Chronic Adrenocorticotropic Hormone Treatment Research Articles

Glucagon-like peptide-2-induced memory improvement and anxiolytic effects in mice

We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) on memory impairment in lipopolysaccharide (LPS)-treated mice, and anxiety-like behavior in adrenocorticotropic hormone (ACTH)-treated mice. In the Y-maze test, LPS (10 µg/mouse, i.c.v.) significantly decreased spontaneous alternation, which was prevented by pretreatment with GLP-2 (0.01–0.3 µg/mouse, i.c.v.). The GLP-2 treatment just before the Y-maze test also improved LPS-induced memory impairment. Continuous treatment with GLP-2 (3 µg/mouse, i.c.v.) had no effect on the open-field test in saline-treated or ACTH-treated mice. Chronic ACTH treatment did not cause anxiogenic effects in the elevated plus-maze test. GLP-2 showed weak anxiolytic-like effects in the elevated plus-maze test in ACTH-treated, but not saline-treated mice. Moreover, GLP-2 increased 5-HT, but not 5-HIAA and tryptophan hydroxylase 2 levels in the amygdala of ACTH-treated mice. Pharmacological depletion of 5-HT prevented the anxiolytic effects of GLP-2. These results suggest that GLP-2 protected and improved memory function in LPS-treated mice, and also had anxiolytic effects due to changes in the 5-HT system.

Glucagon-like peptide-2 but not imipramine exhibits antidepressant-like effects in ACTH-treated mice

We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) against refractory depression in adrenocorticotropic hormone (ACTH)-treated mice as a model of tricyclic antidepressant (TCA)-resistant depression. Chronic ACTH treatment (0.45mg/kg, s.c., 14 days) weakened the antidepressant-like effects of imipramine (20mg/kg, i.p., 6 days) in the forced-swim test (FST). Conversely, GLP-2 (3μg/mice, i.c.v., 6 days) induced antidepressant-like effects in the ACTH-treated mice in the FST. ACTH-treatment increased basal serum corticosterone levels, with an additional increase induced by the FST. Imipramine or GLP-2 had no effect on the basal corticosterone level, but GLP-2 attenuated the additional increase caused by the FST. Moreover, GLP-2 increased 5-HT levels, but not 5-HIAA. These results suggest that GLP-2 induced antidepressant-like effects under imipramine-resistant conditions through increase in 5-HT levels.

Chronic adrenocorticotrophic hormone treatment alters tricyclic antidepressant efficacy and prefrontal monoamine tissue levels

Several animal models are currently utilised in the investigation of major depressive disorder; however, each is validated by its response to antidepressant pharmacotherapy. Few animal models consider the notion of antidepressant treatment resistance. Chronic daily administration of adrenocorticotropic hormone (ACTH) or corticosterone can alter behavioural responses to antidepressants, effectively blocking antidepressant efficacy. Herein, we demonstrate that ACTH-(1-24) (100μg/day; 14 days) blocks the immobility-reducing ‘antidepressant’ effects of a single dose of imipramine (10mg/kg) in the forced swim test. This finding was accompanied by altered monoamine tissue levels in the prefrontal cortex (PFC) 1h after exposure to the acute stress of the forced swim test. PFC tissue from ACTH pre-treated animals contained significantly higher serotonin, noradrenaline and adrenaline concentrations relative to saline pre-treated controls. Conversely, dopamine levels were significantly decreased. Altered plasma corticosterone responses to ACTH injections were observed over the treatment course. Measures were taken on treatment days 1, 4, 8, 11, 14 and 15. ACTH administration initially enhanced plasma corticosterone levels, however, these normalised to levels consistent with control animals by day 14. No differences in corticosterone levels were observed across the treatment time course in saline-treated animals. Taken together these results indicate that pre-treatment with ACTH (100μg/day; 14 days) blocks the antidepressant effects of imipramine (10mg/kg), significantly alters key PFC monoamine responses to stress and downregulates glucocorticoid responses. These results suggest that chronic ACTH treatment is a promising paradigm for elucidation of mechanisms mediating antidepressant treatment resistance.

