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PubMedDate not supplied

Catecholamine and MHPG plasma levels, platelet MAO activity, and 3H-imipramine binding in heroin and cocaine addicts.

This work evaluated in a population of heroin and heroin plus cocaine human addicts: 1. Norepinephrine (NE), epinephrine (Epi) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (the principal metabolite of brain NE) plasma levels; 2. Monoamine oxidase (MAO) activity; and 3. 3H-imipramine specific binding to the amine carrier in platelets. NE plasma levels were significantly lower in the short-term heroin user groups (1-3 and 4-6 yr), a finding not observed in both long-term heroin user ( > 6 yr) and heroin plus cocaine user ( > 6 yr) groups. Epi levels changed in a similar manner, except that a significant increase was noted in heroin plus cocaine abusers. Conversely, dopamine and MHPG plasma levels increased with the duration of heroin use, and even more with cocaine abuse. Platelet MAO activity increased in all groups. Specific 3H-imipramine binding sites showed an increase after 3 yr of heroin abuse and in all heroin plus cocaine addicts. In conclusion, short-term use of heroin decreases NE or Epi release, but with prolonged use, a slow adaptation occurs. In contrast, cocaine inhibits the neuronal Epi uptake, even in a situation of long duration of abuse. Probably the amine levels additionally regulate the amine carrier, resulting in changes that show a different pattern from major depression. These drugs of abuse may also influence directly or indirectly related enzymatic systems.

Adult↗
PubMed1997

Individual differences in response to imipramine in the mouse tail suspension test.

The tail suspension test is a behavioural primary screen for detecting potential antidepressant drugs. In this test, a reduction of duration of immobility after treatment with imipramine is obtained in mice of the NMRI strain but not of the CD1 strain. The present experiments evidence important differences between individuals of the latter strain in both the amount of immobility observed in naive mice and the effects of three antidepressants. The reproducibility of the tail suspension-induced behavioural despair was high in individual CD1 male mice and allowed a preselection of spontaneous high and low immobility scorers. Only the high immobility scorers were responsive to imipramine (30 mg/kg), desipramine (30 mg/kg) and paroxetine (10 mg/kg). The percentage of spontaneous high immobility scorers was higher in NMRI (50%) than in CD1 (20%) mice, justifying the use of the former strain for screening potential antidepressants. However, controlling for individual differences in the spontaneous performance in this animal model of depression may provide a useful tool to study behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Animals↗
PubMed1998

The pharmacology of impulsive behaviour in rats II: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and other drugs on fixed consecutive number schedules (FCN 8 and FCN 32).

The effects of drugs on one aspect of impulsive behaviour were evaluated using a schedule in which rats were trained to complete a fixed consecutive number of responses on one of two levers before pressing the second to obtain a reinforcer (FCN). Terminating the chain before completing the FCN resulted in the omission of the food, and can be considered an impulsive decision. Two groups of food-deprived rats were trained to press either 8 or 32 times on the left lever (FCN lever) of a two lever operant chamber before pressing the right lever (Reinforcement lever) to deliver a food pellet. Responding on the Reinforcement lever before completion of the sequence resulted in a short time-out and the rat had to begin the sequence again. After responding had stabilised, the rats were treated with a range of doses of a number of drugs. Impulsivity was assessed by several measures, including the mean chain length and the proportion of chains terminating in food delivery, and the distribution of chain lengths was analysed. The efficiency of the rats was similar under both FCN 8 and FCN 32, although it was more difficult to maintain a consistent baseline under FCN 32. Under the FCN 8 schedule, significant decreases in chain length were obtained with d-amphetamine (0.8-2.4 mg/kg), haloperidol (0.1 mg/kg), ethanol (1 and 3 g/kg) and chlordiazepoxide (10.0 mg/kg), and there were alterations in other measures consistent with an increase in impulsivity. Imipramine (1-10 mg/kg), citalopram (1-10 mg/kg) and metergoline (0.3-3.0 mg/kg) had no effect on mean chain length, although the first two drugs shifted the chain length distribution to the left. d-Amphetamine (0.4-1.2 mg/kg) and PCPA (100 mg/kg) reduced chain length and had other effects consistent with increased impulsivity under FCN 32 schedule, whereas imipramine had little, and citalopram no, effect. Taken generally, effect of the active drugs was relatively non-specific, including both a reduction in response rate and alterations in choice measures proposed to reflect an increase in impulsivity. Detailed analysis of the effect of amphetamine revealed that three processes were at work: chain shortening, an increased preference for the lever most closely associated with food delivery, and a gradual shift in the control over responding from the response sequence (pattern) to the individual lever press (act).

Amphetamine↗
PubMed1998

The pharmacology of impulsive behaviour in rats III: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and ethanol on a paced fixed consecutive number schedule.

