Use of potentiation of thyrotrophin releasing hormone (TRH)-induced hyperthermia as a test for screening antidepressants which activate alpha-adrenoceptor systems.

1 The minimal dose which significantly potentiates the hyperthermia induced by thyrotrophin releasing hormone (TRH, 40 mg/kg i.p.) in mice has been established for tricyclic and other antidepressants (imipramine, amitriptyline, clomipramine, nortriptyline, maprotiline, nomifensine, viloxazine) including a specific inhibitor of noradrenaline (NA) uptake (nisoxetine). 2 The minimal effective dose in this test has been compared with the minimal dose of the same compounds antagonizing reserpine-induced hypothermia. The ratio of the two doses for each substance indicates that potentiation of TRH-induced hyperthermia is, in general, the more sensitive test. 3 A correlation seems to exist between the alpha-adrenergic effect of antidepressants and the potentiation of TRH- induced hyperthermia. Those antidepressants which do not act on alpha-adrenergic systems (butriptyline, amineptine, trazodone, danitracen, fluoxetine) are inactive in this test. 4 This property may be used to select antidepressants that activate alpha-adrenoceptor systems.     

Potentiation by TRH of the effect of imipramine on the forced-swimming test.

Discovery of the potentiation of thyrotropin releasing hormone (TRH)-induced hyperthermia in mice by antidepressants which activate alpha-adrenergic systems instigated investigation of other relations between TRH and antidepressants. For this study the forced-swimming test using mice was chosen since this test is more sensitive for selection of antidepressants which modify catecholaminergic systems than for those affecting 5-hydroxytryptaminergic systems. The effects of imipramine were potentiated by TRH. The involvement of alpha-adrenergic systems was then investigated in this effect since it is already known that these systems are directly implicated in the potentiation of TRH-induced hyperthermia by some antidepressants. Then the involvement of opiate systems was investigated since endogenous opiates are implicated in the action of some antidepressants, and some interactions between TRH and opiate systems are known to exist. TRH made effective a completely inactive dose of imipramine as small as 2 mg kg-1 (i.p.) or 1 microgram per mouse (i.c.v.). Pretreatment by both alpha 1- and alpha 2-adrenoceptor antagonists (phenoxybenzamine, 8 mg kg-1 i.p.; phentolamine, 4 mg kg-1 i.p.) or by a alpha 1-adrenoceptor antagonist (prazosin, 2 mg kg-1 i.p.) did not prevent this potentiation. In contrast the alpha 2-adrenoceptor antagonist (Yohimbine, 2 mg kg-1 i.p.) blocked the TRH effect. The imipramine potentiation by TRH was blocked by pretreatment with an opiate antagonist (naloxone, 1 mg kg-1 i.p.) and the potentiation was decreased in morphine-tolerant mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

PRESENCE OF CHOLINOCEPTORS IN MESENCEPHALIC RAPHE NUCLEI CONCERNED IN THERMOREGULATION IN RABBITS

1. The thermal effects of cholinomimetics and cholinoceptor blocking agents microinjected into mesencephalic nucleus raphe medianus (NRM) were investigated in rabbits to determine the nature and role of these cholinoceptors in thermoregulation. 2. Microinjection of cholinoceptor agonists, carbachol and pilocarpine, into NRM resulted in significant hyperthermia which could be blocked by local pretreatment with chlorisondamine (a nicotinic receptor blocker) as well as by ethybenztropine (a muscarinic receptor blocker). 3. Intracerebroventricular pretreatment with LM 5008 (serotonin reuptake blocker) significantly inhibited the carbachol-induced hyperthermia. 4. Both nicotinic and muscarinic cholinoceptors are present in mesencephalic NRM which may be involved in thermoregulation in rabbits. Activation of these cholinoceptors in NRM results in hyperthermia which seems to be due to an inhibition of a serotonin sensitive hypothalamic heat loss mechanism.     

