The effect of various centrally active drugs on adenosine uptake by the central nervous system

1. Adenosine and its analogs depress the firing of neurons in various brain regions. The primary mode of action of adenosine in exerting this effect appears to be the depression of transmitter release from presynaptic nerve terminals. This is a result of reduced calcium mobilization. 2. Adenosine uptake inhibitors and deaminase inhibitors depress the firing of central neurons. Adenosine antagonists, caffeine and theophylline, excite central neurons. Adenosine is therefore likely to be released in sufficient quantities to exert an ongoing modulation of synaptic transmission in the intact brain. 3. A number of groups of centrally active drugs inhibit adenosine uptake by brain synaptosomal preparations. These include the benzodiazepines, phenothiazines, various other sedatives and hypnotics, tricyclic antidepressants, non-steroidal anti-inflammatory analgesics, some steroids, diphenylhydantoin, puromycin and toyocamycin. 4. It is proposed that many agents with anxiolytic, sedative, analgesic or anti-convulsant actions may achieve their effects by inhibiting adenosine uptake and thus potentiating extracellular adenosine levels. 5. Morphine also elevates extracellular adenosine levels but achieves this by enhancing adenosine release.     

Complex Inhibition of [3H]Imipramine Binding by Serotonin and Nontricyclic Serotonin Uptake Blockers

Tricyclic antidepressant drugs inhibit [3H]imipramine binding to the rat brain cortex in a competitive manner, giving linear Hofstee plots and Hill coefficients of approximately 1.0. Serotonin, the only neurotransmitter to inhibit [3H]imipramine binding, does so in a complex manner, exhibiting a Hill coefficient of 0.40-0.50. Nontricyclic inhibitors of serotonin uptake such as fluoxetine, paroxetine, norzimelidine, and citalopram inhibit [3H]imipramine binding in the same complex manner as serotonin. These results are interpreted as suggesting that [3H]imipramine binds to a site associated with the serotonin uptake system but different from either the substrate recognition site for serotonin or the site of action of the nontricyclic inhibitors of neuronal uptake of serotonin.     

Effects ofp-chloroamphetamine on brain serotonin neurons

p-Chloroamphetamine (PCA) is a useful pharmacologic tool for selectively increasing brain serotonin function acutely by release of serotonin into the synaptic cleft. PCA produces behavioral, neurochemical and neuroendocrine effects believed due to serotonin release after doses in the range of 0.5–5 mg/kg. At higher doses and at longer times, PCA causes depletion of brain serotonin. The mechanisms of this depletion are not well understood but require the serotonin uptake carrier. Antagonism of PCA-induced depletion of brain serotonin is a useful means of assessing the ability of a compound to block the serotonin uptake carrier on brain serotonin neurons. PCA can also be used as a neurotoxic agent to deplete brain serotonin in functional studies, apparently by destroying some serotonergic nerve terminals. Used in this way, PCA has an advantage over 5,6- and 5,7-dihydroxytryptamines in being effective by systemic injection, and it affects brain serotonergic projections with a different neuroanatomic specificity than the dihydroxytryptamines.Special issue dedicated to Dr. Morris H. Aprison.     

