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PubMed1991

Avoidance learning during antidepressant withdrawal in mice.

Shuttle-box avoidance acquisition, locomotor activity and density of adrenoreceptors in the cerebral cortex have been evaluated, in CD-1 mice, during withdrawal from repeated treatment with desipramine or mianserin (5 or 14 daily injections of antidepressant drug, 10 mg kg-1). Withdrawal from mianserin did not produce any behavioural or neurochemical change. Mice withdrawn from desipramine exhibited avoidance facilitation, when training started 24 h (but not 72 or 120 h) after the last injection. Locomotor activity was not affected and no change was found in the density of beta-adrenoreceptors. An up-regulation of alpha 2- and, to a lesser extent, of alpha 1-adrenoreceptors, occurred 72 h following desipramine withdrawal. However, the assessment of the role played by these neurochemical changes in the avoidance facilitation observed during withdrawal from the antidepressant treatment requires further study.

Animals↗
PubMed2004

Chronic antidepressant treatment causes a selective reduction of mu-opioid receptor binding and functional coupling to G Proteins in the amygdala of fawn-hooded rats.

We have previously documented that chronic alcohol consumption or alcohol withdrawal affects mu-opioid receptor density and receptor-mediated G protein coupling in Fawn-Hooded (FH) rat brain, especially in mesolimbic regions. FH rats demonstrate comorbid depression and high voluntary alcohol consumption; treatment with standard antidepressants improves both facets of this phenotype. Accordingly, we sought to examine whether mu-opioid receptor binding and the receptor-mediated functional coupling to G protein is affected by this drug treatment. Using quantitative autoradiography, binding of mu-opioid receptors labeled by [125I]FK33,824 (D-Ala2,N-Me-Phe4,Met(O)5-ol enkephalin) and the coupling between receptors and G proteins determined by agonist-stimulated guanosine 5'-O -(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding was mapped throughout brain sections of FH rats after 10-day treatment with vehicle, desipramine, or sertraline. Both desipramine and sertraline produced significant decreases of [125I]FK33,824 binding in many brain regions; 13 of 20 measured regions for desipramine and 16 of 20 measured regions for sertraline. The coupling efficiency of mu-opioid receptors to G proteins was determined by an increase of [35S]GTPgammaS binding induced by stimulation with the mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 microM). In contrast to the receptor binding profile, functional coupling of receptors to G proteins was only significantly reduced in the amygdala, whereas it remained unchanged in other regions compared with control. The present findings suggest that antidepressants regulate opioid systems; however, this occurs differentially, and region-specific alteration of functional coupling of mu-opioid receptors to G proteins in the amygdala suggests that opioid function within the amygdala may be modulated by antidepressants.

Amygdala↗
PubMed2001

Chronic treatment of C6 glioma cells with antidepressant drugs results in a redistribution of Gsalpha.

Previous studies have demonstrated that chronic treatment of C6 glioma cells with the antidepressants desipramine and fluoxetine increases the Triton X-100 solubility of the G protein Gsalpha (Toki et al., 1999). The antidepressants also caused a 50% decrease in the amount of Gsalpha localized to caveolae-enriched membrane domains. In this study, laser scanning confocal microscopy reveals that Gsalpha is localized to the plasma membrane as well as the cytosol in both treated and control cells. However, striking differences are seen in the distribution of Gsalpha in the long cellular processes after chronic treatment with these antidepressant drugs. Control cells display Gsalpha along the entire process with an especially high concentration of that G protein at the distal ends. Desipramine- or fluoxetine-treated cells show a more centralized clustering of Gsalpha in the Golgi region of the cell and a drastic reduction of Gsalpha in the cellular processes. There is no change in the distribution of Goalpha after desipramine treatment and the antipsychotic drug chlorpromazine does not alter Gsalpha. These results suggest that antidepressant-induced changes in the association of Gsalpha with the plasma membrane may translate into altered cellular localization of this signal transducing protein. Thus, modification of the coupling between Gs-coupled receptors and adenylyl cyclase may underlie both antidepressant therapy and depressive illnesses. This report also suggests that modification of the membrane domain occupied by Gsalpha might represent a mechanism for chronic antidepressant effects.

Animals↗
PubMed1969

Tricyclic antidepressants: evidence for an intraneuronal site of action.

