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Modulation of Neuronal Serotonin Uptake by a Putative Endogenous

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Modulation of Neuronal Serotonin Uptake by a Putative Endogenous Proc. NatL Acad. Sci. USA Vol. 80, pp. 5134-5138, August 1983 Neurobiology Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites (serotonergic axons/adenylate cyclase/p-adrenergic receptor function/antidepressants) MARIA LUISA BARBACCIA, OTTAVIo GANDOLFI, DE-MAW CHUANG, AND ERMINIO COSTA Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D.C. 20032 Contributed by Erminio Costa, May 16, 1983 ABSTRACT Imipramine inhibits the serotonin uptake by [3H]imipramine recognition sites, prevented the down-regu- binding with high affinity to regulatory sites of this uptake located lation of f3-adrenergic recognition sites elicited by two daily in- on axons that release serotonin. The number of imipramine rec- jections of DMI repeated for 3 weeks (18). These data sug- ognition sites located on crude synaptic membrane preparations gested to us that a neuronal regulatory loop might connect 5HT is reduced by two daily injections of imipramine or desmethyl- terminals with the neuron where ,B-adrenergic receptors are imipramine for 3 weeks. When the binding sites for [3H]imipra- located and that this link participates in the attenuation of NE mine are down-regulated the Vma of the neuronal uptake of sero- receptor function and, perhaps, in the antidepressant action of tonin is increased. Moreover, in minces prepared from the brain imipramine and drugs (17, 18). hippocampus of rats receiving imipramine in a dose regimen that related These findings have been reduces the number of [3H]imipramine recognition sites, the ef- replicated by us with repeated daily injections of imipramine ficiency of imipramine as a blocker of the serotonin uptake is di- (19) and confirmed by other laboratories (20). Therefore we de- minished. Hence the high-affinity binding sites for [3H]imipra- cided to study the effect of repeated imipramine injections on mine may have a physiological role in modulation of serotonin the 5HT uptake as a departure point to elucidate the neuronal reuptake. Probably this is mediated by an endogenous effector of circuitry and identify the molecular nature of the modulator(s) these regulatory sites. A nonpeptidic constituent of rat brain ca- that may physiologically operate at the sites where imipramine pable of displacing [3H]imipramine from its high-affinity binding binds, thereby triggering a modulation of the 5HT uptake site and of inhibiting the serotonin uptake in a dose-related man- mechanism. ner has been extracted and its partial purification is described. METHODS Imipramine and desmethylimipramine (DMI) have been used Animals. Male Sprague-Dawley rats (150-250 g) from Zivic- for longer than two decades to relieve the symptoms of depres- Miller were used for all the experiments. The animals were sion (1, 2). Their capacity to block norepinephrine (NE) and housed under standard laboratory conditions with a 12-hr light/ serotonin (5-hydroxytryptamine; 5HT) uptake has been consid- dark cycle and food and water ad lib. The rats were injected ered to be important for their therapeutic action, but when it with imipramine or DMI (10 mg/kg intraperitoneally, twice daily was noted that imipramine and DMI block amine uptake almost for 21 days) and were decapitated 72 hr after the last drug in- instantaneously, whereas their antidepressant action occurs with jection. The control rats received saline intraperitoneally with a latency time of 1-2 weeks (1), the importance of the uptake the same injection schedule. inhibition in explaining their therapeutic action was deem- Materials. Imipramine hydrochloride either was a gift from phasized. Upon repeated daily administration to rats imipra- CIBA-Geigy or was purchased from Sigma. DMI as the hy- mine and a number of its congeners down-regulate the function drochloride was a gift from Merrel Laboratories (Cincinnati, of NE recognition sites in several brain structures (3-6); be- OH). Fluoxetine hydrochloride (LY 110140) and nisoxetine hy- cause the onset of this down-regulation and that of the anti- drochloride (LY 94939) were gifts from Eli Lilly. 5HT as the depressant action are delayed with respect to the beginning of creatine sulfate and pargyline hydrochloride were purchased the treatment, it has been suggested that the NE response down- from Sigma; 5,7-DHT as the creatine sulfate was purchased from regulation and the antidepressant action may be related (6). An Calbiochem-Behring; Pronase was purchased from Boehringer additional tool to study the mechanism of the down-regulation Mannheim; [3H]5HT creatine sulfate (=20 Ci/mmol) and [3H]- of /3-adrenergic receptors became available when Langer and imipramine (-24 Ci/mmol) were from New England Nuclear his colleagues reported that specific Na+-dependent and high- (1 Ci = 3.7 X 1010 Bq). Bio-Gel P-10 (200-400 mesh) and AG affinity binding sites for [3H]imipramine are located in crude 50W-X8 (-SO3 strong cation exchanger) resin were from Bio- synaptic membranes prepared from various structures of mam- Rad. malian brains (7, 8). The maximal number, Bmax, of [3H]imip- 5HT Uptake Assay. 