Synaptic and Extrasynaptic Secretion of Serotonin

Serotonin is a major modulator of behavior in vertebrates and invertebrates and deficiencies in the serotonergic system account for several behavioral disorders in humans.The small numbers of serotonergic central neurons of vertebrates and invertebrates produce their effects by use of two modes of secretion: from synaptic terminals, acting locally in hard wired circuits, and from extrasynaptic axonal and somatodendritic release sites in the absence of postsynaptic targets, producing paracrine effects.In this paper, we review the evidence of synaptic and extrasynaptic release of serotonin and the mechanisms underlying each secretion mode by combining evidence from vertebrates and invertebrates. Particular emphasis is given to somatic secretion of serotonin by central neurons.Most of the mechanisms of serotonin release have been elucidated in cultured synapses made by Retzius neurons from the central nervous system of the leech. Serotonin release from synaptic terminals occurs from clear and dense core vesicles at active zones upon depolarization. In general, synaptic serotonin release is similar to release of acetylcholine in the neuromuscular junction.The soma of Retzius neurons releases serotonin from clusters of dense core vesicles in the absence of active zones. This type of secretion is dependent of the stimulation frequency, on L-type calcium channel activation and on calcium-induced calcium release.The characteristics of somatic secretion of serotonin in Retzius neurons are similar to those of somatic secretion of dopamine and peptides by other neuron types. In general, somatic secretion by neurons is different from transmitter release from clear vesicles at synapses and similar to secretion by excitable endocrine cells.     

Properties allowing the attribution to gamma-hydroxybutyrate the quality of neurotransmitter in the central nervous system

gamma-Hydroxybutyrate (GHB) fulfills the main criteria of a neurotransmitter: it is unevenly distributed in C.N.S.; it is synthesized from succinic semi-aldehyde by a specific semi-aldehyde succinic reductase localized in neurons, in some dendrites and synaptic terminals; GHB is released by tissue slice depolarization, this release being reduced by 50-60% in a Ca++ free medium. Tetrodotoxin and verapamil strongly inhibited the depolarization evoked-release; high affinity heterogenously distributed binding sites for gamma-hydroxybutyrate exist in the brain. This binding does not require Na+. The bound gamma-hydroxybutyric acid is not displaceable by GABA or GABA agonists. Binding sites are enriched in the synaptosomal fraction; after micro-iontophoretic application, GHB exerts a depressant action on nigral and neocortical cells which is resistant to the presence of bicuculline methiodide. In neuronal cultures, GHB causes a hyperpolarization similar to that produced by GABA; high affinity uptake system for GHB exists both in purified plasma membrane vesicles and in brain tissue slices. This uptake is dependent on an Na+ gradient and is inhibited by ouaba?n and dinitrophenol; GABA does not modify GHB uptake by rat brain slices; GABA derived GHB has a turnover time almost three times faster than that of whole brain serotonin, 6-8 times as rapid as that of whole brain dopamine and 13-19 times as rapid as that of whole brain norepinephrine.     

Inhibition of vesicular uptake of monoamines by hyperforin

Hyperforin is the major active ingredient of Hypericum perforatum (St John's Wort), a traditional antidepressant medication. This study evaluated its inhibitory effects on the synaptic uptake of monoamines in rat forebrain homogenates, comparing the nature of the inhibition at synaptic and vesicular monoamine transporters. A hyperforin-rich extract inhibited with equal potencies the sodium-dependent uptake of the monoamine neurotransmitters serotonin [5-HT], dopamine [DA] and norepinephrine [NE] into rat brain synaptosomes. Hyperforin inhibited the uptake of all three monoamines noncompetitively, in marked contrast with the competitive inhibition exerted by fluoxetine, GBR12909 or desipramine on the uptake of these monoamines. Hyperforin had no inhibitory effect on the binding of [3H]paroxetine, [3H]GBR12935 and [3H]nisoxetine to membrane presynaptic transporters for 5-HT, DA and NE, respectively. The apparent presynaptic inhibition of monoamine uptake could reflect a "reserpine-like mechanism" by which hyperforin induced release of neurotransmitters from synaptic vesicles into the cytoplasm. Thus, we assessed the effects of hyperforin on the vesicular monoamine transporter. Hyperforin inhibited with equal potencies the uptake of the three tritiated monoamines to rat brain synaptic vesicles. Similarly to the synaptosomal uptake, the vesicular uptake was also noncompetitively inhibited by hyperforin. Notably, hyperforin did not affect the direct binding on [3H]dihydrotetrabenazine, a selective vesicular monoamine transporter ligand, to rat forebrain membranes. Our results support the notion that hyperforin interferes with the storage of monoamines in synaptic vesicles, rather than being a selective inhibitor of either synaptic membrane or vesicular monoamine transporters.     