Desipramine, a tricyclic antidepressant drug, almost completely prevents the accumulation of tritiated norepinephrine by sympathetic neurons of the rat heart after the injection of a tracer dose of the labeled amine. However, desipramine does not alter the accumulation of norepinephrine after the injection of a large dose of the neurohormone. Despite the failure of desipramine to block the neuronal uptake of norepinephrine, it still prevents exogenous norepinephrine from displacing the endogenous neurohormone (previously labeled with H(3)-norepinephrine) from intraneuronal storage sites.

Animals↗
PubMed2006

Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation.

We have proposed that activation of cerebral perivascular sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03-0.1 microM) but inhibited at higher concentrations (0.3-10 microM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1-30 mM)-evoked inward currents were reversibly blocked by 1-30 microM mecamylamine, 1-30 microM methyllycaconitine, 10-300 nM alpha-bungarotoxin, and 0.1-10 microM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.

Animals↗
PubMed1994

Constitutive nonexocytotic norepinephrine release in sympathetic curves of in situ canine heart.

Nonexocytotic norepinephrine bulk overflow from sympathetic nerves has been previously demonstrated in the perfused isolated heart only after inhibition of sympathetic nerve metabolism by hypoxia, ischemia, or metabolic inhibitors. The measurement, however, ignores simultaneous uptake of norepinephrine by sympathetic nerves. We quantitated simultaneous norepinephrine uptake and release in pentobarbital-anesthetized dogs by the use of a transient tracer approach, the multiple indicator dilution technique, combined with measurement of endogenous arterial and venous plasma norepinephrine levels. Sympathetic vesicles were previously depleted by reserpine, and desipramine was used to inhibit the neuronal membrane pump. Labeled albumin, sucrose, and norepinephrine were injected into the coronary artery, and sequential samples were collected from the coronary sinus. Reserpine pretreatment significantly depleted tissue and decreased plasma norepinephrine levels; tracer norepinephrine uptake increased slightly, and there was a substantial decrease in the rate of release of unlabeled norepinephrine. Desipramine then decreased tracer uptake and virtually eliminated norepinephrine release. We conclude that desipramine-suppressible, constitutive nonexocytotic norepinephrine release is present in cardiac sympathetic nerves.

Animals↗
PubMed2004

Effects of neuronal norepinephrine uptake blockade on baroreflex neural and peripheral arc transfer characteristics.

Neuronal uptake is the most important mechanism by which norepinephrine (NE) is removed from the synaptic clefts at sympathetic nerve terminals. We examined the effects of neuronal NE uptake blockade on the dynamic sympathetic regulation of the arterial baroreflex because dynamic characteristics are important for understanding the system behavior in response to exogenous disturbance. We perturbed intracarotid sinus pressure (CSP) according to a binary white noise sequence in anesthetized rabbits, while recording cardiac sympathetic nerve activity (SNA), arterial pressure (AP), and heart rate (HR). Intravenous administration of desipramine (1 mg/kg) decreased the normalized gain of the neural arc transfer function from CSP to SNA relative to untreated control (1.03 +/- 0.09 vs. 0.60 +/- 0.08 AU/mmHg, mean +/- SE, P < 0.01) but did not affect that of the peripheral arc transfer function from SNA to AP (1.10 +/- 0.05 vs. 1.08 +/- 0.10 mmHg/AU). The normalized gain of the transfer function from SNA to HR was unaffected (1.01 +/- 0.04 vs. 1.09 +/- 0.12 beats.min(-1).AU(-1)). Desipramine decreased the natural frequency of the transfer function from SNA to AP by 28.7 +/- 7.0% (0.046 +/- 0.007 vs. 0.031 +/- 0.002 Hz, P < 0.05) and that of the transfer function from SNA to HR by 64.4 +/- 2.2% (0.071 +/- 0.003 vs. 0.025 +/- 0.002 Hz, P < 0.01). In conclusion, neuronal NE uptake blockade by intravenous desipramine administration reduced the total buffering capacity of the arterial baroreflex mainly through its action on the neural arc. The differential effects of neuronal NE uptake blockade on the dynamic AP and HR responses to SNA may provide clues for understanding the complex pathophysiology of cardiovascular diseases associated with neuronal NE uptake deficiency.