5HT uptake was measured either in syn- ramine binding sites is down-regulated by repeated injections aptosomes or in minces freshly prepared from hippocampi of of imipramine or DMI (9-11). These recognition sites are lo- rats receiving saline or imipramine. The animals were decap- cated on 5HT axon terminals (12-14) and appear to be anatom- itated and the hippocampi were dissected on ice within 45 sec ically and functionally associated with the 5HT uptake mech- and placed in ice-cold Krebs bicarbonate buffer (NaCl, 114 mM; anism (15-17). KCI, 4.7 mM; CaCl2, 2.0 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 In 1981 at a symposium on the mode of action of antide- mM; NaHCO3, 25 mM; dextrose, 2 mg/ml; ascorbic acid, 0.2 pressants we reported that the selective destruction of 5HT ax- mg/ml; Na2EDTA, 0.05 mg/ml; pargyline, 10 AM) until minces ons by 5,7-dihydroxytryptamine (5,7-DHT), which eliminates or synaptosomes were prepared. Minces from rat hippocampi were prepared according to the The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertise- Abbreviations: DMI, desmethylimipramine; NE, norepinephrine; 5HT, ment" in accordance with 18 U.S.C. §1734 solely to indicate this fact. serotonin (5-hydroxytryptamine); 5,7-DHT, 5,7-dihydroxytryptamine. 5134 Downloaded by guest on October 3, 2021 Neurobiology: Barbaccia et al. Proc. Natl. Acad. Sci. USA 80 (1983) 5135 procedure described by Shaskan and Snyder (21) with minor modifications. The hippocampi were cross cut (300 x 300 tim) 0~ by using a tissue chopper (McIlwain and Rodnight). These tis- E Total uptake sue prisms (two hippocampi per 10 ml of buffer) were gently 04 dispersed in Krebs bicarbonate buffer, saturated with O2/CO2 $0 (95%:5%, vol/vol). Aliquots of the mince dispersion (800 .ld b1-3 Fluoxetine blank 0.5 mg of protein) were transferred into test tubes and incu- 0 bated for 20 min at 370C in a Dubnoff metabolic shaker under CS- 02/CO2 atmosphere in the presence or in the absence of 50 a, tkM fluoxetine. The net 5HT uptake was determined as the dif- bf Net uptake ference in the [3H]5HT taken up in the absence and in the pres- LO ence of fluoxetine. In some experiments, blank values were determined in parallel at 00C, and, in these cases, the samples were incubated for 20 min in ice. Accumulation of 5HT was 0 100 300 500 700 proportional to the amount of-tissue present in each tube. The 1,000 incubation was started by adding to each tube (final volume 1 5HT, nM ml) 100-jul aliquots of [3H]5HT (to attain final concentrations FIG. 1. Saturation isotherm of [3H]5HT uptake in minces pre- ranging between 0.01 and 1 ,uM) dissolved in Krebs bicarbon- pared from rat hippocampus. The net uptake was determined from the ate buffer. The uptake was allowed to continue for 4 min and difference between the total uptake and the uptake in the presence of the reaction was stopped by dilution with 4 ml of ice-cold saline 50 ,uM fluoxetine. The incubation was at 370C for 4 min. Tissue minces and by rapid filtration under reduced pressure through Milli- were preincubated with fluoxetine for 20 min at 37°C under 02/CO2 pore filters (type HA; 0.45-,um pores). Each filter was washed atmosphere. three times with 3 ml of ice-cold saline. The minces were then collected from each filter and placed in glass vials, where they between 0.01 and 1.0 ,uM a monophasic 5HT uptake was de- were allowed to dissolve in 1 ml of 1 M NaOH. Protein content tectable. This, like the high-affinity 5HT uptake previously de- was determined in 25- or 50-1LI aliquots of this solution. The scribed (21), showed an apparent Km value for 5HT of -0.4- [3H]5HT taken up by the tissue was determined by scintillation 0.5 ,M and approached saturation at a 5HT concentration of spectrometry after adding 10 ml of scintillation fluid (Atom- about 1 ,uM. When higher 5HT concentrations (up to 10 tLM) light, New England Nuclear) to each vial. When the synap- were used a biphasic 5HT uptake was detected due to a second, tosomal uptake of 5HT was studied the synaptosomes were pre- low-affinity, uptake component (data not shown). In order to pared as described (22) and aliquots (50 ,ul) of the synaptosome measure the blank values the samples were preincubated with preparation were incubated with [3H]5HT in concentrations a maximally active concentration (50 uM) of fluoxetine, a se- ranging between 0.01 and 0.5 /iM.
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