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PubMed1990

Histamine H3 receptor-mediated inhibition of noradrenaline release in pig retina discs.

Discs of pig retina were preincubated with 3H-noradrenaline, 3H-dopamine or 3H-serotonin and then superfused. Electrical field stimulation increased the outflow of tritium from discs preincubated with 3H-noradrenaline or 3H-dopamine, but no from discs preincubated with 3H-serotonin. The tritium content at the end of superfusion was similar in discs preincubated with 3H-noradrenaline or 3H-dopamine but about tenfold lower in discs preincubated with 3H-serotonin. The tritium content in discs preincubated with 3H-noradrenaline was markedly reduced when desipramine was present during preincubation but was not affected by selective inhibitors of dopamine and serotonin uptake. The tritium content in discs preincubated with 3H-dopamine and 3H-serotonin, in contrast, was reduced or tended to be reduced by a selective dopamine and serotonin uptake inhibitor, respectively. The electrically evoked overflow of tritium from discs preincubated with 3H-noradrenaline was abolished by tetrodotoxin or omission of Ca2+. In discs superfused with desipramine, the electrically evoked overflow was enhanced by phentolamine but not affected by histamine. When both desipramine and phentolamine were present in the superfusion medium, histamine inhibited the evoked overflow (pIC15 6.85). This effect was mimicked by the histamine H3 receptor agonist R-(-)-alpha-methylhistamine as well as by its S-(+)-enantiomer (pIC15 7.85 and 5.30, respectively) but not by the H1 receptor agonist 2-(2-thiazolyl)ethylamine and the H2 receptor agonist dimaprit (each 10 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit.

The purpose of this study was to elucidate the finding of Friedgen et al. (1993 b) that catechol-O-methyltransferase (COMT) inhibition is much more effective in increasing the plasma concentration of endogenous dihydroxyphenylglycol (DOPEG) than in increasing the plasma concentration of infused DOPEG. To this end, reserpine-pretreated rabbits were anaesthetized and infused with noradrenaline and/or DOPEG, and the plasma clearances of infused noradrenaline (ClNA) and DOPEG (ClDOPEG) as well as the plasma DOPEG response to noradrenaline infusion [as reflected by the ratio of the steady-state increase in plasma DOPEG (delta DOPEG) to that in plasma noradrenaline (delta NA)] were determined before and after blockade of neuronal uptake by desipramine. Experiments were carried out either under control conditions or after COMT inhibition by i.v. administration of 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592). On the assumption that rates of neuronal noradrenaline uptake equal steady-state rates of neuronal DOPEG formation, the desipramine-sensitive components of ClNA and delta DOPEG/delta NA were used to estimate the apparent plasma clearance of DOPEG formed intraneuronally (Clf-DOPEG) in response to noradrenaline infusion. ClNA was 83.6 ml kg-1 min-1 in the absence and 48.1 ml kg-1 min-1 in the presence of desipramine. Neither the former nor the latter value was altered after COMT inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effect of ageing on the number of neuronal noradrenaline uptake sites in the rat vas deferens.

Previous work has shown an age-related reduction in neuronal uptake of noradrenaline in the prostatic, but not in the epididymal portion of the rat vas deferens. In the present paper, the influence of ageing on the number of [3H]desipramine binding sites and on the effect of lithium on neuronal [3H]noradrenaline uptake were studied in the prostatic and epididymal portions of vasa deferentia from 4- and 20-month-old rats. The affinity for [3H]desipramine (Kd values) in the epididymal and prostatic portions did not change with age. However, ageing reduced the maximal number of [3H]desipramine binding sites (Bmax values) in the prostatic, but not in the epididymal portion. Lithium potentiated neuronal [3H]noradrenaline uptake only in the prostatic portion and this potentiation was not changed by ageing. The results showed differences in neuronal noradrenaline uptake between the two portions of the vas deferens. Furthermore, the data suggest that the age-related reduction in neuronal uptake in the prostatic portion is due to a reduction in the number of neuronal uptake sites for noradrenaline.

Aging↗
PubMed1984

A study of the effects of clonidine on the EEG in rats treated with single and multiple doses of antidepressants.

