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Tritiated imipramine binding in obsessive-compulsive volunteers and psychiatrically normal controls.

The authors evaluated platelet tritiated imipramine binding in 22 outpatients with obsessive-compulsive disorder (OCD) and 22 psychiatrically normal controls matched for age and gender. Mean maximal binding site density (Bmax) and equilibrium dissociation affinity (Kd) values were not significantly different. In OCD patients, Bmax was positively associated with age but was not associated with age of onset, gender, personality disorder, or five measures of illness severity. Eight patients with OCD were subsequently treated with clomipramine up to 300 mg/day for 10 weeks. Among these 8 patients, Bmax values had a 65% mean decrease from baseline, but Bmax values did not change among 7 OCD patients receiving placebo. The results suggest that a reduced density of tritiated imipramine binding sites may not be associated with OCD.

Adult↗

Response of depression to very high plasma levels of imipramine plus desipramine.

Forty-five depressed patients were treated with imipramine for 6 weeks. Seven of 7 patients (100%) who had plasma levels of imipramine plus desipramine greater than 500 ng/ml showed a 50% or greater improvement in Hamilton depression scores compared with 23 of 38 patients (60%) with plasma levels less than 500 ng/ml (p less than 0.057).

Adult↗

Serotonin uptake and imipramine binding in the blood platelets of obsessive-compulsive disorder patients.

14C-Serotonin (5-HT) uptake and 3H-imipramine binding (IB) were studied in the blood platelets of 20 obsessive-compulsive disorder (OCD) patients, 53 normal controls (5-HT uptake) and 32 normal controls (IB binding). The maximum number of binding sites (Bmax) was significantly decreased in OCD patients compared to normal controls, but there was no difference in the affinity for 3H-imipramine (Kd). The affinity for 5-HT uptake (Km) was also decreased in the OCD patients but the maximum velocity of 5-HT uptake sites (Vmax) was not significantly different in OCD patients and normal volunteers. There were trends for the Slowness Subscale of the Maudsley Obsessional-Compulsive Inventory (MOCI) to be positively correlated with the Km of 5-HT uptake (p = 0.094), whereas the Global Scale, Checking Subscale, and Doubting Conscientiousness Subscale of MOCI were negatively correlated with the Kd of IB (p = 0.066, p = 0.08, and p = 0.062, respectively). The results provide further evidence for the dysfunction of the serotonergic system in OCD.

Adult↗

Platelet 3H-imipramine binding sites in obsessive-compulsive behavior.

Several studies indicate a serotonergic dysfunction in patients with obsessive-compulsive disorder (OCD). We examined serotonergic function in OCD by determining platelet 3H-impiramine binding sites in patients with OCD during a drug-free baseline period as well as normal control volunteers. The maximum number of binding sites (Bmax) and apparent dissociation constant (Kd) was determined using 3H-imipramine (IMI) as the binding ligand. We observed that the mean 3H-IMI binding Bmax (fmol/mg protein) determined in 24 patients with OCD was not significantly different from that in 23 normal control subjects. There were no significant differences in the Kd between patients with OCD and normal control subjects. Our results are thus similar to those reported by Insel et al (1985) and Black et al (1990), who observed no significant differences in platelet 3H-IMI binding between OCD patients and controls; but different from those reported by Weizmann et al (1986), who observed decreased 3H-IMI Bmax in OCD patients. The discrepancy in the results is not clear, but may be related to several factors. Our results thus indicate that any abnormality in serotonergic function present in patients with OCD is not related to imipramine binding sites in the platelets. However, the possibility that there may be an abnormal platelet serotonin uptake or other serotonergic function in OCD cannot be ruled out.

Adult↗

Effects of imipramine on the nocturnal behavior of bilateral olfactory bulbectomized rats.

Experiments were performed to characterize the circadian behavior of bilateral olfactory bulbectomized (OB) rats and to investigate the effects of imipramine on that behavior. OB and sham-operated (SO) rats were housed individually for 2 weeks in activity monitors on a 13-hr light/11-hr dark cycle. OB rats were significantly more active than SO rats during the dark phase of the cycle, and both groups of rats were equally inactive during the light phase. Seven daily injections of imipramine [10.0 mg/kg, intraperitoneally (IP)] significantly reduced the nocturnal activity of OB rats, such that OB rats displayed nocturnal activity equivalent to SO rats. Abnormally high nocturnal activity is another important characteristic of the OB rat. This behavioral characteristic may prove to be valuable for the evaluation of novel antidepressive compounds.

Animals↗

Laterality and 3H-imipramine binding: studies in the frontal cortex of normal controls and suicide victims.