Prostacyclin-induced hyperthermia: implication of a protein mediator

Intracerebroventricular administration of prostacyclin (PGI2) at room temperature (21 degrees C) induced dose-related hyperthermia in rabbits and also produced hyperthermia at low (4 degrees C) and high (30 degrees C) ambient temperatures. The PGI2-induced hyperthermia was not mediated by its stable metabolite 6-keto prostaglandin F1 alpha. Of the three anion transport systems (iodide, hippurate and liver-like) present in the choroid plexus, only the liver transport system seems to be important to central inactivation of pyrogen, prostaglandin E2 (PGE2) and the PGI2. Iodipamide (an inhibitor of the liver transport system) augmented the hyperthermia produced by PGI2, PGE2 and pyrogen. Phenoxybenzamine and pimozide had no thermolytic effect on PGI2-induced hyperthermia. After norepinephrine (NE) and dopamine levels were depleted by 6-hydroxydopamine, PGI2 still induced hyperthermia. Indomethacin and SC-19220 (a PG antagonist) did not antagonize PGI2-induced hyperthermia. Furthermore, the hyperthermia due to PGI2 was not accentuated by theophylline. In contrast, the hyperthermic response to PGI2 was attenuated by central administration of the protein synthesis inhibitor, anisomycin. These results indicate that PGI2-induced hyperthermia is not mediated by NE, dopamine, PGS, cyclic AMP, but, rather, that a protein mediator is implicated in the induction of fever by PGI2.     

4-Methylthioamphetamine-induced hyperthermia in mice: influence of serotonergic and catecholaminergic pathways

4-Methylthioamphetamine (4-MTA), also known as p-methylthioamphetamine, is a new amphetamine derivative which in humans has been increasingly associated with severe intoxications and several deaths. As hyperthermia is considered to be one of the most life-threatening acute physiological consequences of amphetamine-related intoxications, it was our aim to determine whether 4-MTA induces changes in body temperature in a mouse model. Accordingly, we measured the subcutaneous temperature after acute administration of 4-MTA in CD1 mice. Because hyperthermia seems to result from the central and peripheral actions of catecholamines and serotonin (5-hydroxytriptamine or 5-HT), we also investigated the possible interactions of some catecholaminergic and serotonergic receptor blockers and the inhibition of monoamine oxidase (MAO) with this effect. 4-MTA induced hyperthermia in CD1 mice. Blockade of the 5-HT receptors with methysergide and MAO inhibition with pargyline resulted in the potentiation of the 4-MTA-induced hyperthermic effect. Blockade of the alpha(1)-adrenergic receptors with prazosin completely reverted the 4-MTA-induced hyperthermia while with the beta-adrenergic receptor blocker dl-propranolol this reversal was not complete. Blockade of the alpha(2)-adrenergic receptors with yohimbine had no effect on the hyperthermia induced by 4-MTA. These results suggest that 4-MTA-induced hyperthermia is highly influenced by the catecholaminergic and serotonergic receptor activation and the MAO activity.     

Antidepressants are weak competitive antagonists of histamine H2 receptors in dissociated brain tissue

Guinea pig hippocampus dissociated by mechanical means into uniform clumps of cells (approximately 100 micron in diameter) contains histamine receptors (H1 and H2) which mediate the formation of cyclic AMP. In this preparation, antidepressants are very potent antagonists of histamine H1 receptors but are weak antagonists of histamine H2 receptors. The latter result is contrary to data derived by others using homogenates of the guinea pig hippocampus and seems to dispel the idea that antidepressants derive their efficacy by blocking histamine H2 receptors in brain.     

Do animal models of anxiety predict anxiolytic-like effects of antidepressants?

Chronically administered antidepressant drugs, particularly selective serotonin (5-HT) reuptake inhibitors (SSRIs), are clinically effective in the treatment of all anxiety disorders, while the clinical effectiveness of "traditional" anxiolytics, such as benzodiazepines (BDZs), is limited to generalised anxiety disorder or acute panic attacks. This implies that animal models of anxiety should be sensitive to SSRIs and other antidepressants in order to have predictive validity. We reviewed the literature on the effects of antidepressants in the so-called animal models of anxiety and found that only the isolation-induced calls in guinea-pig pups may reveal anxiolytic-like action of all antidepressant classes after acute administration. Some other models, such as marble-burying or conditioned-freezing behaviours, and isolation- or shock-induced ultrasonic vocalisation models, may detect anxiolytic-like activity of acutely administered antidepressants, although the sensitivity of these models is usually limited to SSRIs and other drugs affecting 5-HT uptake. The predictive validity of models of "anxiety", such as the plus-maze and light-dark transition tests or stress-induced hyperthermia, appears to be limited to BDZ-related drugs. Far less work has been done on chronic administration of antidepressants in animal anxiety models. Unless and until such studies have been undertaken, the true predictive value of the anxiety models will remain unknown.     

