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Substantial evidence indicates that brain neurons containing and secreting norepinephrine (NE) and corticotrophin-releasing hormone (CRH) are activated during stress. The acoustic startle reflex (ASR) can be enhanced by CRH neuronal activity in the central nucleus of the amygdala. Our previous study demonstrates an augmentation of the footshock-induced ASR (f-ASR) 1 day after chronic variable stress (CVS) for 13 days. In this study, to evaluate a long-term neural plasticity in NE-CRH systems after CVS, we examined f-ASR 1, 8 or 15 days after CVS. The augmented magnitude of the f-ASR 15 day after CVS was potentiated and delayed compared with that 1 day after CVS. The delayed augmentation of f-ASR was inhibited by repeated treatment with desipramine, maprotiline or paroxetine for 14 days after CVS. A single treatment with any antidepressant agent had no influence the f-ASR while a marked inhibition by a single dose of alprazolam, CRH1-receptor antagonist, prazosin and propranolol was observed. The decreased tyrosine hydroxylase activity in the locus coeruleus and the beta-adrenoceptor down-regulation in the amygdaloid complex might be involved in the inhibiton of the delayed augmentation of f-ASR by repeated antidepressant treatment, leading to the possibility that the delayed sensitization of CRH response to stress after CVS might contribute to the biological mechanism underlying the formation of pathological states such as anxiety and depressive disorders.

Background: Isoflurane anesthesia has been shown to have a possibility of inducing a biphasic effect on dopamine release in rat striatum. The current study investigated the effect of isoflurane on the extracellular concentration of dopamine in the rat striatum pretreated by a classical antidepressant, imipramine, using in vivo microdialysis techniques., Methods: After intraperitoneal administration of 5 and 10 mg x kg(-10 of imipramine, the rats were anesthetized with 1 and 2.5% isoflurane inhalation. The control group was injected saline. Isoflurane anesthesia increased the extracellular concentration of dopamine metabolites without any change in dopamine concentration., Results: Under pretreatment of 5 mg x kg(-1) of imipramine, the effect of isoflurane on the change in dopamine and its metabolites was preserved. Whereas, 10 mg x kg(-1) of imipramine pretreatment induced a marked increase in the extracellular concentration of dopamine when only 1% isoflurane was applied but not with 2.5% isoflurane. In the rat administered 10 mg x kg(-1) of imipramine, anesthesia-induced increase of 3-methoxytyramine was not found., Conclusions: Our previous investigation suggested that the isoflurane anesthesia has a biphasic effect on dopamine release in rat striatum under pargyline pretreatment. The same effect was shown in the rat administered imipramine. Isoflurane anesthesia might modify dopaminergic neural activity and release of neurotransmitters through different and complex ways.

Locus coeruleus (LC) is the major component of noradrenergic neurons in the brain. corticotropine-releasing hormone (CRH) and norepinephrine (NE) are suggested to play significant roles in the pathophysiology of depression, although the involvement of the serotonergic system in the CRH-NE systems is not elucidated. Chronic inescapable and unpredictable stress can result in a sustained dysregulation of both of CRH and NE systems. In the present study we have investigated the TH immunoreactivity in the LC by immunohistochemical staining in rats treated with chronic variable stress (CVS) and concurrent administration with clomipramine or fluvoxamine. There was a significant decrease in TH levels 24 h after the last stressor of CVS, followed by a further decrease in that of 72 h later, whereas a marked increase was observed in TH levels immediately after the last stress of CVS 13 d. Concurrent clomipramine and fluvoxamine treatment prevented the sensitization of TH reactivity and the delayed decrease until 72 h later. These data suggest that an increase in serotonin availability would contribute to the normalization of both hypoactivity and sensitization of LC-NE neurons modified under "chronically stressful" situations.