Depressive-like behavior in adrenocorticotropic hormone-treated rats blocked by memantine

Hyperactivity of the hypothalamic pituitary–adrenal (HPA) axis plays a role in the pathophysiology of major depressive disorder (MDD). Recent studies suggest the role of the glutamatergic system in the pathophysiology of MDD, and N-methyl-d-aspartate (NMDA) receptor antagonists have shown antidepressant effects in both preclinical and clinical studies. However, little is known about the role of adrenocorticotropic hormone (ACTH) specifically in the glutamatergic response to HPA axis activation. Glutamate is an NMDA receptor agonist, and glycine and d-serine act as co-agonists. Here, we measured brain concentrations of these amino acids in rats given repeated administration of ACTH (100μg/rat/day, sc, for 14days). Further, we also evaluated behavioral effects of memantine, a non-competitive NMDA antagonist, on immobility time in the forced swimming test and on locomotor activity in ACTH-treated rats. Compared with control rats, glutamine, glycine, l-serine, and d-serine levels were increased in the hippocampus of ACTH-treated rats; glutamate, glutamine, glycine, l-serine, and d-serine were increased in the cerebellum; and glutamine and glycine were increased in the frontal cortex and striatum, all with statistical significance. Remarkably, these increases in agonists and co-agonists might have led to the augmentation of NMDA receptor activity. ACTH treatment increased immobility time in the forced swimming test and decreased locomotor activity in rats. On the contrary, memantine (10mg/kg, ip) significantly decreased immobility time in the forced swimming test and increased locomotor activity in ACTH-treated rats. Furthermore, imipramine (15mg/kg, ip) did not alter immobility time in the forced swimming test whereas this drug significantly decreased locomotor activity in ACTH-treated rats. These results suggest that depressive-like behaviors by chronic ACTH treatment could be blocked by memantine.

Investigation on the Mechanisms for the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in ACTH Treated Rats

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.

Validation of the rat model of cryptogenic infantile spasms

To determine whether a new model of cryptogenic infantile spasms consisting of prenatal priming with betamethasone and postnatal trigger of spasms by N-methyl-D-aspartate (NMDA) responds to chronic adrenocorticotropic hormone (ACTH) treatment, and has electroencephalography (EEG) signature, efficacy of treatments, and behavioral impairments similar to those in human infantile spasms. Rats prenatally primed with betamethasone on gestational day 15 were used. Spasms were triggered with NMDA between postnatal days (P) 10 and 15 in a single session or in multiple sessions in one subject. The expression of spasms was compared to prenatally saline-injected controls. Effects of relevant treatments (ACTH, vigabatrin, methylprednisolone, rapamycin) were determined in betamethasone-primed rats. In the rats after spasms, behavioral evaluation was performed in the open field and elevated plus maze on P20-22. NMDA at P10-15 (the rat "infant" period) triggers the spasms significantly earlier and in greater numbers in the prenatal betamethasone-exposed brain compared to controls. Similar to human condition, the spasms occur in clusters. Repeated trigger of spasms is associated with ictal EEG electrodecrements and interictal large-amplitude waves, a possible rat variant of hypsarrhythmia. Chronic ACTH treatment in a randomized experiment, and chronic pretreatment with methylprednisolone significantly suppress the number of spasms similar to the human condition. Pretreatment with vigabatrin, but not rapamycin, suppressed the spasms. Significant behavioral changes occurred following multiple bouts of spasms. The model of infantile spasms has remarkable similarities with the human condition in semiology, EEG, pharmacologic response, and long-term outcome. Therefore, the model can be used to search for novel and more effective treatments for infantile spasms.

P.3.c.007 Excitatory amino acids serum levels affected by antipsychotics in patients with schizophrenia

Hyperactivity of the hypothalamic pituitary–adrenal (HPA) axis plays a role in the pathophysiology of major depressive disorder (MDD). Recent studies suggest the role of the glutamatergic system in the pathophysiology of MDD, and N-methyl-d-aspartate (NMDA) receptor antagonists have shown antidepressant effects in both preclinical and clinical studies. However, little is known about the role of adrenocorticotropic hormone (ACTH) specifically in the glutamatergic response to HPA axis activation. Glutamate is an NMDA receptor agonist, and glycine and d-serine act as co-agonists. Here, we measured brain concentrations of these amino acids in rats given repeated administration of ACTH (100 μg/rat/day, sc, for 14 days). Further, we also evaluated behavioral effects of memantine, a non-competitive NMDA antagonist, on immobility time in the forced swimming test and on locomotor activity in ACTH-treated rats. Compared with control rats, glutamine, glycine, l-serine, and d-serine levels were increased in the hippocampus of ACTH-treated rats; glutamate, glutamine, glycine, l-serine, and d-serine were increased in the cerebellum; and glutamine and glycine were increased in the frontal cortex and striatum, all with statistical significance. Remarkably, these increases in agonists and co-agonists might have led to the augmentation of NMDA receptor activity. ACTH treatment increased immobility time in the forced swimming test and decreased locomotor activity in rats. On the contrary, memantine (10 mg/kg, ip) significantly decreased immobility time in the forced swimming test and increased locomotor activity in ACTH-treated rats. Furthermore, imipramine (15 mg/kg, ip) did not alter immobility time in the forced swimming test whereas this drug significantly decreased locomotor activity in ACTH-treated rats. These results suggest that depressive-like behaviors by chronic ACTH treatment could be blocked by memantine.