The influence of repeated and single administrations of desipramine, amitryptiline, and mianserin on the EEG effects of clonidine has been investigated in rats implanted with chronic cortical electrodes. Clonidine induced a dose-dependent EEG synchronization in control animals. Signs of behavioral depression occurred after administration of moderate (0.1 mg/kg) and higher (0.2 mg/kg) doses of clonidine. Single doses of desipramine and amitryptiline attenuated the clonidine effect, while mianserine potentiated clonidine-induced synchronization. Antidepressants given once daily for 14 days completely (desipramine and amitryptiline) or partially (mianserin) reduced the effect of clonidine. Antidepressants alone produced only a slight effect on cortical EEG pattern.

Amitriptyline↗
PubMed1982

The noradrenaline rate in the anaesthetized rabbit: facilitation by adrenaline.

1. 3H-Noradrenaline was infused intravenously into pentobarbitone anaesthetized rabbits to reach a steady-state plasma 3H-noradrenaline level, from which the noradrenaline plasma clearance was calculated. The plasma level of endogenous noradrenaline was determined simultaneously and the rate of noradrenaline release was then derived. 2. Pargyline, amezinium, desipramine and guanethidine all reduced the noradrenaline plasma clearance. The noradrenaline release rate was decreased by desipramine, guanethidine and clonidine. 3. Adrenaline (6 nmol/kg i.v. twice) enhanced the noradrenaline release rate by 53%. This effect was apparent after the plasma adrenaline has returned to basal levels. The adrenaline levels in sympathetically innervated tissues were elevated at this time. 4. When the rabbits were pretreated with either propranolol HCl (1 mg/kg i.p.) to block beta-adrenoceptors, or desipramine HCl (1 mg/kg i.v.) to block neuronal uptake, the facilitatory effect of adrenaline was abolished. Noradrenaline (6 nmol/kg i.v. twice) had no effect on the noradrenaline release rate. 5. These findings suggest that if the sympathetic transmitter stores contain sufficient adrenaline neuronally released adrenaline may modulate noradrenaline release in vivo by activating facilitatory presynaptic beta-adrenoceptors.

Anesthesia↗
PubMed1986

Further characterization of brain 3,4-dihydroxyphenylethyleneglycol (DHPG) formation: dependence on noradrenergic activity and site of formation.

The dependence of brain and plasma 3,4-dihydroxyphenylethyleneglycol (DHPG) formation upon CNS noradrenergic neutronal activity was evaluated following manipulations that are known to alter the firing rate of the locus coeruleus (LC) neurons and as a consequence, noradrenaline (NA) release and turnover. In addition, the relative degree of intraneuronal formation of brain DHPG was assessed by studying the metabolism of released NA during uptake inhibition. Electrical stimulation of the LC for 20 min induced an increase in rat cortical (40-42%), hypothalamic (22-29%) and plasma (68-79%) total DHPG and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) levels. Two hours following administration of the alpha-2 adrenoceptor antagonist yohimbine (10 mg/kg, i.p.), rat brain cortical conjugated DHPG and MHPG as well as free MHPG concentrations were increased whereas cortical free DHPG levels remained unchanged. The same treatment also increased plasma total DHPG and MHPG levels. In mice given the NA uptake inhibitor desipramine (10 mg/kg, i.p.) 2 h prior to sacrifice, brain free DHPG and MHPG concentrations were significantly reduced by 30 and 40%, respectively, whereas yohimbine (1-20 mg/kg, i.p.) induced a dose-dependent increase in brain DHPG (60-80%) and MHPG (60-220%) concentrations. Pretreatment with desipramine (10 mg/kg, i.p.) 30 min prior to yohimbine reduced, in rat, or abolished, in mice, the yohimbine-induced elevation of brain DHPG levels. In contrast, desipramine augmented the effect of yohimbine on brain MHPG levels resulting in a shift to the left of the dose response curves. These findings indicate that brain and plasma DHPG levels are sensitive to changes in brain noradrenergic neuronal impulse flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Involvement of norepinephrine neurons in the hypothermia induced by intracerebroventricular administration of 6-hydroxydopamine in mice, evidenced by antidepressants.