Adrenergic Uptake Inhibitors↗
PubMed1987

Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm.

Disturbances in peripheral norepinephrine release or removal by neuronal and extraneuronal uptake may have pathogenetic significance in cardiovascular disease states. We investigated the mechanisms of removal of norepinephrine in the forearm of healthy subjects under basal conditions, using measurements of arterial and venous plasma norepinephrine concentrations, blood pressure, heart rate, and forearm blood flow. The specific inhibitor of neuronal uptake, desipramine, was infused intra-arterially into the brachial artery of five subjects. Net norepinephrine overflow from the forearm increased markedly, revealing considerable local release of norepinephrine. Six other subjects received four intra-arterial infusions of norepinephrine, 1.18 pmol/kg/min, with various doses of desipramine and the extraneuronal uptake-inhibiting drug hydrocortisone. The forearm extraction rate for circulating norepinephrine decreased with increasing doses of desipramine (from 69.4 +/- 3.0 [SEM] to 35.3 +/- 8.4%; p less than 0.001). Increasing doses of hydrocortisone during continued inhibition of neuronal uptake resulted in decreased forearm extraction of norepinephrine (from 63.3 +/- 4.9 to 40.6 +/- 4.4%; p less than 0.01). In six other subjects who received the highest dose of hydrocortisone without concomitant inhibition of neuronal uptake, forearm extraction of norepinephrine decreased from 57.1 +/- 4.9 to 51.5 +/- 4.7% (p less than 0.05). These results suggest that neuronal uptake contributes markedly to the removal of circulating and endogenously released norepinephrine in the forearm. For circulating norepinephrine, a corticosteroid-sensitive mechanism of extraneuronal uptake was also demonstrated. These results indicate that neuronal and extraneuronal uptake can be estimated separately in this vascular bed. Similar organ-specific studies in patients may reveal disturbances in mechanisms of norepinephrine removal.

Adult↗
PubMed1986

Decreased basal cardiac interstitial norepinephrine release after neuronal uptake inhibition in dogs.

The effect of neuronal uptake inhibition on basal interstitial release of norepinephrine in the canine heart was examined by use of the multiple tracer dilution-bulk balance technique. A kinetic model incorporating the effects of flow, capillary permeability-surface product for norepinephrine, the interstitial uptake rate constant for neurotransmitter, and plasma norepinephrine input and output values was used to estimate rates of uptake from and release of norepinephrine into the interstitial space. The intravenous injection of the neuronal uptake inhibitor desipramine in anesthetized dogs under basal conditions reduced interstitial uptake of tracer norepinephrine in the heart, without significant changes in plasma concentration of norepinephrine in aorta and coronary sinus. The lack of change in the arteriovenous balance for norepinephrine across the heart, in the face of the lowered uptake for this amine, suggested that the liberation of norepinephrine by cardiac sympathetic fibers was reduced. Analysis of the data with the norepinephrine tracer kinetic-bulk model showed that, after desipramine, the interstitial release of norepinephrine was reduced to the same extent as uptake was diminished. As a result, the concentration of norepinephrine in the extracellular space of the heart did not increase significantly. The findings indicate the presence of a presynaptic neuronal feedback inhibition of release, which serves to fine tune the myocardial interstitial concentration of norepinephrine in the basal state; with this, after desipramine, both norepinephrine uptake and release are correspondingly diminished.

Animals↗
PubMed1993

Pulmonary complications following tricyclic antidepressant overdose in an adolescent.

OBJECTIVE: To report a case of pulmonary edema following a tricyclic antidepressant (TCA) overdose in an adolescent. CASE SUMMARY: A 14-year-old girl with a history of prior suicide attempts ingested 54 50-mg desipramine hydrochloride tablets (45 mg/kg ingestion). The patient developed a cardiac dysrhythmia and hypotension, which were successfully treated. She subsequently developed pulmonary edema and a clinical picture suggestive of adult respiratory distress syndrome (ARDS). She was successfully managed with fluid restriction, tracheal intubation, application of positive end-expiratory pressure (PEEP), and vasopressors. The patient was discharged without any clinical sequelae. DISCUSSION: Pulmonary complications secondary to TCA overdose have rarely been reported in children. We reviewed literature pertaining to the etiology, epidemiology, pathophysiology, and management of TCA-induced lung injury, as well as other case reports. We discuss the potential relationship between sequelae resulting from TCA ingestion (e.g., cardiac disturbances, hypotension, acidosis, gastric aspiration, pneumonia) and the development of ARDS and pulmonary edema, and relate this association to our patient. CONCLUSIONS: Pulmonary edema and a clinical picture suggestive of ARDS was noted in an adolescent girl who ingested a large quantity of desipramine. Her lung injury may have been the result of a variety of factors including hypotension, metabolic acidosis, possible aspiration, or a direct action on the lung parenchyma by desipramine. We attribute her favorable clinical outcome to early intervention consisting of tracheal intubation, PEEP, fluid restriction, and vasopressor therapy.