Clostridium neurotoxins influence serotonin uptake and release differently in rat brain synaptosomes

Clostridium neurotoxins produce inhibition of both basal and K(+)-evoked serotonin release in rat brain synaptosomes. To produce these effects, tetanus toxin (TeTx), as well as botulinum neurotoxin type A (BoNT/A), added to brain synaptosomes, must be incubated at 37 degrees C over a long interval (hours). This serotonin exocytosis inhibition was abolished with previous treatment with specific Zn2(+)-metalloprotease inhibitors. Nevertheless, a short incubation time produces different behavior of the indicated neurotoxins: TeTx significantly blocks the sodium-dependent, high-affinity serotonin uptake, whereas a small increase of this uptake was found with BoNT/A. Both Zn2(+)-metalloprotease active fragments, light chains of TeTx and BoNT/A, are unable to reproduce the block of the serotonin uptake, whereas the C-terminal portion of the TeTx heavy chain (Hc-TeTx), which binds specifically to the target tissue, inhibited the serotonin uptake in a dose-dependent manner. The IC50 of Hc-TeTx ranges from 0.62 to 2.08 nM. Binding of [3H]imipramine and [3H]serotonin did not change after toxin treatments, which indicates that these clostridium neurotoxins do not act on the serotonin high-affinity site at the serotonin transporter or at other serotonin high-affinity sites. These results could indicate that TeTx and Hc-TeTx bind to different targets than BoNT/A in the plasma membrane.     

Spatial-specific action of serotonin within the leech midbody ganglion

Serotonin is a conspicuous neuromodulator in the nervous system of many vertebrates and invertebrates. In previous experiments performed in the leech nervous system, we compared the effect of the amine released from endogenous sources [using selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine] with that of bath-applied serotonin. The results suggested that the amine does not reach all its targets in a uniform way, but produces the activation of an interneuronal pathway that generated specific synaptic responses on different neurons. Taking into account that the release of the amine is often regulated at the presynaptic level, we have investigated whether autoreceptor antagonists mimic the SSRIs effect. We found that methiothepin (100 microM) produced similar effects than fluoxetine. To further test the hypothesis that endogenous serotonin produce its effect by acting locally at specific sites, we analyzed the effect of iontophoretic applications of serotonin. We found a site in the neuropil of the leech ganglia where serotonin application mimicked the effect of the SSRIs and the 5-HT antagonist. The results further support the view that the effect of serotonin exhibits a spatial specificity that can be relevant to understand its modulatory actions.     

Relation between brain 5-HIAA levels and the release of serotonin into brain synapses

Our findings in experiments using reserpine, an amine releaser, and fluoxetine, a serotonin uptake blocker, indicate that the reuptake of serotonin from brain synapses precedes its transformation to 5-hydroxyindoleacetic acid (5-HIAA). Male rats were injected with reserpine or fluoxetine alone, or with fluoxetine one hour before reserpine; control animals received diluents. Reserpine lowered brain serotonin and raised brain 5-HIAA levels. Fluoxetine alone did not change serotonin levels but lowered 5-HIAA. Fluoxetine completely antagonized the reserpine-induced increase in 5-HIAA, and significantly enhanced its depletion of serotonin. In order to determine whether the ability of fluoxetine to block the rise in 5-HIAA after reserpine resulted from its effect on serotonin reuptake or from suppression of impulse flow along serotoninergic neurons, we also examined the effects of the drugs on serotonin metabolism in distal portions of acutely transected neurons (which, presumably, were no longer able to conduct impulses). No differences were noted between the responses of intact and lesioned serotoninergic neurons, indicating that fluoxetine's blockade of the rise in brain 5-HIAA results from its effect on serotonin reuptake.     