The intracerebroventricular (i.c.v.) administration of increasing doses of 6-hydroxydopamine (6OHDA) (12.5-50 micrograms) induces in mice a dose-dependent hypothermic effect. This hypothermic effect is not affected either by serotonin uptake inhibitors (indalpine, clomipramine, trazodone, fluoxetine) or by dopamine uptake inhibitors (GBR 12783, amineptine). On the contrary, the hypothermia is partly antagonized by norepinephrine uptake inhibitors (desipramine, nomifensine, viloxazine, maprotiline, protryptiline), as well as amfonelic acid. The antagonism elicited by desipramine is observed when the drug is administered intraperitoneally (from 5 mg/kg) or intracerebroventricularly (from 5 microgram per mouse). 6-hydroxydopamine-induced hypothermia is antagonized by imipramine after a time lag of 1 hour; this antagonism lasts 6-11 hours after intraperitoneal administration of the drug (20 mg/kg). The hypothermic effect of 6-hydroxydopamine is diminished by a previous 6-hydroxydopamine i.c.v. administration (50 micrograms, 7 days before), except in mice pretreated with desipramine at the time of the first 6-hydroxydopamine injection. The hypothermic effect is completely abolished by two previous 6-hydroxydopamine i.c.v. administrations (50 micrograms, 7 days interval). It is also decreased in mice receiving DSP4 15 days before testing (50 mg/kg, i.p.). Finally, neither haloperidol (0.5 mg/kg i.p.) nor SCH23390 (100 micrograms/kg s.c.) antagonize 6-hydroxydopamine-induced hypothermia. It is concluded that this effect is largely depending on central norepinephrine neurons.

Animals↗
PubMed1980

Test-specific effects of the 5-HT reuptake inhibitors alaproclate and zimelidine on pain sensitivity and morphine analgesia.

The effects of the specific 5-HT uptake inhibitors alaproclate and zimelidine, the 5-HT releasing compound p-chloroamphetamine (PCA) and the specific NA uptake inhibitor desipramine on pain sensitivity were examined in male rats using the hot-plate and tail-flick methods. The effects of alaproclate and zimelidine on 5-HT uptake mechanisms in the hypothalamus and spinal cord were also studied. Alaproclate, zimelidine, PCA and desipramine produced hypoalgesia in the hot-plate but not in the tail-flick test. Naloxone (1 mg/kg) failed to block the hypoalgesia produced by alaproclate and PCA in the hot-plate test. Zimelidine but not desipramine pretreatment blocked the analgetic action of PCA in the hot-plate test. Alaproclate significantly enhanced morphine analgesia in the hot-plate test but did not affect morphine analgesia in the tail-flick test. In contrast, zimelidine tended to enhance and significantly prolonged morphine analgesia in the tail-flick test but did not affect morphine analgesia in the hot-plate test. Zimelidine inhibited 5-HT uptake with equal potency in the hypothalamus and spinal cord, while alaproclate produced a greater inhibition of 5-HT uptake in the hypothalamus. These findings show test-specific effects after enhancement of central 5-HT neurotransmission. It is suggested that various aspects of pain sensitivity and morphine analgesia may involve different 5-HT pathways in the brain and spinal cord. Moreover, 5-HT pathways in the forebrain may mediate analgesia of a non-opiate type.

Alanine↗
PubMed1984

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on beta-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex.

The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of beta-adrenoceptors and 5-HT2 binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in beta-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the beta-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the beta-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT2 binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT2 binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.

Alanine↗
PubMed1985

Adaptive and differential changes on beta- and alpha 2-adrenoreceptors mediated hyperthermia after chronic treatment with antidepressant drugs in the rat kept at high ambient temperature.