The effects of the antidepressant drugs trazodone and imipramine on the circadian rhythm were studied by means of the sleep propensity test (SPT; sleep latency was examined by 35-minute EEG records at 09:00, 11:00, 13:00, 15:00, 17:00). The subjects were 11 healthy male volunteers (mean age, 23.6 years old). The drugs were administered 4 times a day with single blind trials using an inactive placebo as a control. The dosages of the drugs were trazodone 50-100 mg/day and imipramine 20-40 mg/day. We discussed the circadian rhythm referring to previous polysomnograhy (PSG) studies using the same drugs and dosages with most of the same subjects. As a result, the mean sleep latency of SPT was the shortest at 09:00 (p<0.1) with a placebo, at 11:00 (p<0.05) with trazodone and at 13: 00 (not significantly) with imipramine administration. These results suggested that neither drug affected sleepiness. They affected the circadian rhythm during the daytime (=the day rhythm). They delayed the day rhythm. Delay of the day rhythm was due to trazodone and have been caused by not only trazodon administration itself, but also by the increase of slow-wave sleep obtained in the previous night's PSG study. And the day-rhythm delay was due to imipramine and might have been caused by not only imipramine administration itself, but also by the decrease in the percentage of slow-wave sleep and REM sleep, and an increase in REM latency obtained in the previous night's PSG study. Therefore, we concluded that neither drug affected the tendency toward sleepiness, but did affect the day rhythm in healthy subjects.

Psychoendocrinology studies of depressed patients focus on the disregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Abnormalities in the HPA axis have been noted in depressed patients. Numerous data have demonstrated the existence of reciprocal interactions between the central serotonin (5-HT) system and HPA axis. These interactions are of particular relevance when considering pathological conditions, such as depression, in which modifications of both the 5-HT system and HPA axis have been evidenced. In our laboratory, we examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test and on the wet-dog shakes induced by the DOI, 5-HT2 receptor agonist with the administration of imipramine and lithium. The reduction of immobility, induced by the chronic administration of imipramine for 15 days, was blocked by treatment with ACTH for 14 days. And, chronic ACTH treatment for 14 days increased the wet-dog shake response. This effect of ACTH was not inhibited by a 14-day administration of imipramine. Accordingly, the chronic treatment of rats with ACTH may prove to be an effective model for antidepressant-treatment-resistant depression. We believe that behavioral pharmacological and molecular biological research into the interaction between the 5-HT and HPA axis will elucidate the pathogenesis of depression or antidepressant-treatment-resistant depression and the mechanism of antidepressants action.

Tricyclic antidepressive agents(TCAs) are conventional antidepressant. Cytochrome P450(CYP) 2D6 is involved in the hydroxylation of TCAs, while N-demethylation of TCAs is mediated by other such as CYP2C19, 3A4 and 1A2. The elimination of TCAs is impaired by CYP2D6 inhibitors such as quinidine. Newer antidepressants, selective serotonin uptake inhibitors(SSRIs), are also metabolized in the liver. Fluvoxamine, an SSRI, is a potent inhibitors for CYP1A2 and CYP2C19, moderate for CYP3A4 and weak for CYP 2D6. Paroxetine, another SSRI, causes substantial inhibition of CYP2D6 activity. Milnacipran, a serotonin and noradrenaline reuptake inhibitor, is mainly excreted unchanged in urine and some part as its glucronide conjugate. In contrast to many SSRIs, milnacipran is devoid of metabolic inhibition.

Respiratory insufficiency is a major cause of death in Duchenne muscular dystrophy (DMD). The earliest sign is a hypoventilation which appears in REM sleep. We administered 20 mg of clomipramine hydrochloride before sleep to two DMD patients with periodic nocturnal hypoxemia. The complaints such as morning headache, nausea and somnolence disappeared promptly. Polysomnography revealed complete suppression of REM sleep and disappearance of periodic hypoxemia in both cases. The most important untoward effect was intractable constipation observed in one patient. Although clomipramine dramatically improved the nocturnal periodic hypoventilation, the therapeutic effects lasted less than three months. Permanent REM sleep suppression is requisite for optimal drug therapy of periodic nocturnal hypoventilation in DMD.