Adolescent↗
PubMed1999

Tricyclic antidepressant use in diabetic neuropathy.

OBJECTIVE: To determine whether all tricyclic antidepressants are equally effective in the treatment of painful diabetic neuropathy. DATA SOURCES: A MEDLINE search for randomized controlled studies was conducted from January 1966 to December 1998. CONCLUSIONS: Amitriptyline, imipramine, and desipramine are superior to placebo in relieving painful diabetic neuropathy. Desipramine has been shown in one small study to have efficacy equal to amitriptyline. Imipramine has been compared with amitriptyline in another small study, but the lack of statistics and adverse effect evaluation did not allow for critical comparison between the two agents. No randomized studies on nortriptyline monotherapy in diabetic neuropathy have been published. Data are insufficient to determine whether all tricyclic antidepressants are equally effective. Amitriptyline and desipramine are reasonable first choices in treating diabetic neuropathy.

Amitriptyline↗
PubMed1993

Regional differences in the levels of biogenic amines and their metabolites in rat brain after tricyclic antidepressant treatments.

Changes in the levels of biogenic amines in different brain regions and the cerebrospinal fluid in rats were measured after acute or chronic treatment with tricyclic antidepressants. After single or 3 weeks' treatment with imipramine or desipramine, blocks of tissues were obtained from seven regions of the brain (frontal cortex, corpus striatum, hippocampus, thalamus, hypothalamus, substantia nigra and cerebellum) immediately after collection of the cerebrospinal fluid (CSF) from the cisterna magna. The concentrations of biogenic amines and their metabolites (norepinephrine, epinephrine, dopamine, 5-hydroxytryptamine (5-HT), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA)) in brain tissues and the CSF were measured using the high performance liquid chromatography-electrochemical detection system (HPLC-ECD). Treatment with desipramine or imipramine caused major alterations in the concentrations of central norepinephrine or 5-HT and its metabolite, respectively. Brain regional responses were variable according to the kind of tricyclic antidepressants and the duration of treatment. It is noteworthy that chronic treatment with both desipramine and imipramine caused altered hippocampal concentrations of norepinephrine and/or 5-HT and its metabolites. Striatal DOPAC concentrations were also changed after acute or chronic treatment with both drugs. These results suggest that tricyclic antidepressants altered neurotransmission according to the brain region, and the hippocampal norepinephrine and 5-HT and/or the striatal dopamine may have a significant role for the expression of antidepressant action of tricyclic antidepressants.

Animals↗
PubMed1999

Do depressed subjects who have failed both fluoxetine and a tricyclic antidepressant respond to the combination?

BACKGROUND: Recent evidence suggests that the combination of fluoxetine and desipramine may provide a rapid and effective treatment for depression. METHOD: The current study evaluated 13 subjects with DSM-III-R nonpsychotic major depression who had previously failed either desipramine or imipramine and who were currently unsuccessfully treated with fluoxetine. Desipramine or imipramine was added to fluoxetine and Hamilton Rating Scale for Depression (HAM-D) scores, Beck Depression Inventory (BDI) scores, and plasma tricyclic levels were monitored for 3 weeks. RESULTS: Of the 13 subjects, 7 (54%) had a greater than 40% decline in HAM-D scores and 4 of these (31%) had 50% or greater decline in HAM-D. At week 3, responders (767 +/- 282 nmol/L) had a significantly higher mean tricyclic level as compared with nonresponders (515 +/- 95 nmol/L, F = 25.1, p < .0001), and change in BDI scores was significantly correlated with tricyclic level (r = -0.60, p < .05). CONCLUSION: These findings suggest that in some subjects the positive clinical effect of combining fluoxetine and a tricyclic antidepressant may be related to the plasma levels of the tricyclic compound.