The effects of combined treatment with MK-801 and antidepressant drugs in the forced swimming test in rats.

We found previously that combined administration of imipramine, citalopram and, to a lesser extent, mianserin with MK-801, a non-competitive NMDA receptor antagonist, reduced the immobility time in the forced swimming test in rats more potently than administration of the antidepressant or MK-801 alone. In present paper we examined the effect of other antidepressants in this model. (+)-Oxaprotiline and (-)-oxaprotiline which, when given alone, showed a weak positive effect, increased the action of MK-801. Fluoxetine, inactive when given alone, markedly increased the effect of MK-801. Moreover, the positive effect after combined treatment was found in the experiments in which antidepressants and MK-801 given separately were inactive. A reduction in the immobility time was also observed in those experimental paradigms in which the locomotor activity was not increased. The effects of combined treatment with the antidepressants studied + MK-801 were antagonized by haloperidol, but not by prazosin. The obtained results indicate that mainly a dopamine mechanism seems to be involved in the synergistic action of MK-801 and the antidepressants in the forced swimming test.     

Effect of different treatments of the endotoxin-induced modifications in serum iron levels

The effects of hyperthermia, injection of endotoxin and different antipyretics on serum iron levels in rabbits have been determined. Three antipyretics, Ketoprofen (K), Indomethacin (I), and Polymyxin B (P) induced a rise in serum iron concentration. The rise in serum levels induced by Ketoprofen seems to be related to the half life of the compound. Pretreatment with these antipyretics inhibits the rise in body temperature and the fall in serum concentration observed after the administration of bacterial endotoxin. The hyperthermia failed to modify serum iron levels.     

Antidepressants in the management of chronic pain syndromes

Conditions in which antidepressants have been used include diabetic neuropathy, postherpetic neuralgia, headaches, arthritis, chronic back pain, cancer, thalamic pain, facial pain, and phantom limb pain. Although much of the available information is derived from inadequately controlled trials, it seems that antidepressants provide analgesia in many of these disorders. The analgesic effects tend to be independent of antidepressant effects, and doses of heterocyclic antidepressants used for analgesia seem to be lower than those considered effective in the treatment of depression. Doses should be started low and gradually increased until the patient reaches the highest tolerable dose. Onset of analgesia is variable, ranging from 1 day to 10 weeks. Common side effects include dry mouth, drowsiness, urinary retention, orthostatic hypotension, and constipation. Optimum dosages and schedules have not been established.     

Treatment of bulimia

Bulimia (bulimia nervosa; binge eating) is characterized by episodic eating of large amounts of food, followed by self-induced vomiting or laxative abuse. Psychotherapy has been the mainstay of treatment and often has been unsuccessful. The similarity of bulimia to major depression has led to evaluation of antidepressant drugs for treatment of the disease. Imipramine has proven effective in reducing binging episodes, and further evaluation of antidepressants seems warranted. Phenytoin also has been effective in some cases, suggesting that bulimia may be a neurologic disorder analogous to epilepsy. Optimal treatment may be antidepressants combined with a nutrition/psychotherapy program.     

Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents.

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFalpha and IL-1beta mRNA in the spleen (assessed by semiquantitative in situ hybridization) was not altered following chronic treatment with either fluoxetine or imipramine. The effects of antidepressants on the acute phase response may have important clinical implications for the psychiatric and neuroendocrine disturbances that are commonly associated with various medical conditions.     

Effects of drugs on hyperactivity and aggression induced by raphe lesions in rats.

Midbrain raphe lesions in rats induce hyperactivity and aggressive behavior including muricide. Hyperactivity in raphe lesioned rats (raphe rats) was significantly suppressed by α-methyl-p-tyrosine (α-MT), tetrabenazine and neuroleptics such as chlorpromazine and haloperidol, but was reduced only with large doses of L-5-hydroxytryptophan (L-5-HTP). These results seem to suggest that hyperactivity in raphe rats is resulted from the activation of catecholaminergic system which is secondary to reduced serotonergic function. On the other hand, muricide in raphe rats was markedly inhibited by L-5-HTP, but was not suppressed by α-MT at doses which markedly reduced hyperactivity in raphe rats. The reduction of serotonergic function, therefore, seems to be directly attributable to muricide in raphe rats, indicating that the neural mechanism for inducing muricide is distinct from that for hyperactivity in raphe rats. In addition, muricide in raphe rats was different from that induced by olfactory bulbectomy with respect to the effects of antidepressants, and it would also be useful as a new model for evaluating the effect of antidepressants.     