The effect of alpha 2-adrenoceptor agonist, clonidine (CLN) (100 micrograms/kg, i.p.), on the noradrenalin metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG)-total in the rat nucleus accumbens after desipramine (DMI) (20 mg/kg, i.p.) and clomipramine (CMI) (20 mg/kg, i.p.) treatment was estimated in the freely moving rat by intracerebral dialysis. Locomotor activity was measured simultaneously by the Animex. Locomotor activity in the control decreased after CLN administration, in accordance with the decrease in MHPG. The difference of locomotor activity and MHPG between the single dose trial with DMI, CMI and the control did not reach statistical significance throughout the experiment. The results suggest that a single injection of DMI and CMI have not an inhibitory effect on presynaptic alpha 2-adrenergic receptor in the nucleus accumbens. Next, DMI (20 mg/kg, i.p.) and CMI (20 mg/kg, i.p.) were injected once daily for 14 days and experiments, the same method as used on the single dose trial. A difference in locomotor activity and MHPG between the chronic DMI treatment and the control reached statistical significance. A significant reduction of locomotor activity was found during the 60 min period of the experiment. In addition, a significant reduction of MHPG was found during the 30-90 min period. A difference in locomotor activity and MHPG between the chronic CMI treatment and the control reached statistical significance. A significant reduction of locomotor activity was found during the 60 min period of the experiment. In addition, a significant reduction of MHPG was found during the 30-120 min period. The results suggest that the chronic DMI treatment and the chronic CMI treatment may diminish the CLN-induced reduction of MHPG via the subsensitivity of presynaptic alpha 2-adrenergic receptor in the nucleus accumbens.

Electroencephalographic (EEG) effect of quinupramine was investigated in unanesthetized rabbits with chronic electrode implants, and it was compared with those of imipramine and amitriptyline. Quinupramine (0.56-3.2 mg/kg) induced a marked drowsy pattern of spontaneous EEG: high voltage slow waves increased in the cortex, while the hippocampal theta rhythm was desynchronized. Imipramine (1.0-5.6 mg/kg) and amitriptyline (0.56-3.2 mg/kg) also elicited similar EEG effects. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus was markedly suppressed by quinupramine, imipramine and amitriptyline. The EEG arousal response induced by i.v. injection of physostigmine was markedly suppressed by quinupramine, amitriptyline and imipramine. Quinupramine showed no significant effect on the photic driving response and recruiting response. Quinupramine slightly enhanced the limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation, while amitriptyline and imipramine caused an initial suppression followed by a quick recovery. The EEG effects of quinupramine were similar to those of amitriptyline in both qualitative and quantitative aspects.

Electroencephalographic (EEG) effects of lopramine, a new antidepressant, were investigated in rabbits with chronic electrode implants, and compared with those of imipramine and amitriptyline. All drugs were administered i.v. Lopramine (10, 20 mg/kg) induced a drowsy pattern of spontaneous EEG consisted of high voltage slow waves in the cortex and amygdala, and desynchronization of hippocampal thetha waves. Imipramine and amitriptyline (1-5 mg/kg) also elicited similar EEG changes but were much more potent than lopramine in this effect. Lopramine (10, 20 mg/kg) failed to suppress the EEG arousal responses induced by not only auditory stimulation but also electrical stimulation of the mesencephalic reticular formation, centromedian thalamus and posterior hypothalamus, whereas imipramine and amitriptyline (1 approximately 5 mg/kg) markedly inhibited these responses. The EEG arousal response induced by i.v. injection of physostigmine 0.1 mg/kg showed no change after lopramine (20 mg/kg), while the response was significantly suppressed by imipramine (2, 5 mg/kg) and amitriptyline (1, 2 mg/kg). Lopramine showed no effect on the recruiting response induced by electrical stimulation (8 Hz) of the centromedian thalamus and slightly enhanced the limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation, while imipramine (2, 5 mg/kg) and amitriptyline (1--5 mg/kg) caused an initial depression followed by sustained enhancement of these afterdischarges. These results demonstrate lopramine to be an antidepressant of a new type which has no effect on the ascending reticular activating system and no central anticholinergic action.