The behavioural trait of impulsivity may be made up of different components, including rapid decision making, intolerance to the delay of reward and a tendency to terminate chains of responses prematurely. It has been proposed to measure the last of these in rats using fixed consecutive number (FCN) schedules. The present study uses a modified version of the FCN procedure in which responding was paced by retracting the response lever for short periods between presses. In this way, the experimenter could control the maximum rate of responding. The procedure was made up of two components based on an FCN 8 schedule of food reinforcement. In the Fast component, lever presses were spaced by a minimum of 2 s and in the Slow component by a minimum of 5 s. The average chain length was significantly shorter, and the rats were less efficient in the Slow component. Five drugs were tested on this baseline, imipramine (1.0-10.0 mg/kg), ethanol (300-3000 mg/kg administered PO), haloperidol (0.01-0.1 mg/kg), chlordiazepoxide ( 1.0-10.0 mg/kg) and d-amphetamine (0.2-0.8 mg/kg). All the drugs reduced responding at the highest dose, but imipramine was different from the others in that it increased the average number of responses in the chain and produced a shift in the chain length distribution to the right, possibly reflecting a reduction in impulsivity. The other four drugs reduced chain length at the highest dose, although in the case of ethanol this effect was very small and, unlike the other three drugs, did not result in a shift in the distribution to the left. The paced FCN procedure can differentiate the effects of different drugs on one aspect of impulsivity, and is likely to be a useful procedure for further study of this aspect of behaviour.

Amphetamine↗
PubMed2002

Initial serotonin transport into viable platelets and imipramine binding to platelet membranes.

Transport of serotonin into human platelets is a paradigm for neuronal reuptake to investigate putatively low neurotransmitter availability in certain psychiatric diseases. However, inconsistent results have been obtained on serotonin binding to platelet membranes at equilibrium and transport during initial phase into isolated platelets. In the present study we applied a rapid oil-centrifugation technique to study (14)C-serotonin transport for 15s into viable human platelets during the initial phase, compared to the binding of (3)H-imipramine at equilibrium (60 min) to membranes isolated from platelets of the same individuals and to their blood serotonin levels. Platelets were viable for two h after the isolation procedure; concomitant with the decrease in viability transport also decreased. Initial transport into viable cells was observed for two min. Across 19 healthy individuals blood serotonin levels correlated with the halfmaximal saturation constants of binding, K(D), for imipramine but not with any other transport or binding parameters, such as V(max) or B(max). Inhibition studies with psychoactive drugs showed good correlation between transport during the initial phase and binding at equilibrium (r = 0.83). It is speculated that changes in the V(max) of transport reflect problems with isolation, pretreatment with drugs, the energy load of the cell, and polymorphism of the serotonin transporter. The latter shows a polymorphism in the 5'regulatory region with a 44-bp insertion (l, long form) or deletion (s, short form). Results by Greenberg et al. indicate that in platelets from healthy men the l-variant was associated with increased initial serotonin uptake. Thus for genotyping, we suggest to subdivide patient and control groups in addition to psychopathology also according to their peripheral biochemical lesions.

Adult↗
PubMed2006

Effect of imipramine on the behavior and cerebral 5-HT1A serotonin receptors in mice genetically predisposed to catalepsy.

Acute injection of imipramine to NPK mice hereditary predisposed to pinching catalepsy reduced immobility in the forced swimming test, but had no effect on catalepsy. Chronic treatment with imipramine reduced the severity of catalepsy and functional activity of 5-HT1A serotonin receptors, but did not modify their expression in the hippocampus. NPK mice can be a convenient model for studies of the effects of antidepressant.

Adrenergic Uptake Inhibitors↗
PubMed1984

Comparison of filtration and equilibrium dialysis methods for [3H]imipramine binding to human platelets.

Receptor binding of imipramine in human platelets was assessed by filtration through glass-fiber filters and by equilibrium dialysis. Both methods yield drug-receptor dissociation constants of similar magnitude (10(-9) M) to literature values. However, the density of binding sites (Bmax) was fivefold lower by filtration (473 +/- 92 fmol/mg protein) compared to equilibrium dialysis (2652 +/- 765 fmol/mg protein). Dialysis allows direct assessment of free imipramine and avoids drug loss during the separation step of the filtration assay. Additional advantages were found for computer nonlinear regression analysis of untransformed data to eliminate errors owing to linear transformation in the Scatchard analysis and for simultaneous quantitation of nonspecific and total drug binding.

Blood Platelets↗
PubMed1992

A meta-analysis of treatments for panic disorder with agoraphobia: imipramine, alprazolam, and in vivo exposure.