We found previously that the beta-agonist clenbuterol and the alpha-agonist clonidine produced hyperthermia in rats kept at high ambient temperature, which effects were mediated by beta- and alpha 2-adrenoceptors, respectively. In the present paper this observation was used for testing the responsiveness of beta- or alpha 2-adrenoceptors, changed by a pharmacological manipulation, i.e., by chronic treatment with antidepressants. The animals were pretreated with desipramine, imipramine or amitriptyline twice a day for 1 or 2 weeks. All antidepressants significantly attenuated the clenbuterol-induced hyperthermia after 2 weeks of treatment. The effect of desipramine was stronger than that of the other antidepressants and appeared as little as 1 week after the treatment. The hyperthermic effect of clonidine was significantly reduced by repeated treatment with desipramine, increased after 2 weeks administration of imipramine, whereas amitriptyline produced no significant changes. In conclusion, these data suggest that, after repeated treatment, the antidepressants tested produce an adaptive decrease in function of beta-adrenoceptors while the same drugs exert differential effects on alpha 2-receptors. Moreover, clenbuterol induced hyperthermia may be a useful test for examining possible functional changes in beta-adrenoceptor sensitivity.

Amitriptyline↗
PubMed1991

Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat.

Cocaine inhibits the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). To investigate the relative role of such reuptake processes in the discriminative stimulus properties of cocaine, male rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination task and were administered neuroactive compounds during substitution or combination tests. The DA reuptake inhibitor GBR 12909 (2-16 mg/kg) completely mimicked cocaine. The reuptake inhibitors for NE (desipramine; 2-8 mg/kg) and 5-HT (fluoxetine; 0.625-5 mg/kg) did not substitute for the training drug. A low dose of either desipramine (3 mg/kg), fluoxetine (1.25 mg/kg), or GBR 12909 (2 mg/kg) coadministered with low doses of cocaine (0.625-2.5 mg/kg) enhanced the discriminative stimulus properties of this psychostimulant. The dose predicted to elicit 50% drug-lever responding is reduced (ED50) in the presence of desipramine (0.38 mg/kg), fluoxetine (0.79 mg/kg) or GBR 12909 (0.84 mg/kg) compared to the ED50 for cocaine (1.57 mg/kg) in the absence of any reuptake inhibitor. The finding that GBR 12909 mimics the cocaine cue corroborates the hypothesis that the stimulus properties of cocaine are mediated predominantly by DA systems. The potentiation of the stimulus effects of cocaine by monoamine reuptake inhibitors in rats suggests that these drugs could also amplify the subjective effects of cocaine in humans, a possibility that should be considered given the current use of antidepressants in the treatment of cocaine abusers.

Animals↗
PubMed2005

Protection of LLC-PK1 cells against hydrogen peroxide-induced cell death by modulation of ceramide level.

Oxidative stress has been reported to elevate ceramide level during cell death. The purpose of the present study was to modulate cell death in relation to cellular glutathione (GSH) level and GST (glutathione S-transferase) expression by regulating the sphingolipid metabolism. LLC-PK1 cells were treated with H2O2 in the absence of serum to induce cell death. Subsequent to exposure to H2O2, LLC-PK1 cells were treated with desipramine, sphingomyelinase inhibitor, and N-acetylcysteine (NAC), GSH substrate. Based on comparative visual observation with H2O2-treated control cells, it was observed that 0.5 microM of desipramine and 25 mM of NAC exhibited about 90 and 95% of cytoprotection, respectively, against H2O2-induced cell death. Desipramine and NAC lowered the release of LDH activity by 36 and 3%, respectively, when compared to 71% in H2O2-exposed cells. Cellular glutathione level in 500 microM H2O2-treated cells was reduced to 890 pmol as compared to control level of 1198 pmol per mg protein. GST P1-1 expression was decreased in H2O2-treated cells compared to healthy normal cells. In conclusion, it has been inferred that H2O2-induced cell death is closely related to cellular GSH level and GST P1-1 expression in LLC-PK1 cells and occurs via ceramide elevation by sphingomyelinase activation.

Acetylcysteine↗
PubMed1997

Efflux studies allow further characterisation of the noradrenaline and 5-hydroxytryptamine transporters in rat lungs.

