Acute Antidepressant Administration Research Articles

Acute Inhibitory Effects of Antidepressants on Lacrimal Gland Secretion in the Anesthetized Rat.

PurposePatients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However, regulation of tear production includes a substantial reflex-evoked component and is regulated via distinct centers in the brain. Further, the anticholinergic component varies greatly among antidepressants with different mechanisms of action. In the current study it was wondered if acute administration of antidepressants can disturb production of tears by affecting the afferent and/or central pathway.MethodsTear production was examined in vivo in anesthetized rats in the presence or absence of the tricyclic antidepressant (TCA) clomipramine or the selective serotonin reuptake inhibitor (SSRI) escitalopram. The reflex-evoked production of tears was measured by challenging the surface of the eye with menthol (0.1 mM) and cholinergic regulation was examined by intravenous injection with the nonselective muscarinic agonist methacholine (1–5 µg/kg).ResultsAcute administration of clomipramine significantly attenuated both reflex-evoked and methacholine-induced tear production. However, escitalopram only attenuated reflex-evoked tear production, while methacholine-induced production of tears remained unaffected.ConclusionsThis study shows that antidepressants with different mechanisms of action can impair tear production by attenuating reflex-evoked signaling. Further, antimuscarinic actions are verified as a likely cause of lacrimal gland hyposecretion in regard to clomipramine but not escitalopram. Future studies on antidepressants with different selectivity profiles and mechanisms of action are required to further elucidate the mechanisms by which antidepressants affect tear production.

Effects of acute administration of antidepressants with simultaneous blockade of cannabinoid CB2 receptors on the endocannabinoid levels in rat brain structures

Effects of acute administration of antidepressants with simultaneous blockade of cannabinoid CB2 receptors on the endocannabinoid levels in rat brain structures

Facilitation of emotion regulation with a single dose of escitalopram: A randomized fMRI study

Acute antidepressant administration modulates neural activity consistent with decreases in negative emotion processing bias. However, studies are yet to examine whether treatment facilitates neural activity during reappraisal, an adaptive emotion regulation strategy associated with behavioral treatment response. Here we examine the impact of acute administration on reappraisal of negative stimuli using pharmaco-fMRI. Thirty-six healthy female participants completed two sessions of fMRI scanning, separated by a one-week washout period. A single dose of the selective serotonin reuptake inhibitor, escitalopram (20mg) was administered to participants using a double-blind, randomized, placebo-controlled crossover design. When participants were administered escitalopram (relative to a placebo) and asked to reappraise negative emotional stimuli, left amygdala activation was decreased and right inferior frontal gyrus (R IFG) activation was increased. Also observed was a greater negative left amygdala-R IFG functional connectivity when participants were administered escitalopram relative to placebo, and this change in connectivity was associated with reductions in subjective ratings of valence and arousal of negative stimuli. Further analysis revealed connectivity modulation across multiple frontal regions. Results suggest that the acute effect of a commonly prescribed antidepressant may include facilitating the regulation of negative emotional stimuli, providing new important leads for models of antidepressant action.

REM Sleep Deprivation Reverses Neurochemical and Other Depressive-Like Alterations Induced by Olfactory Bulbectomy

There is compelling evidence that sleep deprivation (SD) is an effective strategy in promoting antidepressant effects in humans, whereas few studies were performed in relevant animal models of depression. Acute administration of antidepressants in humans and rats generates a quite similar effect, i.e., suppression of rapid eye movement (REM) sleep. Then, we decided to investigate the neurochemical alterations generated by a protocol of rapid eye movement sleep deprivation (REMSD) in the notably known animal model of depression induced by the bilateral olfactory bulbectomy (OBX). REMSD triggered antidepressant mechanisms such as the increment of brain-derived neurotrophic factor (BDNF) levels, within the substantia nigra pars compacta (SNpc), which were strongly correlated to the swimming time (r = 0.83; P < 0.0001) and hippocampal serotonin (5-HT) content (r = 0.66; P = 0.004). Moreover, there was a strong correlation between swimming time and hippocampal 5-HT levels (r = 0.70; P = 0.003), strengthen the notion of an antidepressant effect associated to REMSD in the OBX rats. In addition, REMSD robustly attenuated the hippocampal 5-HT deficiency produced by the OBX procedure. Regarding the rebound (REB) period, we observed the occurrence of a sustained antidepressant effect, indicated mainly by the swimming and climbing times which could be explained by the maintenance of the increased nigral BDNF expression. Hence, hippocampal 5-HT levels remained enhanced in the OBX group after this period. We suggested that the neurochemical complexity inflicted by the OBX model, counteracted by REMSD, is directly correlated to the nigral BDNF expression and hippocampal 5-HT levels. The present findings provide new information regarding the antidepressant mechanisms triggered by REMSD.