The most common pharmacological treatments for panic disorder with agoraphobia (PDA) include the use of imipramine and alprazolam while the most common behavior therapy is the use of graded in vivo exposure. Several studies have found these treatments to be superior to placebo in the treatment of PDA, but it has not been clear if there are differences among these three treatments. It has also not been clear for what aspects of PDA each treatment is the most effective. The purpose of this study was to conduct a meta-analysis of the results of relevant treatment outcome studies on a number of dependent variables (e.g., panic attack severity, dysphoria, avoidance behavior). Few studies satisfied the minimum criteria for inclusion and the final data pool consisted of 34 treatment studies. Imipramine was found to be generally ineffective for most variables. Alprazolam was significantly effective for panic and anxiety variables in PDA, while exposure was significantly effective for phobia variables. Exposure had the most consistently strong effect sizes.

Agoraphobia↗
PubMed1992

Differential regulation of the imipramine-sensitive serotonin transporter by cAMP in human JAr choriocarcinoma cells, rat PC12 pheochromocytoma cells, and C33-14-B1 transgenic mouse fibroblast cells.

The imipramine-sensitive serotonin transporter appears to be the receptor for clinically important antidepressants. Some studies suggest that this protein may fall under the influence of abnormal and as yet uncharacterized regulatory effects during depressive illness. Despite these putative disease-related effects, regulation has never been demonstrated in either the platelet or synaptosome model systems. Here we demonstrate for the first time that the imipramine-sensitive serotonin transport activity in either JAr choriocarcinoma or PC12 pheochromocytoma cell lines is subject to regulation by cAMP. Unexpectedly, the regulatory effect is opposite in the two cases, causing stimulation in JAr (increased Vmax) and inhibition in PC12 (kinetically complex). Appearance of these kinetic effects lagged 15 to 20 hours behind peak cAMP levels. The results are consistent with the interesting possibility that different tissues may express isoforms of the recently cloned serotonin transporter cDNAs. We suggest, therefore, that JAr and PC12 are attractive models in which to pursue detailed analysis of serotonin transport and its manner of regulation by cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Pitfalls in demonstrating an endogenous ligand of imipramine recognition sites.

The recognition sites for the 5-hydroxytryptamine (5-HT) uptake inhibitors imipramine and paroxetine may represent receptors for a presently unknown endogenous ligand, whose function would be to modulate 5-HT uptake. Attempts to isolate such a factor from rat brain tissue are described, following a published procedure. It is shown that chromatographic fractions found to inhibit the binding of [3H]imipramine and [3H]paroxetine to rat brain membranes consisted of material essentially unretained by the reverse-phase HPLC column, and they were of high osmolarity. Thus, the activity was probably unspecific in nature, and the presence in rat brain of the factor has not been unequivocally demonstrated.

Animals↗
PubMed1987

Modulation of neuronal MAO activity, 5-HT uptake and imipramine binding by endogenous substances in dog cerebrospinal fluid.

Addition of small amounts of dog cerebrospinal fluid (CSF) inhibited both type A and type B monoamine oxidase (MAO) in dog brain mitochondria. The inhibition was competitive with 5-HT as substrate, but non-competitive with beta-phenylethylamine as substrate. Tricyclic antidepressants also exhibited competitive inhibition with type A MAO, but were non-competitive with type B MAO. The endogenous materials in CSF activate [3H]-imipramine specific, dose-dependent binding in dog brain preparations. The maximum number of binding sites (Bmax) increased, but the dissociation constant (Kd) was altered significantly in the presence of CSF. Addition of CSF induced a marked activation of uncompetitive [14C]-5-HT uptake in dog brain preparations. Moreover, there were reversibilities of the inhibition of MAO activity or of the activation of imipramine binding and 5-HT uptake by CSF substance after dilution experiment. These results indicate the possible presence of an endogenous psychotic drug-like substance in CSF.

Animals↗
PubMed1987

Low-affinity binding of [3H]imipramine to primary astrocyte cultures.

High-affinity uptake of serotonin (5-HT) by primary cultures of rat cortical astrocytes has been shown recently to be potently inhibited by tricyclic antidepressants in a manner similar to that described for brain synaptosomes [Katz and Kimelberg, J. Neurosci. 5, 1901 (1985)]. Since the high-affinity binding of [3H]imipramine (IMI) to brain membranes has been well correlated with the inhibition of synaptosomal 5-HT uptake, the binding of [3H]IMI to these astrocyte cultures was examined. No evidence for the existence of a high-affinity binding site was detected in either intact astrocytes or membranes prepared from astrocyte cultures. However, a very dense population of low-affinity binding sites was observed using both methods. This site was similar in affinity (0.606 microM for membranes and 0.959 microM for intact cells) to a low-affinity site observed with rat brain membranes (1.79 microM) but was present at a much greater density in astrocytes (1610 pmoles/mg protein for membranes and 672 for intact cells versus 53 pmoles/mg protein in brain), and may have prevented detection of the high-affinity site. Low-affinity binding to astrocytes was sodium independent, as was low-affinity binding to brain membranes. There was a poor correlation between the inhibitory potencies of the drugs tested against imipramine binding and 5-HT uptake. The binding of 15 nM [3H]IMI was nearly equipotently inhibited by all of the antidepressants tested with IC50 values ranging from 0.56 to 2.6 microM. Other receptor ligands such as 5-HT, chlorpheniramine, quipazine, atropine and benztropine were relatively weak inhibitors of [3H]IMI binding, whereas chlorpromazine was more potent than the tricycle antidepressants.