The aim of the present study was to further characterise the noradrenaline and 5-hydroxytryptamine [5-HT] transporters in rat lungs by examining the efflux of noradrenaline and 5-HT, respectively. Lungs from rats were isolated and perfused via the pulmonary artery. After loading the tissue with 3H-5-HT or 3H-noradrenaline the efflux of the relevant amine from the lungs was examined for 15-25 min. The rate constant for efflux of 3H-5-HT increased by 81% when Na+ ions were removed from the perfusion solution; increased gradually when a selective 5-HT transporter inhibitor, 200 nM citalopram, was added to the perfusion solution for the final 6 min of efflux; and increased markedly and rapidly when substrates of the 5-HT transporter, tryptamine (18 microM) and 7-methyltryptamine (12 microM), were added for the final 6 min of efflux. These effects of the substrates were abolished by 1 microM citalopram, but were not significantly affected by 1 microM desipramine, a selective uptake, inhibitor. On the other hand, the previously described substrate-induced increase in the rate of efflux of noradrenaline was significantly reduced by desipramine but was unaffected by citalopram. The results show that efflux of 5-HT is mediated only by the 5-HT transporter, with no significant contribution of uptake1, and efflux of noradrenaline from rat lungs is mediated only by uptake1 and not by the 5-HT transporter. The effects of dopamine on the efflux of noradrenaline over a concentration range of 100-600 nM were investigated and the results showed that 50% of the maximal increase in the rate of efflux occurred at a concentration of 275 nM. This value did not differ from the Km for uptake of dopamine. This result implies that the only factor affecting the substrate-induced increase in noradrenaline efflux is the affinity of the substrate for uptake1. The efflux of noradrenaline was also examined in the absence and presence of two concentrations of desipramine (0.35 and 1.5 microM). Analysis of these results showed that uptake1 contributed approximately 81% and diffusion 19% to the total efflux of noradrenaline and that 90% of the total noradrenaline efflux was subject to reuptake by uptake1 into the pulmonary endothelial cells.

Adrenergic Uptake Inhibitors↗
PubMed2004

Antidepressant-like effects of a novel pentapeptide, nemifitide, in an animal model of depression.

BACKGROUND: Nemifitide is a novel peptide analog of melanocyte-inhibiting factor (MIF) that has been reported to relieve depressive symptoms in a very short period. OBJECTIVES: The Flinders Sensitive Line (FSL) rat, a genetic animal model of depression with innate exaggerated immobility in the forced swim test, was used to obtain more detailed information about the antidepressant-like effects of nemifitide. METHODS: The FSL rats were treated chronically with various doses of nemifitide or reference antidepressants desipramine and fluoxetine for 5 or 14 days and the forced swim test was conducted 22-24 h after the last treatment. RESULTS: Nemifitide significantly increased swimming in the FSL rats at both low (0.025-0.3 mg/kg) and high (3.0-15.0 mg/kg) doses but not at intermediate (0.4-2.4 mg/kg) doses. Nemifitide (0.3 mg/kg) and desipramine (5.0 mg/ kg) significantly increased swimming in the FSL rats after just 5 days of treatment, but fluoxetine (5.0 mg/kg) did not. Nemifitide (0.3 mg/kg) and fluoxetine (5.0 mg/kg) had long-lasting effects, but desipramine (5.0 mg/kg) did not. CONCLUSIONS: These findings support the value of developing nemifitide and its analogs as potential antidepressants.

Animals↗
PubMed1985

Obsessive-compulsive disorder and serotonin: is there a connection?

Reports of the antiobsessional efficacy of clomipramine have led to a "serotonin hypothesis" of obsessive-compulsive disorder (OCD). To test this hypothesis, 16 outpatients with DSM-III OCD were studied using several measures of serotonergic function. Platelet 3H-imipramine binding and serotonin uptake were not significantly different between the OCD patients and a normal, age-matched control group. The level of the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) was significantly higher in a small cohort of obsessionals compared with healthy volunteers, possibly reflecting increased brain serotonin turnover. In a direct test of the role of serotonin uptake in clomipramine's antiobsessional effects, the serotonin uptake inhibitor zimelidine was compared with the noradrenergic uptake inhibitor desipramine in a double-blind, controlled study. Zimelidine reduced CSF 5-HIAA, but was clinically ineffective in this group. Desipramine had weak but significant clinical effects. Nonresponders to zimelidine or desipramine improved significantly during a subsequent double blind trial of clomipramine. These findings demonstrate that pharmacological blockade of serotonin reuptake alone is not sufficient for an antiobsessional response.