Partitioning of the serotonin transporter into lipid microdomains modulates transport of serotonin

The serotonin transporter (SERT) is an integral membrane protein responsible for the clearance of serotonin from the synaptic cleft following the release of the neurotransmitter. SERT plays a prominent role in the regulation of serotoninergic neurotransmission and is a molecular target for multiple antidepressants as well as substances of abuse. Here we show that SERT associates with lipid rafts in both heterologous expression systems and rat brain and that the inclusion of the transporter into lipid microdomains is critical for serotonin uptake activity. SERT is present in a subpopulation of lipid rafts, which is soluble in Triton X-100 but insoluble in other non-ionic detergents such as Brij 58. Disaggregation of lipid rafts upon depletion of cellular cholesterol results in a decrease of serotonin transport capacity (V(max)), due to the reduction of turnover number of serotonin transport. Our data suggest that the association of SERT with lipid rafts may represent a mechanism for regulating the transporter activity and, consequently, serotoninergic signaling in the central nervous system, through the modulation of the cholesterol content in the cell membrane. Furthermore, SERT-containing rafts are detected in both intracellular and cell surface fractions, suggesting that raft association may be important for trafficking and targeting of SERT.     

Functional expression of the serotonin transporter in immortalized rat brain microvessel endothelial cells

There is evidence from recent studies that the brain endothelium (of capillaries and/or larger vessels) may serve as a specific target for serotonin [5-hydroxytryptamine (5-HT)]. This neurotransmitter is expected to be involved in the regulation of the blood-brain barrier (BBB) permeability and/or of the cerebral blood flow via receptor-mediated mechanisms. Effective control of these processes depends on a speedy uptake and metabolism of released 5-HT molecules. To realize this, a similar mechanism of 5-HT uptake as in brain may exist at the BBB. In this study, we have demonstrated using RT-PCR that 5-HT transporter mRNA is present in the brain endothelium and that a saturable transport system for 5-HT is functionally expressed in immortalized rat brain endothelial cells (RBE4 cells). These cells take up [3H]5-HT by an active saturable process with a Km value of 397 +/- 64 nmol/L and a transport capacity of 51.7 +/- 3.5 pmol x g(-1) x min(-1). The 5-HT uptake depends on Na+, as indicated by the replacement of NaCl by LiCl. The 5-HT uptake was sensitive to specific 5-HT transport inhibitors such as paroxetine, clomipramine, fluoxetine, and citalopram but not to inhibitors of the vesicular amine transporter such as reserpine or tetrabenazine. Our results demonstrate that cerebral endothelial cells are able to participate actively in the removal and metabolism of the released 5-HT, which supports the concept of direct serotoninergic regulation of the BBB function.     

Assessment of blood platelets as a model for CNS response: comparative effects of caffeine on 5-HT uptake and release mechanisms in rat platelets and rat brain serotonin neurons

We have previously reported that caffeine significantly enhanced 5-HT uptake and reduced 5-HT release from crude synaptosomal fractions obtained from rat cerebral cortex and from midbrain raphe region. Blood platelets, as reported by many laboratories and also demonstrated in our own labs, have a very active mechanism for 5-HT uptake and storage. In this regard platelets bear a high degree of similarity to brain serotonin neurons. The present experiments were, therefore, carried out to investigate the effects of caffeine on 5-HT uptake and release from rat platelets in an attempt to assess the possibility of using platelets as a model for studying the CNS effects of caffeine. Platelet rich plasma was prepared from the trunk blood of decapitated rats. Effects of caffeine were investigated at 10(-7), 10(-6), 10(-5) and 10(-4)M, on both the high affinity 3H-5-HT uptake and the spontaneous 5-HT release from 3H-5-HT preloaded platelets. The results show that caffeine did not change 5-HT uptake into platelets. In brain synaptosomes the same concentration of caffeine, however, increased 5-HT uptake dose-dependently. The results also revealed that caffeine increased 5-HT release from rat platelets in a concentration-dependent manner. The concentrations 10(-6), 10(-5), and 10(-4)M increased release significantly compared to control. This finding is also in contrast to that observed in synaptosomes of brain serotonin neurons where caffeine decreased 5-HT release. It is concluded, therefore, that the rat blood platelet is not a suitable model for studying these CNS actions of caffeine. Furthermore, our observations imply that rat platelet serotonin uptake and release mechanisms are not identical to those mechanisms in brain serotonin neurons.     