Effects of Imipramine and Bupropion on the Duration of Immobility of ACTH-Treated Rats in the Forced Swim Test: Involvement of the Expression of 5-HT<sub>2A</sub> Receptor mRNA

We examined the effect of chronic administration of imipramine and bupropion, monoamine reuptake inhibitors, on the duration of immobility in the forced swim test and serotonin (5-HT)(2A) receptor function in the form of 5-HT(2A) receptor mRNA levels in rats chronically treated with adrenocorticotropic hormone (ACTH). The immobility-decreasing effect of bupropion without imipramine did not influence the chronic ACTH treatment. The effect on the expression of 5-HT(2A) receptor mRNA of chronic ACTH treatment was decreased by bupropion, but not imipramine. These results suggest that bupropion has the effect of reducing immobility time in the forced swim test in the tricyclic antidepressant-resistant depressive model induced by chronic ACTH treatment in rats, and that decreased 5-HT(2A) receptor mRNA levels may be involved in this phenomenon.

Increased DOI-Induced Wet-Dog Shakes in Adrenocorticotropic Hormone–Treated Rats Are Not Affected by Chronic Imipramine Treatment: Possible Involvement of Enhanced 5-HT2A–Receptor Expression in the Frontal Cortex

We examined the influence of imipramine, a traditional tricyclic antidepressant, on the binding to serotonin (5-HT)2receptors and levels of 5-HT2A–receptor mRNA in the frontal cortex of rats treated with adrenocorticotropic hormone (ACTH). Chronic treatment with ACTH significantly increased the binding of [3H]-ketanserin to 5-HT2receptors and the expression of 5-HT2A–receptor mRNA in the frontal cortex. However, it did not alter the concentration of 5-HT or 5-hydroxyindole acetic acid. The effect of chronic ACTH treatment on 5-HT2receptor and 5-HT2A–receptor mRNA levels was not altered by the chronic administration of imipramine. Also, imipramine did not affect the hyperfunction of 5-HT2Areceptors caused by chronic ACTH treatment. These findings suggest that chronic treatment with ACTH acts to increase 5-HT2A– receptor synthesis through increased gene transcription, without modulating presynaptic serotonergic neurotransmission.

Chronic coadministration of carbamazepine together with imipramine produces antidepressant-like effects in an ACTH-induced animal model of treatment–resistant depression: Involvement of 5-HT 2A receptors?

The use of carbamazepine has been reported to be an effective treatment for severe depression. We have already shown that the antidepressant-like effects of tricyclic antidepressants in the rat forced swim test (FST) are blocked by chronic treatment with adrenocorticotropic hormone (ACTH). In the present study, we examined the effect of the chronic administration of carbamazepine on the FST and the wet-dog shakes induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT 2A receptor agonist, in ACTH-treated rats. Chronic administration of carbamazepine did not affect the duration of immobility in saline-treated and ACTH-treated rats. The reduction of immobility, induced by chronic administration of imipramine, was blocked by treatment with ACTH. When carbamazepine was administered concurrently with imipramine, we observed a significant decrease in immobility in rats treated with ACTH. Chronic ACTH treatment increased the number of the wet-dog shakes induced by DOI. This effect of ACTH was significantly increased by the coadministration of carbamazepine and imipramine. These results suggest that the use of carbamazepine together with tricyclic antidepressants had the effect of reducing immobility time in the FST in a tricyclic antidepressant–treatment–resistant depressive model induced by chronic ACTH treatment.

Effects of imipramine on extracellular serotonin and noradrenaline concentrations in ACTH-treated rats

We investigated the effect of imipramine on extracellular serotonin (5-HT) and noradrenaline concentrations in the medial prefrontal cortex of rats treated with adrenocorticotropic hormone (ACTH) for 14 days using in vivo microdialysis. Chronic ACTH treatment did not affect basal extracellular 5-HT and noradrenaline concentrations compared with chronic saline treatment. Acute imipramine treatment plus chronic ACTH treatment significantly increased extracellular 5-HT concentrations, compared with imipramine treatment alone. 8-hydroxy-2-di- n-propylamino tetralin (8-OH-DPAT), a 5-HT 1A receptors full agonist, caused a significant decrease in extracellular 5-HT concentrations. However, its inhibitory effect was attenuated by the treatment with ACTH for 14 days. These findings suggest that chronic treatment with ACTH enhances the increasing effect release of 5-HT by imipramine through the desensitization of somatodendritic 5-HT 1A autoreceptors.