Adult↗
PubMed1999

LLC-PK(1) cells stably expressing the human norepinephrine transporter: A functional model of carrier-mediated norepinephrine release in protracted myocardial ischemia.

In myocardial ischemia, adrenergic terminals undergo ATP depletion, hypoxia, and intracellular pH reduction, causing the accumulation of axoplasmic norepinephrine (NE) and intracellular Na(+) [via the Na(+)-H(+) exchanger (NHE)]. This forces the reversal of the Na(+)- and Cl(-)-dependent NE transporter (NET), triggering massive carrier-mediated NE release and, thus, arrhythmias. We have now developed a cellular model of carrier-mediated NE release using an LLC-PK(1) cell line stably transfected with human NET cDNA (LLC-NET). LLC-NET cells transported [(3)H]NE and [(3)H]N-methyl-4-phenylpyridinium ([(3)H]MPP(+)) in an inward direction. This uptake was abolished by the NET inhibitors desipramine (100 nM) and mazindol (300 nM) and by extracellular Na(+) removal. Na(+)-gradient reversal induced an efflux of (3)H-substrate from preloaded LLC-NET cells. Desipramine and mazindol blocked this efflux. Because of its greater intracellular stability and higher sensitivity to Na(+)-gradient reversal, [(3)H]MPP(+) proved preferable to [(3)H]NE as an NET substrate; therefore, only [(3)H]MPP(+) was used for subsequent studies. The K(+)/H(+) ionophore nigericin (10 microM) evoked a large efflux of [(3)H]MPP(+). This efflux was potentiated by the Na(+),K(+)-ATPase inhibitor ouabain (100 microM), was sensitive to desipramine, and was blocked by the NHE inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA; 10 microM). In contrast, EIPA failed to inhibit the [(3)H]MPP(+) efflux elicited by the Na(+) ionophore gramicidin (10 microM). Furthermore, [(3)H]MPP(+) efflux induced by the NHE-stimulant proprionate (25 mM) was negatively modulated by imidazoline receptor activation. Our findings suggest that LLC-NET cells are a sensitive model for studying transductional processes of carrier-mediated NE release associated with myocardial ischemia.

1-Methyl-4-phenylpyridinium↗
PubMed1975

Interaction between centrally acting hypotensive drugs and tricyclic antidepressants.

From clinical experience it is known that the hypotensive action of clonidine and alpha-methyl-DOPA is antagonized by desipramine. This antagonism was investigated in detail in chloralose-anaesthetized cats. Both the centrally acting hypotensive agents and the tricyclic antidepressants where infused into the left vertebral artery. (1) The central hypotensive action clonidine was antagonized by desipramine, imipramine, amitriptyline, protriptyline and mianserine. For the inhibition of the hypotensive action of clonidine by protriptyline a parallel shift of the dose-response curve was obtained, indicating the possibility of a competitive antagonism. The central hypotensive action of alpha-methyl-DOPA was antagonized by desipramine and imipramine and that of amphetamine by imipramine. (2) The modest central hypotensive action of tricyclic antidepressants themselves and that of cocaine is explained by means of the inhibition of noradrenaline re-uptake in the CNS, brought about by these compounds. (3) It seems likely that the antagonism occurs at the level of central alpha-adrenoreceptors in the brain stem. (4) The antagonism probably reflects a general interaction between centrally acting hypotensive drugs and tricylclic antidepressants. The alpha-sympatholytic properties of the tricyclic antidepressants probably give rise to a blockade of the central alpha-adrenoreceptors, stimulated by clonidine, noradrenaline (via amphetamine) and alpha-methylnoradrenaline (from alpha-methyl-DOPA). The cocaine-like activity of antidepressants does not play a part.

Amphetamine↗
PubMedDate not supplied

Effects of classic and newer antidepressants on the oxidation pathways of caffeine in rat liver. In vitro study.

Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N-demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of the present study was to investigate the influence of clomipramine, desipramine, sertraline, nefazodone and mirtazapine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated antidepressants, with an exception of mirtazapine, added in vitro to liver microsomes had an inhibitory effect on caffeine metabolism (via competitive or mixed mechanism), though their potency towards particular metabolic pathways was different. Dixon analysis of caffeine metabolism carried out in the control liver microsomes, in the absence and presence of the antidepressant drugs showed that desipramine and clomipramine exerted the most potent inhibitory effect on caffeine metabolism. Desipramine decreased the rates of 1-N-, 3-N- and 7-N-demethylations, and 8-hydroxylation of caffeine (Ki = 23.3, 36.6, 23.3 and 63.3 microM, respectively), the effect on 1-N- and 7-N-demethylation being the most pronounced. Clomipramine showed distinct inibition of 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine, the effects on N-demethylations being the most pronounced (Ki = 38.6, 34.8, 45.6 microM, respectively). Its effect on 7-N-demethylation was rather weak (Ki = 97.8 microM). Sertraline decreased significantly the rate of 1-N- and 3-N-demethylation and 8-hydroxylation (Ki = 37.3, 69.3 and 64 microM, respectively), while its effect on 7-N-demethylation of caffeine was less pronounced (Ki = 92.1 microM). Nefazodone displayed clear effect on 3-N- and 7-N-demethylation (Ki = 68.8 and 66.4 microM, respectively), but was weak in inhibiting 1-N-demethylation and 8-hydroxylation of caffeine (Ki = 110 and 186 microM, respectively). In contrast to the above-tested antidepressants, mirtazapine did not decrease significantly the oxidation rates of 3-N-demethylation or 8-hydroxylation (Ki = 264 and 455 microM, respectively) and had no effect on other oxidation pathways of caffeine. In summary, we have observed intra- and inter-drug differences in the inhibitory effects of the antidepressants on the four oxidation pathways of caffeine in rat liver microsomes. The tested antidepressants (with an exception of mirtazapine) may lead to drug-drug metabolic interactions at a level of a few CYP isoforms. The obtained results provide further indirect evidence that apart from CYP1A2, other CYP isoforms are also important for the metabolism of caffeine.

Animals↗
PubMed1992

Sensitization of locus ceruleus neurons during withdrawal from chronic stimulants and antidepressants.

The effects of chronic exposure to cocaine, amphetamine and desipramine on noradrenergic neurons in the locus ceruleus were examined using intracellular recordings in rat brain slices. Animals were treated for 2 weeks with either cocaine, amphetamine or desipramine, and all recordings were made after a 1-week withdrawal period. Cells from all three drug-treated groups showed a significant increase in sensitivity to the acute effects of cocaine and amphetamine in prolonging the time course of the noradrenaline-mediated inhibitory postsynaptic potential. At the highest cocaine and amphetamine doses tested (10 and 3 microM, respectively), the inhibitory postsynaptic potential duration was increased approximately 233% in the drug-treated groups relative to saline controls. In addition, locus ceruleus neurons from the cocaine-, amphetamine- and desipramine-treated groups showed a significant 10, 12 and 17% increase, respectively, in the maximum outward current produced by clonidine. There was also a significant increase in the behavioral sensitivity of the drug-treated animals to the sedative effects of clonidine. The mechanisms responsible for the increased sensitivity to the acute effects of cocaine, amphetamine and alpha-2 agonists may play a role in the withdrawal response to psychostimulants.

Amphetamine↗
PubMed1992

Increased glucocorticoid receptor gene promoter activity after antidepressant treatment.

We have tested the hypothesis that antidepressants affect the expression of the glucocorticoid receptor gene, by looking at glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and glucocorticoid-binding activity after treatment of different cell lines with desipramine. Treatment of LTK- cells or Neuro 2A cells with desipramine produced a 50-200% increase in chloramphenicol acetyltransferase activity transcribed from a 2.7-kilobase glucocorticoid receptor gene promoter region. In cell lines derived from both neuronal and non-neuronal sources, glucocorticoid receptor mRNA concentration doubled after desipramine treatment, and this was associated with a 2-fold higher functional glucocorticoid binding capacity and increased glucocorticoid sensitivity, as measured with the reporter plasmid pMMTVCAT. Antidepressant-induced increases in glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and functional glucocorticoid binding activity suggest a novel mechanism of action for these drugs on the hypothalamic-pituitary-adrenal axis.

Animals↗