Animals↗
PubMed1990

A monoclonal anti-imipramine antibody with antidepressant binding properties similar to the muscarinic receptor.

A murine monoclonal antibody raised using imipramine conjugated to bovine serum albumin bound free imipramine with high affinity (KD = 24 nM). The antibody had a binding affinity profile for tricyclic and other uptake-inhibitor type antidepressants which correlated highly with the affinities of the same compounds for the brain acetylcholine muscarinic receptor, but not for plasma-membrane 5-hydroxytryptamine carriers. This antibody was not similar in binding properties to polyclonal antisera produced using the same antigen but was highly similar in binding properties to a monoclonal anti-nortriptyline antibody, ANT3, raised by Marulo et al. (Marulo S, Hoebeke J, Guillet JG, Andre C and Strosberg AD, J Immunol 138: 524-526, 1987) using a different antigen.

Animals↗
PubMed1985

Effect of protein concentration on kinetic constants (Kd and Bmax) of 3H-imipramine binding in blood platelets.

3H-imipramine binding was studied in the blood platelets of 80 normal controls and 50 depressed (psychotic and nonpsychotic) patients. Protein concentration in the incubation mixture, and Kd and Bmax values were correlated in normal controls and depressed patients. A small but significant correlation between protein in the incubation mixture and Bmax was observed in normal controls and depressed patients. There was also a significant correlation between protein and Kd of imipramine binding in the blood platelets of unipolar psychotic depressed patients. However, analysis of covariance to remove the effect of protein on Kd and Bmax did not change the basic finding of decreased Bmax in the blood platelets of psychotic depressed patients.

Adult↗
PubMed1988

Platelet MAO deamination of serotonin in depressed patients. Changes after imipramine treatment and clinical correlations.

Monoamine oxidase (MAO) in blood platelets has been used as a model to study MAO in the central nervous system, where disorders in serotonergic systems are thought to occur in depression. Inconsistent changes in platelet MAO of depressed patients have been reported when several substrates other than serotonin (5-HT) have been used. To correlate changes in platelet MAO activity with the enzyme activity in central serotonergic systems, the platelet MAO activity of depressed patients (first unmedicated and then after 3 weeks and 2 months of imipramine treatment) and normal controls was measured using 5-HT as substrate. The results showed that there is a steady, measurable platelet MAO activity with that substrate. This activity was significantly higher in unmedicated depressed patients than in controls, and it decreased progressively with imipramine treatment, reaching a normal level when the patients were clinically recovered from depression after 2 months of therapy.

Adult↗
PubMed1988

Acute changes in sleep-related hormone secretion of depressed patients following oral imipramine.

Tricyclic antidepressants have acute effects on hormone secretion when given either orally or parenterally in the morning. These drugs also have acute effects on the sleep electroencephalogram (EEG) when given immediately before sleep onset. In particular, imipramine significantly delays the REM-nREM cycle and increases the amount of delta wave activity. This study shows that an oral dose of 50 mg imipramine given at bedtime to depressed patients has little effect on the secretion of prolactin and melatonin, but acutely advances the secretion of growth hormone and cortisol. This suggests that sleep and hormone secretion may only be temporally related, as they can be dissociated pharmacologically.

Administration, Oral↗
PubMed1989

Circadian variation of platelet 3H-imipramine binding, platelet serotonin content, and plasma cortisol in healthy volunteers.

Platelet 3H-imipramine binding, platelet serotonin content, and plasma cortisol were measured in 10 healthy female volunteers. Samples were taken on 5 occasions with a 6-hr interval during a 24-hr period within 1 week in May. Although there were individual variations in the biochemical parameters over a 24-hr period, we could not establish a clear common circadian rhythm for all subjects in platelet 3H-imipramine binding and platelet serotonin concentrations. During the night, there was a significant decrease in Bmax values and a slight, but not significant, increase in serotonin concentrations. A distinct circadian rhythm was obtained for plasma cortisol, with lowest values during the night.

Adult↗