL surges were manifested after cervical stimulation in the rats with chronic POA-RS or F2-cut and their vaginal cyclicities were resumed. These results suggest that the limbic forebrain structures are not indispensable for the initiation of nocturnal PRL surges induced by cervical stimulation but may modify the hypothalamic mechanism(s) initiating a nocturnal PRL surge through the rostral part of the hypothalamus.     

Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens

Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs). Lack of response could be due to inhibition of dopamine (DA) release by serotonin (5-HT) through 5-HT_2C receptors. Combining an SSRI with a 5-HT_2C antagonist may result in improved efficacy by causing simultaneous increases of 5-HT and DA. In order to test this augmentation strategy, male Wistar rats were treated (s.c.) with an acute dose of the SSRI citalopram (Cit, 5 mg/kg), the 5-HT_2C antagonist SB 242084 (SB, 2 mg/kg), or Cit + SB, and the effect on 5-HT and DA release in the nucleus accumbens (NAcc) was assessed by microdialysis. In a separate experiment, animals were treated with vehicle, Cit (20 mg/kg/d), SB (2 mg/kg/d) or Cit + SB for a period of 2 days (s.c.), and the impact on the release of 5-HT and DA in the ventral tegmental area (VTA) and NAcc was studied. On the day of microdialysis, 5-HT_2C receptor sensitivity was assessed with an SB challenge. Acutely administered Cit + SB increased 5-HT release in the NAcc more than Cit alone. SB alone increased DA release in the NAcc (not in the VTA), but when administered together with Cit, this effect was abolished. A 2-day treatment with Cit or Cit + SB increased 5-HT release in both VTA and NAcc. Combining Cit with SB augmented the effect of Cit in the VTA. DA release in VTA and NAcc was only significantly increased after 2-days of treatment with Cit + SB. In conclusion, Cit + SB had synergistic effects on 5-HT and DA release after 2-days of treatment, probably related to a decreased tonic inhibition of DA release via 5-HT_2C receptors. Regional differences occur and future studies should elucidate if this augmentation strategy is beneficial at the behavioral level.     

Induction of daily PRL surges in rats by chronic treatment with progesterone

The effect of a high plasma progesterone level on the PRL releasing mechanism was investigated in rats of both sexes. Progesterone levels were maintained by implanting silicone tubes filled with the steroid. In the intact female, 6 progesterone tubes (inner diameter 2 mm; outer diameter 3 mm; length 40 mm) were implanted subcutaneously on the estrous day. With 2- to 5- day latent periods, the daily rise in the plasma PRL level was observed coincident with the time of nocturnal surge in the pseudopregnant rats induced by cervical stimulation. The same treatment applied to ovariectomized rats induced by cervical stimulation. The same treatment applied to ovariectomized rats induced diurnal and nocturnal surges. The peak height was lower in ovariectomized rats than that in intact or normal pseudopregnant rats, and was restored to almost the normal range by concomitant implantation of estradiol with progesterone. This latter protocol, however, did not induce any PRL surge in chronically orchidectomized rats. These results suggest that chronically elevated progesterone levels can induce such PRL surges as are observed in pseudopregnant rats, estradiol enhances the magnitude of the PRL surge, and the progesterone sensitive central mechanism, controlling the PRL surge, does not exist in adult male rats.     

Effects of muscimol and baclofen on levels of monoamines and their metabolites in the El mouse brain

We compared the changes in monoamines and their metabolites in the El mouse brain induced by GABA-A and GABA-B receptor agonists. Muscimol was used as a GABA-A receptor agonist, and baclofen as a GABA-B receptor agonist. Muscimol (3 mg/kg) significantly increased the DOPAC level in all parts of the mouse brain and the HVA level in the cortex, striatum, and midbrain. No significant change was observed in the dopamine (DA) level. These findings suggest that muscimol may accelerate both the synthesis and catabolism of DA. Baclofen (20 mg/kg) increased the DA level in the hippocampus and midbrain, and the DOPAC level in the hippocampus. Muscimol increased 5-HIAA levels and decreased 5-HT levels. This result suggests that 5-HT metabolism is accelerated by muscimol. No change in 5-HT or 5-HIAA levels was induced by baclofen. The GABA-A receptor system seems to have a potent effect not only on DA neurons, but on 5-HT neurons. However, the GABA-B receptor system appears to have almost no effect on 5-HT neurons, though it appears to have some effect on DA neurons.     

Alterations in Extracellular and Tissue Levels of Biogenic Amines in Rat Brain Induced by the Serotonin2 Receptor Antagonist, Ritanserin

Systemic administration of ritanserin elicited rapid changes in dopamine (DA) and serotonin (5-HT) levels in both dialysate and neuronal tissue extracts. These effects occurred in both a site-selective and a dose-related manner. Increases in extracellular levels of DA and 5-HT in the nucleus accumbens were maximal at 120-140 min after treatment. A dose of 0.63 mg/kg of ritanserin elicited larger and more prolonged increases in extracellular DA and 5-HT levels than did the 0.3 mg/kg dose. By contrast, 0.63 mg/kg of ritanserin elicited no changes in either DA or 5-HT levels with dialysate collected from the striatum. Ritanserin also induced dose-related decreases in tissue levels of DA and 5-HT from the nucleus accumbens. The site specificity of action was again noted in that there were no dose-dependent decreases in tissue levels of DA or 5-HT measured from the striatum. Ritanserin exerted little effect on metabolite levels from either dialysate or tissue extracts. Taken together, these findings show that selective 5-HT2 receptor antagonism modulates DA and 5-HT neurotransmission in a specific manner. These actions appear to involve increased release of DA and 5-HT rather than significant changes in metabolism. These findings add further weight to the importance of 5-HT2 receptor interactions as an important component of antipsychotic activity.     

Activation of 5-HT(1A) but not 5-HT(1B) receptors attenuates an increase in extracellular dopamine derived from exogenously administered L-DOPA in the striatum with nigrostriatal denervation

In order to determine whether L-DOPA-derived extracellular dopamine (DA) in the striatum with dopaminergic denervation is affected by activation of serotonin autoreceptors (5-HT(1A) and 5-HT(1B) receptors), we applied in vivo brain microdialysis technique to 6-hydroxydopamine-lesioned rats and examined the effects of the selective 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the selective 5-HT(1B) receptor agonist CGS-12066 A on L-DOPA-derived extracellular DA levels. Single L-DOPA injection (50 mg/kg i.p.) caused a rapid increase and a following decrease of extracellular DA, with a peak value at 100 min after L-DOPA injection. Pretreatment with both 0.3 mg/kg and 1 mg/kg 8-OH-DPAT (i.p.) significantly attenuated an increase in L-DOPA-derived extracellular DA and the times of peak DA levels were prolonged to 150 min and 225 min after L-DOPA injection, respectively. These 8-OH-DPAT-induced changes in L-DOPA-derived extracellular DA were antagonized by further pretreatment with WAY-100635, a selective 5-HT(1A) antagonist. In contrast, intrastriatal perfusion with the 5-HT(1B) agonist CGS-12066 A (10 nM and 100 nM) did not induce any changes in L-DOPA-derived extracellular DA. Thus, stimulation of 5-HT(1A) but not 5-HT(1B) receptors attenuated an increase in extracellular DA derived from exogenous L-DOPA. These results support the hypothesis that serotonergic neurons are primarily responsible for the storage and release of DA derived from exogenous L-DOPA in the absence of dopaminergic neurons.