Effects of the typical psychotropic drugs such as neuroleptics, tricyclic antidepressants and benzodiazepines on the monosynaptic reflex (MSR) and polysynaptic reflex (PSR) were investigated using intact and spinal cats. Drugs used were chlorpromazine, levomepromazine, perphenazine, prochlorperazine, droperidol, haloperidol, amitriptyline, imipramine, diazepam and flurazepam. Neuroleptics depressed the ventral root reflexes markedly to slightly in both preparations. The inhibitory effects of these drugs on MSR of intact cats were stronger than those on MSR of spinal cats, and the activity was slightly higher than that of PSR depression in intact preparations. In intact cats, those depressants effects of neuroleptics on PSR produced various characteristic action patterns in comparison with MSR inhibition. Tricyclic antidepressants were similar in the mode of action to the dimethylamino side-chain groups in phenothiazines, but the inhibitory effects of ventral root reflexes were distinctly weaker than that of neuroleptics. Benzodiazepines depressed only PSR without MSR inhibition, especially in spinal cats. Thus, it is suggested that the structure-activity relationship considered, a classification of the psychotropic drugs can be given according to the inhibitory activities on spinal ventral root reflexes in intact and spinal cats.

Five mg/kg of imipramine (IMI) or desipramine (DMI) was injected s.c. to Wistar-Imamichi male and female rats daily from 7 approximately 19 days of age. Control pups received saline. The body temperature of IMI-females showed a significant rise at 7, 8 and 12 weeks of age. Thermic responses to thyrotropin-releasing hormone (TRH, 10 mg/kg, i.p.) at 5 weeks of prepubertal age showed no marked changes. At 9 weeks of age, IMI-males showed a significant hyperthermia 15 approximately 30 min after TRH. Control and IMI-males were castrated at 9 weeks of age. At 11 weeks of age, castrated IMI-males showed a significant decrease in the TRH-induced hyperthermia compared to sham-operated or intact IMI-males. These castrated male rats were treated with a single dose of 20 mg/kg of testosterone enanthate (s.c.) at 11 weeks of age. There was no significant difference in the TRH-induced hyperthermia between the groups when tested at 13 weeks of age. Results suggest that the exposure of the infantile rats to imipramine induces sex-related functional alterations in the thermoregulatory system after puberty and that sex hormones may play a modulatory role for these changes.

Effect of a novel antidepressant, paroxetine, on the uptake of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) as well as on various neuro-receptors were investigated in comparison with those of the tricyclic antidepressants amitriptyline, chlorimipramine and imipramine. Paroxetine showed a potent 5-HT uptake inhibitory action, giving the NA/5-HT ratio of 886 in comparison with the ratios of 1.7, 15 and 1.5 for amitriptyline, chlorimipramine and imipramine, respectively. On the other hand, paroxetine showed almost no inhibitory action on the binding of the [3H]-labeled ligands examined in this study [( 3H]quinuclidinyl benzilate, [3H]5-HT, [3H]ketanserine, [3H]pyrilamine, [3H]dihydroalprenolol, [3H]prazosin, [3H]clonidine and [3H]spiroperidol). In contrast, the tricyclic antidepressants showed inhibitory action on a number of bindings and also revealed comparatively high affinities especially for muscarine, histamine-1 and alpha 1-adrenaline receptors responsible for the side effects. From the above findings, it can be concluded that paroxetine has only a weak affinity for various neuro-receptors and inhibits specifically 5-HT uptake.

The behavioral effects of lopramine [N-methyl-N-(4-chlorobenzoyl-methyl)-3-(10, 11-dihydro-5H-dibenz (b,f) azepin-5-yl) propylamine hydrochloride] were investigated in mice and rats and compared with those of amitriptyline and imipramine. Lopramine inhibited reserpine hypothermia and haloperidol catalepsy in mice and tetrabenazine ptosis in rats. In addition the drug potentiated the effects of methamphetamine, and DOPA- or apomorphine-induced stereotypy in mice, whereas it suppressed muricide of the rat induced by either olfactory bulbectomy or delta9-tetrahydrocannabinol, similar to the responses seen with imipramine and amitriptyline. On the other hand,lopramine increased spontaneous motor activity and markedly potentiated methamphetamine hyperactivity. In contrast to imipramine and amitriptyline, lopramine failed to counteract both the lethal effect of physostigmine and oxotremorine tremor in mice, indicating that the drug had no central anticholinergic effect. Lopramine, even at such a large dose as 5,000 mg/kg p.o., caused neitherimpairment of coordinated motor activity nor muscle relaxation. It is concluded that lopramine is a new type of tricyclic antidepressant with extremely low toxicity and without central anticholinergic action.