The 5-HT1A Receptor Full Agonist, 8-OH-DPAT Inhibits ACTH-Induced 5-HT2A Receptor Hyperfunction in Rats: Involvement of 5-HT1A Receptors in the DOI-Induced Wet-Dog Shakes in ACTH-Treated Rats

We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats.

Effects of monoamine reuptake inhibitors on wet-dog shakes mediated by 5-HT 2A receptors in ACTH-treated rats

We examined the influence of imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, desipramine, a NA reuptake inhibitor, bupropion, a dopamine reuptake inhibitor, fluvoxamine, a selective 5-HT reuptake inhibitor, and mazindol, a catecholamine reuptake inhibitor, on a 5-HT 2A receptor-mediated behavior, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced wet-dog shakes, in naive and adrenocorticotropic hormone (ACTH)-treated rats. Chronic administration of imipramine, desipramine and mazindol suppressed the number of wet-dog shakes in naive rats. Chronic ACTH (100 μg/rat, s.c.) treatment increased the number. Chronic administration of imipramine did not decrease the number of wet-dog shakes in ACTH-treated rats. On the other hand, desipramine and mazindol inhibited the increase in wet-dog shakes in ACTH-treated rats. Fluvoxamine and bupropion did not have any effect on the (±)-DOI-induced response in naive and ACTH-treated rats. NA reuptake inhibitors may improve the hyperfunction of 5-HT 2A receptors induced by chronic ACTH treatment.

Effects of imipramine and lithium on wet-dog shakes mediated by the 5-HT 2A receptor in ACTH-treated rats

We examined the influence of imipramine and lithium on wet-dog shakes induced by the (±)-DOI, 5-HT 2A receptor agonist in adrenocorticotropic hormone (ACTH)-treated rats. The administration of imipramine for 14 days decreased the (±)-DOI-induced wet-dog shakes response; chronic administration of lithium for 14 days, however, had no effect. Chronic ACTH (100 μg/rat sc) treatment increased the wet-dog shake response induced by (±)-DOI. This effect of ACTH for 14 days, increasing the (±)-DOI-induced wet-dog shakes, was not inhibited by a 14-day administration of imipramine. Chronic coadministration of imipramine and lithium, lasting 14 days, decreased the wet-dog shakes response induced by (±)-DOI in rats treated with ACTH for 14 days. These findings indicate that lithium inhibits the hyperfunction of the 5-HT 2A receptor in rats treated with ACTH when coadministered with imipramine.

Interaction of 5-HT and HPA axis in depression and treatment-resistant depression

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.

ACTH-induced hypertension in rats: fact or artifact?

Evidence from numerous laboratories has shown that administration of adrenocorticotropic hormone (ACTH) to rats produces hypertension within 5 days. However, the analysis of blood pressure in these studies was by the tail-cuff technique, an acute and indirect approach. We have now administered ACTH, via a subcutaneous depot injection (5 or 10 U/day for 9 days), to chronically instrumented rats maintained in metabolic cages. Although tail-cuff measurements of arterial pressure indicated that the ACTH treatment produced hypertension, this was not confirmed by direct 24-h measurements of mean arterial pressure. There was no effect of ACTH on 24-h heart rate throughout the treatment period compared with saline-injected controls. We also examined coefficient of variation of all our measurements. None of the factors was altered by ACTH administration. However, ACTH treatment did produce a diuretic effect, further confirming previous work and providing renal, in addition to cardiovascular, evidence for the bioavailability of the ACTH depot. These results demonstrate that chronic ACTH treatment does not produce a true hypertensive state in rats but rather may enhance the cardiovascular response to the stress of the indirect arterial pressure measurement technique.

Effects of ACTH on seizure susceptibility in the developing Brain

Adrenocorticotropic hormone (ACTH) has been frequently used as an anticonvulsant drug in some childhood seizure disorders. Despite its widespread use, few studies have evaluated the effects of ACTH on seizure susceptibility in the developing animal or the long-term consequences of ACTH treatment on brain development. In this study, ACTH was given either for 2 days or 14 days prior to kindling in 15-, 22-, and 30-day-old rats. Morphological changes in the brain were studied using routine light microscopy and dendrite branch counting following Golgi staining. Both acute and chronic ACTH treatment inhibited the rate of kindling in all three age groups. There were no differences in brain morphology between the controls and the ACTH-treated rats killed shortly after kindling. Rats treated with ACTH and killed as adults, however, had significantly more dendrite branches than did controls. In the immature brain, ACTH treatment reduces seizure susceptibility and has no long-term deleterious effects on neuronal growth.