Adult↗
PubMed1989

Reduced REM latency predicts response to tricyclic medication in depressed outpatients.

Forty-two outpatients with major depressive disorder entered a double-blind, randomized trial of either desipramine or amitriptyline for a minimum of 6 weeks. Pretreatment polysomnographic and clinical measures were used to predict response. Response was defined as a 17-item Hamilton Rating Scale for Depression score less than or equal to 9 at the end of treatment. There was a 61.1% response rate for patients treated with amitriptyline and a 66.7% response rate for patients treated with desipramine. Reduced REM latency (2-night mean less than or equal to 65.0 min) predicted a positive response to these tricyclic antidepressants. REM latency did not differentiate between desipramine or amitriptyline responders. More patients with reduced REM latency (80%) responded to treatment compared with patients with nonreduced REM latency (50%). The 80% response rate in reduced REM latency depressed patients confirms our previous findings in a mixed inpatient and outpatient sample. Contrary to our hypothesis, in this sample, endogenous depression was not associated with a good response to tricyclic medication.

Adolescent↗
PubMed1996

Involvement of GABA(B) receptor systems in action of antidepressants: baclofen but not bicuculline attenuates the effects of antidepressants on the forced swim test in rats.

Involvement of GABAergic systems in action of antidepressants was examined in the forced swim test in rats. Rats were forced to swim in a cylinder for 15 min on day 1 and for 5 min on day 2. Desipramine, mianserin and buspirone, administered after the 15-min swim session on day 1 and before the 5-min swim test on day 2, dose-dependently decreased the duration of immobility in the swim test on day 2. Baclofen attenuated the decreased duration of immobility induced by desipramine, mianserin and buspirone in the swim test, although baclofen did not affect the duration of immobility when it was injected alone. Muscimol dose-dependently decreased the duration of immobility in the swim test on day 2. Bicuculline antagonized the decreased duration of immobility induced by muscimol. However, bicuculline failed to antagonize the decreased duration of immobility induced by desipramine, mianserin and buspirone. These results suggest that GABA(B) but not GABA(A) receptor systems may be involved in action of antidepressants.

Animals↗
PubMedDate not supplied

Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons.

The spontaneous activity of the norepinephrine-containing cells of the locus coeruleus was recorded in chloral hydrate-anesthetized rats. The effect of seven tricyclic antidepressants on the firing rate of single cells in the locus coeruleus was studied. All the drugs tested, except iprindole markedly decreased the rate of firing of the noradrenergic cells. Antidepressants having a secondary amine in the side chain, desipramine, nortriptyline and chlordesipramine, were more potent than their respective tertiary amine analogues, imipramine, amitriptyline and chlorimipramine. Alteration of the rate of drug metabolism by pretreatment with SKF-525A or phenobarbital did not change the doses of tertiary antidepressnats required to decrease norepinephrine cell firing. Depletion of the norepinephrine stores by pretreatment with alpha-methyl-p-tyrosine and reserpine markedly increased the dose of desipramine required to depress the norepinephrine cells. The results are in good agreement with previous studies showing that secondary amine antidepressants are more potent than their tertiary amine homologues in blocking the uptake of norepinephrine into brain and peripheral tissues. Despite their lower potency it is concluded that tertiary antidepressants act on noradrenergic neurons in their unchanged form and not via secondary amine metabolites formed during the recording experiments since alterations in liver metabolism did not influence the response. The findings are consistent with the suggestion made from studies on transmitter turnover that antidepressants by inhibiting reuptake of norepinephrine cause a stimulation of postsynaptic receptors which decreases the activity of the presynaptic neurons by a feed-back mechanism. This view is further supported by the finding of an inverse relation between the norepinephrine content of the brain and the dose of desipramine required to decrease the firing rate of the noradrenergic neurons.

Animals↗