Interaction of diet and drugs in the regulation of brain 5-hydroxyindoles and the response to painful electric shock.

The long-term consumption of a tryptophan-poor, corn diet by rats decreases electroshock response thresholds. This hyperalgesia appears to be related directly to diet-induced reductions in the brain concentrations of the putative neurotransmitter, serotinin. Rehabilitating corn-fed animals by feeding them the corn diets supplemented with tryptophan restores brain serotonin and pain thresholds to normal; similarly, injecting the tryptophan-deficient, corn-fed animals with fluoxetine, a drug that blocks the uptake of serotonin into brain neurons, also restores the electroshock response thresholds to control levels. The tryptophan hydroxylase inhibitor, $\text{p}$-chlorophenylalanine, increases the hyperalgesia to electroshock in corn-fed rats and further reduces brain serotonin concentrations. Injection of the amino acid valine, on the other hand, produces hyperalgesia and decreases brain serotonin in casein-fed rats but not in animals fed the corn diet. These data lend support to the hypothesis that serotonin neurons may mediate the sensitivity or reactivity to painful stimuli.     

Nisoxetine prevents the 6-hydroxydopamine induced decrease in post-decapitation convulsions

Intraventricular injection of 6-hydroxydopamine (60HDA) to rats caused a marked reduction in post-decapitation convulsions (PDC), which was also observed in rats given 60HDA systemically at birth. The reduction in PDC and norepinephrine (NE) content in brain and spinal cord was completely prevented by pretreatment with the selective norepinephrine uptake inhibitor, nisoxetine, but not by fluoxetine, a specific serotonin uptake inhibitor. Presumably nisoxetine prevented the reduction in PDC and NE levels by blocking the entry of 60HDA into the neuron via the membrane uptake pump, and thus preventing subsequent NE depletion and neuron degeneration. These data imply that NE neurons are involved in the neurological mechanism of PDC, although this does not exclude a role for other neurotransmitters such as serotonin (5HT) and dopamine (DA).     

Effects of fluoxetine and its complexes with glycyrrizhinic acid on behavior and brain monoamine levels in rats

Effects of serotonin uptake inhibitor fluoxetine (F) and it's complexes with glycyrrizhinic acid (GA) in molar proportions 1GA : 1F (FGA-1) and 4GA : 1F (FGA-4) on rat behavior in elevated plus-maze and brain monoamine concentrations were studied. Drugs (25 mg/kg) were administered per os 1 h before investigations. F-treated rats showed increased anxiety and reduced locomotor activity, whereas FGA-1 and FGA-4 had no effects on the behaviors. None of the compounds modified brain tissue serotonin content, but all of them decreased the level of its metabolite 5-hydroxyindole-3-acetic acid level in the hypothalamus, and FGA-4 also decreased it in the cortex. Noradrenaline levels were increased in the hypothalamus of rats treated with F in both combinations with GA. In the striatum, F increased dopamine and its metabolite DOPAC levels, but their ratio (an indicator of the neurotransmitter turnover) was not altered by this drug. Unlike F, FGA-1 significantly activated dopamine turnover in the striatum. The data obtained suggested that application of F in complexes with GA significantly modified the drug behavioral effects and these alterations may be related to specific effects of the pure compound and its complexes on the functions of the brain monoaminergic systems that regulate investigated behavior.     

5-Hydroxytryptophyl peptides: potent inhibitors of a storage compartment of serotonin.