Effect of tricyclic antidepressants on the uptake of noradrenaline and 5-hydroxytryptamine by rat brain slices incubated in buffer or human plasma

Summary A method is described for measuring the inhibition of transmitter uptake into noradrenaline (NA) and 5-hydroxytryptamine (5-HT) neurons incubated in plasma from patients receiving tricyclic antidepressants. The potency was determined of the tricyclic antidepressants nortriptyline and chlorimipramine in inhibiting NA and 5-HT uptake by rat brain slices incubated in buffer or human plasma. As expected, nortriptyline produced greater inhibition of NA than of 5-HT uptake, and chlorimipramine had more effect on 5-HT uptake. These drugs caused 10 to 100 times more inhibition of monoamine uptake from buffer than from plasma, probably because they were bound to plasma proteins. Plasma from patients taking nortriptyline inhibited NA uptake by brain slices 35—55% of the value found in each subject in a pretreatment sample. During long term therapy the concentration of a drug in plasma should be in equilibrium with its concentration at central receptor sites. Thus, it seems likely that the present results reflect the inhibition of uptake by the central monoaminergic neurons of patients taking tricyclic antidepressants. The method also permits evaluation of inter-individual differences in the effects of various antidepressants on NA and 5-HT nerve terminals. It can also be used to evaluate the relative effects of various antidepressants on these two monoaminergic systems.     

Psychomotor stimulants versus antidepressants in the learned helplessness model of depression

Animal models of depression which use stress to induce abnormal behavior generally cannot discriminate antidepressants from drugs which are central stimulants and predominantly stimulate dopamine (DA) neurons. Thus these models lack pharmacological specificity. The present study shows that the Learned Helplessness (LH) model, applied to Wistar rats, becomes a more valid pharmacological model if registration of the animals' behavior during the interval between each trial of the LH shuttlebox test is added. The DA drugs amphetamine, methylphenidate, nomifensine, apomorphine, quinpirole (specific D2 agonist), SKF 81297 (specific D1 agonist), and the antidepressants imipramine, amitriptyline, and isocarboxazide were tested. The results show that the DA drugs had an acute effect and increased the number of shuttle box crossings in the intervals between the test trials. The antidepressants had no acute effect and did not increase the number of intertrial crossings in the therapeutic dose range. The LH model thus seems to be advantageous when discrimination between drugs with DA psychomotor stimulating properties and drugs with antidepressant properties is needed. © 1993 Wiley-Liss, Inc.     

The effect of repeated treatment with antidepressant drugs on the thyrotropin-releasing hormone (TRH)-induced hyperthermia in mice

The effect of acute (single dose) or repeated (twice daily, for 14 days) administration of 10 mg kg-1 p.o. of imipramine, amitriptyline, citalopram or mianserin has been examined on the hyperthermia induced by thyrotropin-releasing hormone (TRH) (40 mg kg-1 i.p., 2, or 2 and 72 h after single or last dose of antidepressants, respectively) in mice. Both imipramine and amitriptyline, given repeatedly, potentiated the TRH response, though the effect was observed 2 but not 72 h after the last dose of those drugs. Potentiation was also found after the single dose of imipramine or amitriptyline. On the other hand, citalopram and mianserin, administered either acutely or repeatedly, did not affect the TRH-induced hyperthermia.     

Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig

Intracerebroventricular administration of prototype non-peptide opioid receptor (mu, kappa, sigma) agonists, morphine, ketocyclazocine and N-allyl normetazocine (SKF 10,047) and an agonist at both kappa and sigma receptors, pentazocine, induced hyperthermia in guinea-pigs. Similar administration of peptide opioids like beta-endorphin (BE), methionine enkephalin (Met-E), leucine enkephalin (Leu-E) and their synthetic analogues D-ala2-methionine-enkephalinamide (D-ala2-Met-E) and D-ala2-leucine-enkephalinamide (D-ala2-Leu-E) also caused hyperthermia. Of the three anion transport systems (iodide, hippurate and liver-like) present in the choroid plexus, only the liver-like transport system seems to be important to central inactivation of beta-endorphin, D-ala2-Met-enkephalin and D-ala2-Leu-enkephalin since iodipamide (an inhibitor of the liver-like transport system) augmented the hyperthermia. Prostaglandins (PG) and norepinephrine (NE) were not involved in peptide- and non-peptide opioid-induced hyperthermia because a prostaglandin synthesis inhibitor, indomethacin, and an alpha-adrenergic receptor blocker, phenoxybenzamine, had no thermolytic effect. Likewise cAMP was not required since a phosphodiesterase inhibitor, theophylline, did not accentuate the hyperthermia due to administration of peptide and non-peptide opioids. Naloxone-sensitive receptors were involved in the induction of hyperthermia by morphine and beta-endorphin since naloxone attenuated the effect. In contrast, the hyperthermic responses to ketocyclazocine, SKF 10,047, pentazocine, Met-enkephalin, Leu-enkephalin, D-ala2-Met-enkephalin and D-ala2-Leu-enkephalin were not antagonized by naloxone. Lack of antagonism of naloxone on pyrogen, arachidonic acid, PGE2, dibutyryl cAMP and NE-induced hyperthermia indicates that endogenous opioid peptides are not likely to be central mediators of the hyperthermia induced by these agents.     

Studies of various amphetamines,apomorphine and clonidine on body temperature and brain 5-hydroxytryptamine metabolism in rats

Amphetamine and various amphetamine derivatives, phenmetrazine, pipradrol, methylphenidate and NCA can increase the concentration of 5-HIAA in the rat brain without changing that of 5-HT. Metamphetamine produced a decrease in 5-HT and no effect on 5-HIAA whereas p-hydroxyamphetamine produced no effects on 5-HT and 5-HIAA. The experiments performed at different environmental temperatures (12–14C, 21–22C and 21–28C) with simultaneous measurements of the body temperature indicate that no simple correlation exists between the drug induced hyperthermia and the effect on 5-HIAA. The amphetamine and phenmetrazine effect on 5-HIAA seems to be related to hyperthermia whereas the pipradrol and methylphenidate effect on 5-HIAA appears independent of hyperthermia. Apomorphine (2×2.5 mg/kg) which activates central dopamine receptors produced a significant increase in 5-HIAA whereas clonidine (0.5 mg/kg) which activates central noradrenaline receptors produced a significant decrease in 5-HIAA.In conclusion, the effect of various amphetamines on 5-HT metabolism seems very complex in mechanism of action and might be related to hyperthermia, to a direct effect on 5-HT neurons and to the ratio between central dopamine/noradrenaline receptor activation of these drugs.     

Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: a case-control study using spontaneous reports

The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 1985-99 (n = 24,263). The study population comprised all patients using an antidepressant drug at the time the ADR occurred. We calculated ADR-reporting odds ratios (ADR-OR) to estimate the association between SSRI-use and EPS, relative to other antidepressants. We identified 61 patients with EPS. SSRI-use was associated with spontaneous reporting of EPS compared to other antidepressants (adjusted ADR-OR 2.2; 95% confidence interval 1.2-3.9). This risk estimate appeared to be higher in patients concurrently using antipsychotic medication (6.9, 0.7-68.0), although the confidence interval was very wide. In conclusion, SSRI-use seems only to be moderately associated with EPS compared to other antidepressants. However, those concurrently using antipsychotic drugs or presenting with other risk factors may be more susceptible and should be closely monitored.     

The cardioprotection of calcitonin gene-related peptide-mediated preconditioning

Preconditioning induced by brief ischemia or hyperthermia or some drugs shows two phases, early and delayed protection. The cardioprotection afforded by preconditioning is related to stimulation of endogenous mediators release. Calcitonin gene-related peptide (CGRP), a major transmitter of capsaicin-sensitive sensory nerves, has recently been shown to play an important role in mediation of the preconditioning induced by brief ischemia or hyperthermia or by some drugs, and alpha-CGRP seems to play a major role in the mediation of delayed preconditioning. It has been shown that the cardioprotection afforded by CGRP-mediated preconditioning is due to inhibition of cardiac tumor necrosis factor-alpha (TNF-alpha) production, but not to the activation of the K(ATP) channel.