The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin

This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder. In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST. Subjective, physiological and hormonal measures were taken before, during and after the test. The dose of 100 mg of sumatriptan increased speech-induced fear more than either a 50mg dose of the drug or placebo. The largest dose of sumatriptan also enhanced vigilance more than placebo, without any change in blood pressure, heart rate or electrical skin conductance. Sumatriptan decreased plasma levels of prolactin. A significant but moderate increase in plasma cortisol after SPST occurred, independent of treatment. Because sumatriptan decreases 5-HT release into the extracellular space, the potentiation of SPST-induced fear caused by the drug supports the hypothesis that 5-HT attenuates this emotional state. As acute administration of antidepressants has also been shown to enhance speaking fear and increase plasma prolactin, in contrast to sumatriptan, the 5-HT regulation of stress-hormone release is likely to be different from that of emotion.

Accumulation of an Antidepressant in Vesiculogenic Membranes of Yeast Cells Triggers Autophagy

Many antidepressants are cationic amphipaths, which spontaneously accumulate in natural or reconstituted membranes in the absence of their specific protein targets. However, the clinical relevance of cellular membrane accumulation by antidepressants in the human brain is unknown and hotly debated. Here we take a novel, evolutionarily informed approach to studying the effects of the selective-serotonin reuptake inhibitor sertraline/Zoloft® on cell physiology in the model eukaryote Saccharomyces cerevisiae (budding yeast), which lacks a serotonin transporter entirely. We biochemically and pharmacologically characterized cellular uptake and subcellular distribution of radiolabeled sertraline, and in parallel performed a quantitative ultrastructural analysis of organellar membrane homeostasis in untreated vs. sertraline-treated cells. These experiments have revealed that sertraline enters yeast cells and then reshapes vesiculogenic membranes by a complex process. Internalization of the neutral species proceeds by simple diffusion, is accelerated by proton motive forces generated by the vacuolar H+-ATPase, but is counteracted by energy-dependent xenobiotic efflux pumps. At equilibrium, a small fraction (10–15%) of reprotonated sertraline is soluble while the bulk (90–85%) partitions into organellar membranes by adsorption to interfacial anionic sites or by intercalation into the hydrophobic phase of the bilayer. Asymmetric accumulation of sertraline in vesiculogenic membranes leads to local membrane curvature stresses that trigger an adaptive autophagic response. In mutants with altered clathrin function, this adaptive response is associated with increased lipid droplet formation. Our data not only support the notion of a serotonin transporter-independent component of antidepressant function, but also enable a conceptual framework for characterizing the physiological states associated with chronic but not acute antidepressant administration in a model eukaryote.

P.1.d.009 Longterm memory formation in non-association learning task in sham-operated and dentate gyrus lesioned rats

Previous studies have indicated that antidepressant drugs displaying different pharmacological profiles, administered repeatedly, increase the locomotor hyperactivity induced by various dopaminomimetics, among others by quinpirole. As this drug, according to a recent study, shows high affinity not only for dopamine D2 but also for dopamine D3 receptors, the question arises if dopamine D3 receptors are involved in the increase in quinpirole-elicited locomotor hyperactivity induced by repeated treatment with antidepressant drugs. In the present study we administered imipramine, amitriptyline, citalopram and mianserin (in a dose of 10 mg/kg p.o., twice a day, 14 days) to male Wistar rats and then (±)-7-OH-DPAT (7-hydroxy-dipropylaminotetralin), a dopamine D3 receptor agonist, was given (3 mg/kg s.c.). Hyperlocomotion induced by (±)-7-OH-DPAT was significantly increased by repeated administration of antidepressant drugs. The receptor autoradiography technique with [3H]7-OH-DPAT as a radioligand was applied to measure the effects of antidepressant drugs treatment on the dopamine D3 receptors in the islands of Calleja and in the shell of the nucleus accumbens septi, which are brain regions with highly selective expression of dopamine D3 receptors. The biochemical studies indicated that in both examined brain regions there was an increase in the binding of [3H]7-OH-DPAT following the repeated administration of antidepressant drugs. In some cases this increase was also observed after the acute administration of antidepressants. The results obtained in the present study indicate that antidepressant drugs administered repeatedly enhance the responsiveness of dopamine D3 receptors, probably via an increase in the density of these receptors. This mechanism is probably similar to that observed already in the case of dopamine D2 receptors. Therefore it is hypothesized that dopamine D3 receptors are also involved in the increased responsiveness to dopamine D3 receptor agonists observed after antidepressants.

Long-lasting cognitive deficit induced by stress is alleviated by acute administration of antidepressants

Deficits in executive control associated with frontal lobe dysfunction have been reported in affective disorder, which is often precipitated by stressful life events. Here we examined the impact of repeated restraint stress (1h daily for 7 days) on rats' performance in the attentional set-shifting task (ASST). To evaluate the persistence of cognitive deficits, the performance of separate groups of rats was assessed on the 4th, 7th, 14th and 21st day following stress cessation. Stressed rats exhibited unusually long-lasting extra-dimensional (ED) set-shifting impairments, since these deficits were demonstrated even 3 weeks following stress termination. An inhibitor of corticosterone synthesis, the drug metyrapone (50mg/kg, IP) protected rats from the cognitive impairment suggesting an involvement of endogenous adrenal steroids in the debilitating effects of stress. Acute intraperitoneal administration of four different antidepressants (desipramine, nomifensine, fluoxetine and escitalopram) at the minimum effective doses of 3, 0.3, 1 and 1mg/kg, respectively, reversed the deficits of ED set-shifting in stressed animals. Desipramine, nomifensine, fluoxetine and escitalopram at the minimum effective doses of 6, 1, 1 and 1mg/kg, IP, respectively, promoted also cognitive flexibility in unstressed groups. We conclude that stress-induced long-term set-shifting impairment may represent a useful model mimicking clinically relevant aspects of depression, i.e., the persistence of executive dysfunction. The potential utility of antidepressants in treating frontal-like cognitive impairments is suggested.