Several analogues of 5-hydroxytryptophan were tested for their ability to inhibit the binding of serotonin to serotonin-binding protein (SBP), a protein found within serotonergic neurons which has a high affinity for serotonin. An N-substituted dipeptide, N-acetyl-5-hydroxytryptophan-5-hydroxytryptophan amide, was found to be an inhibitor of this binding. The inhibition (50% at 1.0 μM) was specific, since it did not affect other known sites of serotonin binding. The binding of serotonin to its membrane receptor was not affected by the dipeptide (up to 10 μM). Uptake of serotonin by synaptosomes was only slightly affected (9% at 10 μM), and aromatic-L-amino-acid carboxy-lyase(EC 4.1.1.28) and amine: oxygen oxidoreductase (deaminating) (flavin-containing) (EC 1.4.3.4) were not inhibited (10 μM and 5 mM respectively), The peptide was not hydrolyzed by honiogenates of brain or myenteric plexus. The ¹⁴C-labelled dipeptide was shown to be taken up by synaptosomes. However, the uptake of the peptide was not affected either by drugs that inhibit serotonin uptake or by serotonin itself although the uptake was abolished by excess 5-hydroxytryptophan. Intraventricular injection of N-acetyl dipeptide caused a biphasic effect depending on dose. Lower doses (10nmol) induced a decrease in serotonin brain levels (40%). Higher doses (300 nmol) caused a 95% increase in serotonin levels. It is suggested that 5-hydroxytryptophyl peptides may be used as potent specific inhibitors of SBP, a storage compartment of serotonin.     

Neurochemical characterization of the release and uptake of dopamine in ventral tegmental area and serotonin in substantia nigra of the mouse

In the present report, fast-scan cyclic voltammetry was used to identify the monoamines that were released by electrical stimulation in mouse brain slices containing ventral tegmental area (VTA), substantia nigra (SN) -pars compacta (SNc) and -pars reticulata (SNr). We showed that voltammograms obtained in mouse VTA were consistent with detection of a catecholamine, while those in both subregions of the SN were consistent with detection of an indolamine, based on the reduction peak potentials. We used pharmacological blockade and genetic deletion of monoamine transporters to further confirm the identity of released monoamines in mouse midbrain and to assess the control of monoamines by their transporters in each brain region. Inhibition of dopamine and norepinephrine transporters by nomifensine (1 and 10 microm) decreased uptake rates in the VTA, but did not change uptake rates in either subregion of the SN. Serotonin transporter inhibition by fluoxetine (10 microm) decreased uptake rates in the SNc and SNr, but was without effect in the VTA. Selective inhibition of the norepinephrine transporter by desipramine (10 microm) had no effect in any brain region. Using dopamine transporter- and serotonin transporter-knockout mice, we found decreased uptake rates in VTA and SN subregions, respectively. Peak signals recorded in each midbrain region were pulse number dependent and exhibited limited frequency dependence. Thus, dopamine is predominately detected by voltammetry in mouse VTA, while serotonin is predominately detected in mouse SNc and SNr. Furthermore, active uptake occurs in these areas and can be altered only by specific uptake inhibitors, suggesting a lack of heterologous uptake. In addition, somatodendritic dopamine release in VTA was not mediated by monoamine transporters. This work offers an initial characterization of voltammetric signals in the midbrain of the mouse and provides insight into the regulation of monoamine neurotransmission in these areas.     

Halothane induces vesicular and carrier-mediated release of [3H]serotonin from rat brain cortical slices