Serotonin [5-hydroxytryptamine (5-HT)]-sensitive imipramine binding (IB) was determined in the left and right hemisphere of frontal cortex of suicide victims and nonpsychiatric controls who died due to myocardial infarction or accident. The Kd (an inverse measure of affinity of 3H-imipramine to its binding sites) was significantly higher in left hemisphere than right hemisphere in normal controls. There were no differences in Bmax and Kd or Bmax between left hemisphere and right hemisphere in normals and suicides, respectively. These results do not support the finding of hemispheric asymmetry of 5-HT uptake as measured by IB (Bmax) in postmortem tissue from controls and suicide victims.

Carrier Proteins↗

Imipramine and alprazolam effects on stress test reactivity in panic disorder.

The reactivity of 40 panic disorder patients on mental arithmetic, cold pressor, and 5% CO2 inhalation stressors was tested before and after 8 weeks of treatment with imipramine, alprazolam, or placebo. Mean levels of subjective and physiological stress measures were compared during a baseline before any stressors were given, and at anticipation, stressor, and recovery periods for each stressor. After treatment, imipramine patients differed from the other two treatment groups on the prestressor baseline in showing higher systolic blood pressure (mean difference about 10 mmHg), higher diastolic blood pressure (10 mm Hg), higher heart rate (15 bpm), less respiratory sinus arrhythmia, shorter pulse transit time, and lower T-wave amplitude. Respiratory measures, electrodermal measures, body movement, and self-reported anxiety and excitement did not distinguish the groups. Reactivity to the stress tests was unaffected by the medications, but tonic differences present in the baseline persisted.

Adult↗

Decreased platelet imipramine binding in Tourette syndrome children with obsessive-compulsive disorder.

[3H]Imipramine binding to blood platelets was assessed in eight untreated Tourette syndrome (TS) children, nine drug-free TS children with obsessive-compulsive disorder (OCD), and nine age-matched and gender-matched control subjects. The density of [3H]imipramine binding sites in TS + OCD patients was significantly lower compared with TS-OCD patients (28%) as well as when compared with controls (31%). This alteration was not accompanied by differences in the affinity of the binding site to the ligand. The decreased density of the platelet serotonin "transporter" might implicate the involvement of the serotonergic system in the pathophysiology of OCD in TS patients, but not in TS per se.

Adolescent↗

Is platelet imipramine binding reduced in depression? A meta-analysis.

Although it has been suggested that decreased platelet imipramine binding may be a putative biological marker of depressive illness, a number of studies have not confirmed this finding, including a recent multicenter investigation by the World Health Organization (Mellerup and Langer 1990). We performed a meta-analysis of published reports on imipramine binding in groups of depressed and healthy control subjects and found that there was a highly significant decrease in Bmax (maximal binding) values in the depressed subject groups, which was even greater among those who had been free of medication for 4 weeks at the time of investigation. This finding remained highly significant even when only high affinity binding studies (Kd < 1 nmol/L) were considered, although the absolute size of this decrease was smaller.

Biomarkers↗

Seasonal variability in blood platelet 3H-imipramine binding in healthy controls: age and gender effects.

Binding of 3H-imipramine to blood platelet membranes was determined four times (once each season) in 26 healthy volunteers (11 men and 15 women), over the course of 1 year to determine possible seasonal variations. Blood platelets were obtained in April-May, July-August, October-November, and January-February. Significant seasonal variations in the maximum number of binding sites were found in women but not in men, with circannual peak in summer and a nadir in spring. The pattern of seasonal variations was not the same in men and women. The present results highlight the importance of monitoring for gender and season in binding studies. We found no significant correlation between 3H-imipramine binding parameters and age.

Adult↗

Regional distribution of [3H]imipramine binding in rat brain.

[3H]imipramine binding was measured in 23 microdissected areas of the rat brain and compared to published values for the endogenous levels of serotonin, noradrenaline and dopamine in the same areas. The density of [3H]imipramine binding sites appears to be highly correlated with the distribution of endogenous serotonin especially where the serotonin is located mainly in nerve terminals. A weak but still significant correlation also exists with the distribution of endogenous noradrenaline whereas no such correlation could be detected for endogenous dopamine.

Animals↗

Long-term imipramine effects are prevented by NMDA receptor blockade.

Long-term exposure to different antidepressant treatments induces increased motor response to central stimulants, due to a selective supersensitivity of dopamine D2 receptors in the limbic areas. Such an effect is accompanied by down-regulation of dopamine D1 receptor number, and by a decreased response of adenylyl cyclase to dopamine stimulation in the limbic system. Moreover, the number of beta-adrenergic receptors and the response of adenylyl cyclase to beta-adrenergic stimulation in the cortex result to be reduced. The present data confirms that imipramine (10 mg/kg twice a day for 3 weeks) produces such effects, and shows that the co-administration of imipramine with MK-801 (administered by a subcutaneously implanted osmotic minipump delivering 0.05 mg/kg/day of the compound) prevented the occurrence of both the behavioral supersensitivity to quinpirole, and the decrease of dopamine D1 and beta-adrenergic receptor function.