A new antidepressant, mianserin (GB-94, Organon), and other known antidepressants, imipramine (IMP), desipramine (DPM), chlorimipramine (CIP), amitriptyline (ATP) and nortriptyline (NTP) were orally administered to respective groups of 25 mice for consecutive weeks, and changes in monoamine metabolisms in the brain were investigated, neurochemically. On the basis of significant difference from the control group, mianserin 20 mg/kg and DPM 20 mg/kg produced no change of the brain contents of DA and 5-HT; IMP 50 mg/kg and CIP 40 mg/kg did not alter NA and DA values, but did decrease 5-HT levels; ATP 30 mg/kg increased only the amount of NA, left unchanged the DA and 5-HT levels, and NTP 20 mg/kg raised the levels of DA and 5-HT, but had no effect on NA. Mianserin, IMP and DPM all facilitated the decrease of both NE and DA as induced by pre-administration of alpha-methyltyrosine, the substance known to reduce the level of catecholamines. Both NTP and CTP showed no notable effect. ATP suppressed the reduction of the DA level. Accumulation of 5-HIAA induced 1 hour after treatment with probenecid 250 mg/kg was enhanced by mianserin 20 mg/kg, NTP 20/kg and IMP 25 mg/kg, but was not significantly affected by CIP, DPM and ATP. These results suggest that mianserin activated both the NE and 5-HT metabolic systems, IMP activated the NE system in general, but activated the 5-HT system only at low doses and tended to suppress the formation of 5-HT, in high doses; CIP had no effect on the NE system and suppressed 5-HT system, in high doses. The arousal response of hippocampal EEG in the chronic EEG of the rabbit, induced by physostigmine 0.05 mg/kg, i.v., was suppressed by IMP, ATP and CIP, while DMP and NTP were uneffected. Mianserin, rather maintained and prolong the arousal reaction. Observations made on arousal and sleep phases in long time recording of chronic spontaneous EEG in the rat showed a dose-dependent shortening of the para-sleep phase by mianserin in doses over 30 mg/kg and IMP in doses over 5 mg/kg. ATP 15 mg/kg showed a tendency to shorten the para-sleep. Hippocampal and cerebral cortical EEGs at arousal and slow wave stages were analyzed using a signal processor. The power spectra thus obtained showed no significant difference between the effects of mianserin and IMP.

The effects of tricyclic antidepressant drugs on cardiac receptor binding sites and Ca2+ binding to cardiac sarcoplasmic reticulum were investigated in rats. 1) Quinupramine was found to possess higher affinity for muscarinic cholinergic receptor binding sites in brain and heart, compared with imipramine. 2) Repeated quinupramine treatment induced a significant increase in the Bmax value in cardiac muscarinic cholinergic receptors. 3) In imipramine treated heart, isoproterenol-induced stimulation of ornithine decarboxylase activity was significantly decreased compared with that in the vehicle control. 4) Repeated quinupramine and imipramine treatment caused a significant reduction of Bmax of 45Ca2+ binding in cardiac sarcoplasmic reticulum fractions. 5) After single quinupramine treatment, its concentrations in heart were higher than those in brain and plasma. 6) After the repeated quinupramine treatment, its concentration in heart was 2.4 times higher than that after single treatment. These results demonstrate that repeated tricyclic antidepressant drug treatment caused a functional impairment in Ca2+ binding sites of cardiac sarcoplasmic reticulum and adaptive changes of receptor binding sites.