The serotonergic system may play a role during general anesthesia but the effect of the volatile anesthetic halothane on the release of serotonin (5-HT) is not fully understood. Rat brain cortical slices were labeled with [3H]5-HT to investigate the effects of halothane on the release of this neurotransmitter from the central nervous system. Halothane induced an increase on the release of [3H]5-HT that was dependent on incubation time and anesthetic concentration (0.006, 0.012, 0.024, 0.036, 0.048 and 0.072 mM). This effect was independent of extracellular calcium and was not affected by tetrodotoxin (blocker of voltage dependent Na+ channels). In contrast, the halothane-evoked [3H]5-HT release was reduced by BAPTA-AM, a membrane-permeable BAPTA analog that chelates intracellular Ca2+. The anesthetic-induced [3H]5-HT release depends on the ryanodine-sensitive intracellular calcium store since it was blocked by dantrolene and azumolene (inhibitors of the calcium-release through ryanodine receptors) but was not affected by aminoethoxydiphenylborate (2-APB), an inhibitor of inositol 1,4,5-triphosphate receptor. The [3H]5-HT release induced by halothane comes mainly from the vesicular pool since it was reduced in about 70% by reserpine, a blocker of vesicular monoamine transporter. The halothane-evoked release of [3H]5-HT release is reduced by fluoxetine, an inhibitor of 5-HT uptake, and the volatile agent also decreased the uptake of [3H]5-HT into rat brain cortical slices. Moreover, a decrease on halothane-induced release of [3H]5-HT was also observed when the brain cortical slices were incubated at low temperature, which is known to interfere with the carrier-mediated release of the neurotransmitter. Ouabain, a Na+/K+ ATPase pump inhibitor, which induces 5-HT release through reverse transport, also decreased [3H]5-HT release induced by halothane, confirming the involvement of a carrier-mediated release of the neurotransmitter in the presence of halothane. In conclusion, these data suggest that halothane induces vesicular and carrier-mediated release of [3H]5-HT in rat brain cortical slices.     

Pharmacologic evidence for a serotonin neural pathway involved in hypothalamus-pituitary-adrenal function in rats.

The hypothesis that a serotonin neural pathway stimulates ACTH secretion in rats was supported by pharmacologic data. Fluoxetine, an inhibitor of serotonin reuptake, caused a dose-related elevation of plasma corticosterone levels in intact but not in hypophysectomized rats. The previously-reported elevation of plasma corticosterone by 5-hydroxytryptophan (5HTP) was confirmed and shown to be stereospecific, L-5HTP being much more active than D-5HTP. Simultaneous injection of subeffective doses of fluoxetine and L-5HTP caused marked elevation of plasma corticosterone. Fluoxetine pretreatment potentiated the elevation of plasma corticosterone by L-5HTP. Although the elevation of plasma corticosterone by fluoxetine was of short duration (perhaps due to compensatory reduction of serotonin release), the potentiation of the L-5HTP effect by fluoxetine lasted for more than 24 hrs as predicted by the duration of uptake inhibition by fluoxetine. The dose-response characteristics for corticosterone elevation and L-5HTP potentiation by fluoxetine were similar to those for serotonin uptake blockade.     

Behavioral and biochemical actions of p-chlorophenylethylamine (p-CPEA) in mice.

p-chlorophenylethylamine (p-CPEA), a metabolite of p-chlorophenylalanine (p-CPA) induces the “serotonin syndrome” which consists of lateral head weaving, Straub tail, hindlimb abduction, tremor, hyperactivity, reciprocal fore-paw treading, salivation and piloerection. These p-CPEA-induced behavioral signs were partially prevented by pretreatment with serotonin (5-HT) uptake blockers (fluoxetine, chlorimipramine, Org 6582) and 5-HT receptor blockers (methiothepin, methysergide, cinnanserin) but not by two depletors of brain 5-HT (p-CPA, reserpine). p-CPEA (50 mg/kg) produces an initial decrease in 5-HT associated with a concurrent increase in 5-hydroxyindoleacetic acid with a maximum change at 30 minutes after injection; these early biochemical changes are prevented by pretreatment with fluoxetine (10 mg/kg). p-CPEA also competes with (³H)-5-HT for 5-HT receptors. The reported paradoxical effects of p-CPA on several behavioral paradigms could be due to its decarboxylation to p-CPEA which may both stimulate 5-HT receptors and enhance 5-HT release.