Animals↗

Binding of 14C-imipramine by pigmented and non-pigmented tissues.

When pigmented and non-pigmented rabbit irides were incubated with various concentrations of 14C-imipramine at equilibrium (120 min), the accumulation of the drug by the pigmented iris was 1.5 times as great as that by the non-pigmented iris. The accumulated drug is lost from both types of irides in a complex fashion. However, even after 120 min of washing, the differences in accumulation remain nearly constant. When accumulation of the drug in the non-pigmented iris was analyzed by discontinuous sucrose density gradient, it was observed that the drug was bound mainly by the low density sucrose fractions where the synaptosomes separate. On the contrary, in the pigmented iris approximately 70% of the drug was found in the melanin-containing fraction. The homogenate from the substantia nigra accumulated 1.5 times more than that from the human brain cortex. The affinity of the drug for bovine iris melanin granules and the synthetic L-dopa melanin was 9.9 X 10(5) M-1 and 3.8 X 10(3) M-1, respectively. On the rabbit iris sphincter muscles, imipramine was evaluated for antimuscarinic effects. The apparent dissociation constants, KB values, for the antagonist in the non-pigmented and pigmented iris were 1.7 X 10(-7) M and 3.8 X 10(-6) M, respectively. The low antimuscarinic activity in the pigmented iris is attributed to the loss of the drug to the pigment. On this basis, relevancy of the drug binding by pigmented tissues to the effects of this tricyclic drug is discussed.

Animals↗

Imipramine antagonism of apomorphine-induced hypothermia: a non-dopaminergic interaction.

Imipramine antagonized high dose apomorphine-induced hypothermia, and did not modify small dose apomorphine-induced hypothermia. It is suggested that apomorphine-induced hypothermia is the result of two effects. The first, induced by small doses of apomorphine, and antagonized by pimozide and sulpiride, is probably related to dopaminergic receptor stimulation. The second, induced by high doses of apomorphine, and antagonized by imipramine, is probably not related to dopaminergic receptor stimulation.

Animals↗

3H-imipramine binding in neuronal and glial fractions of horse striatum.

The glial fraction prepared from horse striatum contained less than 20% of the specific high affinity 3H-imipramine binding sites found in the neuronal fraction prepared from the same tissue. The binding in the glial fraction was considered to result from minor cross-contamination of the two fractions. It is thus concluded that there is probably no specific 3H-imipramine binding in glial cells.

Animals↗

Serotonin modulates the dissociation of [3H]imipramine from human platelet recognition sites.

The dissociation of [3H]imipramine from human platelet membrane recognition sites was studied. Simple exponential dissociation kinetics were observed indicating an apparent homogeneous class of sites which dissociate by a first order rate process. Inclusion of serotonin in the medium dramatically decreased the dissociation rate. At 0 degree C half-times of dissociation were 61.7 and 170 min in the absence and presence of serotonin, respectively. Other biogenic amines were ineffective in altering the dissociation kinetics. It is suggested that serotonin controls [3H]imipramine dissociation from an allosterically coupled site residing on a larger macromolecular complex.

Binding Sites↗

Solubilization of imipramine-binding protein from human blood platelets.

Various procedures for the solubilization of the imipramine-binding protein (IBP) of human platelets were compared. An IBP of a molecular weight of 300 000-400 000, as determined by exclusion chromatography on Sepharose 6B, was obtained with high amounts of digitonin and with lysolecithin. With smaller amounts of digitonin the molecular weight varied between more than 1 million and about 550 000 depending on the batch of detergent. The KD values and the IC50 values of drugs inhibiting imipramine binding were similar in the soluble preparation and in intact membranes. CHAPS and CHAPSO, even in high amounts, yielded solubilized IBP of high molecular weight (greater than 1 million). Membrane preparations of human platelets solubilized with high amounts of digitonin and with lysolecithin would therefore seem to be the most suitable for further purification of IBP.

Blood Platelets↗

Circadian rhythm of [3H]imipramine binding in the rat suprachiasmatic nuclei.

High affinity imipramine binding undergoes circadian variations of ca. 35% amplitude in many rat brain nuclei. The suprachiasmatic nuclei of the anterior hypothalamus (considered to be the circadian pacemaker driving many overt rhythms) has highest imipramine binding at the end of the dark and lowest at the end of the light phase. A similar circadian rhythm has previously been observed for serotonin uptake in the suprachiasmatic nuclei. In conjunction with other findings, these data indicate that serotonergic turnover in the suprachiasmatic nuclei decreases at lights on and increases at lights off.

Animals↗