Studies were carried out to evaluate the antidepressant action of Mianserin as related to noradrenergic and serotonergic systems. The actions of known tricyclic anti-depressants were comparatively investigated together with Mianserin (Organon). Self-stimulation behavior induced by stimulation of the posterior hypothalamus and substantia nigra was unaffected by Mianserin and imipramine, was suppressed with chlorpromazine and markedly enhanced by methamphetamine. The enhancement due to methamphetamine was suppressed by both Mianserin and chlorpromazine, and was potentiated by imipramine. Mianserin, imipramine and amitriptyline enhanced the rolling movements induced by methamphetamine in rats in which the nigro-striatal dopaminergic system was destroyed by the injection of 6-hydroxydopamine. The excitation induced by ldopa administration, of isocarboxazid treated mouse was enhanced by Mianserin in doses over 25 mg/kg and by imipramine or amitriptyline. The excitation of MK-486 treated mouse, induced by L-5HTP was suppressed by Mianserin, nortriptyline augmented the excitation. The head twitches induced by 5HTP were reduced to 1/10 in onset frequency by Mianserin, 1 mg/kg, p.o. The suppressive potency of amitriptyline in this model was less than 1/5 of that of Mianserin. The potentiation of the flexor reflex of hind limbs of the spinal rat induced by the pretreatment with isocarboxazid and l-dopa, 20 hours after the reserpinization, was markedly suppressed by Mianserin and amitriptyline, but unaffected by imipramine nor chlorimipramine. The potentiation of the extensor reflex of hind limbs of the spinal rat, induced 20 hours after the reserpinization by pretreatment with isocarboxazid and 5-HTP was suppressed by Mianserin, even in a low dose of 0.5 mg/kg, and by amitriptyline in a dose of 10 mg/kg. As far as monoaminergic mechanisms are concerned, the mode of antidepresant action of Mianserin is probably different from that of tricyclic antidepressants.

Pharmacological properties of LOP were compared with those of imipramine(IMP). LOP had little or no effect on electroconvulsive shock and chemoconvulsions in mice, conditioned avoidance response in rats, pain threshold in mice and rats and body temperature in rabbits. LOP, unlike IMP, showed relatively weak effects on general behavior in mice, spontaneous EEG in cats and spontaneous motor activity in mice. LOP prevented oxotremorine-induced hypothermia but not tremor, while IMP antagonized both the responses in mice. In anesthetized dogs, LOP caused a respiratory stimulation and a fall in blood pressure, left ventribular pressure and left ventricular dp/dt without a noticeable effect on heart rate. LOP was less potent than IMP in the depressor and cardiodepressing effects, antispasmogenic activity and in antagonizing the depressor response to acetylcholine. LOP, like IMP, potentiated pressor response to norepinephrine and reduced that to tyramine in anesthetized dogs, but neither antidepressant produced norepinephrine potentiation in isolated guinea-pig vas deferens. Both drugs inhibited spontaneous motility of the jejunum without reducing the gastric motility in anesthetized dogs. These results indicate that, compared with IMP, LOP is characterized by weak general pharmacological activities.

The effects of a new tricyclic antidepressant quinupramine (5-(3-quinuclidinyl)-10,11-dihydro-5H-dibenz [b, f] azepine) on various animal behaviors were examined in mice and rats and compared with those of imipramine, amitriptyline and maprotiline. Quinupramine antagonized haloperidol-induced catalepsy and tetrabenazine-induced ptosis and potentiated methamphetamine- and apomorphine-induced stereotyped behavior. These effects were almost the same as or even more potent than those of imipramine and amitriptyline. Quinupramine decreased locomotor activity in mice, but potentiated methamphetamine-induced hyperactivity to a greater degree than imipramine and amitriptyline. On the other hand, quinupramine inhibited muricide in accumbens-lesioned rats, but did not prominently inhibit muricide in olfactory-bulbectomized and raphe-lesioned rats. Quinupramine decreased the duration of immobility in low doses without affecting locomotor activity, and this effect was almost the same as that of imipramine and amitriptyline and more potent than that of maprotiline. Quinupramine antagonized physostigmine lethality and oxotremorine-induced tremor, suggesting that quinupramine has a central anticholinergic action. Quinupramine, like imipramine and amitriptyline, has no effect on conditioned avoidance behavior. In conclusion, quinupramine generally has the same behavioral profile as typical tricyclic antidepressants, but it has somewhat different effects from imipramine and amitriptyline since quinupramine has a potent central anticholinergic and a weak antimuricide effect.