Locus coeruleus and dorsal raphe neuron activity and response to acute antidepressant administration in a rat model of Parkinson's disease

In addition to noradrenergic and serotonergic systems, dopaminergic neurotransmission seems to play an important role in the aetiopathogenesis of, and recovery from, depression. Moreover, the incidence of depression is higher in patients affected by diseases where the dopaminergic system is highly impaired, such us Parkinson's disease. Here, we investigated the effects of dopamine degeneration on the activity and response to antidepressants of locus coeruleus (LC) noradrenergic and dorsal raphe nucleus (DRN) serotonergic neurons. To this end, single-unit extracellular recordings were performed in control and 6-hydroxydopamine (6-OHDA)-lesioned animals. In this latter group, LC neurons showed a lower basal firing rate as well as less sensitivity to the administration of the serotonin reuptake inhibitor, fluoxetine. The rest of electrophysiological parameters and the response to the administration of the α2-adrenoceptor agonist, clonidine and the noradrenaline reuptake inhibitor, reboxetine remained unaltered. In the DRN, dopamine depletion did not modify the basal electrophysiological characteristics and the response to clonidine or fluoxetine administration. In contrast, the administration of reboxetine more efficiently induced an inhibitory effect in the lesioned group. In additional analyses it was observed that while in control animals, LC and DRN basal firing rate was significantly correlated, this relationship was lost after the 6-OHDA lesion. In conclusion, dopaminergic degeneration alters LC neuron basal activity, the relationship/synteny between both nuclei, and their response to antidepressants. These findings shed fresh light on our understanding of the role of dopamine in depression and the mechanism action of antidepressants.

Effect of Acute Antidepressant Administration on Negative Affective Bias in Depressed Patients

Acute administration of an antidepressant increases positive affective processing in healthy volunteers, an effect that may be relevant to the therapeutic actions of these medications. The authors investigated whether this effect is apparent in depressed patients early in treatment, prior to changes in mood and symptoms. In a double-blind, placebo-controlled, between-groups randomized design, the authors examined the effect of a single 4-mg dose of the norepinephrine reuptake inhibitor reboxetine on emotional processing. Thirty-three depressed patients were recruited through primary care clinics and the community and matched to 31 healthy comparison subjects. Three hours after dosing, participants were given a battery of emotional processing tasks comprising facial expression recognition, emotional categorization, and memory. Ratings of mood, anxiety, and side effects were also obtained before and after treatment. Depressed patients who received placebo showed reduced recognition of positive facial expressions, decreased speed in responding to positive self-relevant personality adjectives, and reduced memory for this positive information compared to healthy volunteers receiving placebo. However, this effect was reversed in patients who received a single dose of reboxetine, despite the absence of changes in subjective ratings of mood or anxiety. Antidepressant drug administration modulates emotional processing in depressed patients very early in treatment, before changes occur in mood and symptoms. This effect may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. It also suggests a mechanism of action compatible with cognitive theories of depression.

Altered serotonin receptor expression is associated with depression-related behavior in the R6/1 transgenic mouse model of Huntington's disease

Dysregulation of the serotonergic signaling system has been implicated in the pathology of mood disorders including depression, and various rodent models of disrupted serotonergic signaling display depression-related behavioral phenotypes. Depression is a common neuropsychiatric feature of preclinical Huntington's disease (HD) but the underlying changes in the HD brain contributing to the development of depression are unknown. Using the R6/1 transgenic mouse model of HD, we show that pre-motor symptomatic HD mice display sex-specific depressive-related behaviors on the forced-swim (FST), tail-suspension (TST) and novelty-suppressed feeding (NSFT) tests while having muted responses to acute anti-depressant administration. The baseline behaviors of HD mice were similar to the behavioral phenotypes of serotonin (5-HT) receptor and transporter null mutants, and gene expression of specific serotonin receptors were subsequently found to be reduced in the hippocampus and cortex of HD mice. Female HD mice had an additional deficit in cortical expression of serotonin transporter (SerT). Environmental enrichment normalized the FST behavioral response of female HD mice corresponding with increased gene expression of specific 5-HT receptors in the hippocampus and cortex. Our findings implicate altered serotonergic signaling as the basis for the development of depression during the preclinical stages of HD.

Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment

Therapeutic efficacy of antidepressant drugs appears to be related to their ability in producing neuroadaptive changes that restore normal brain function. Activity-regulated cytoskeletal associated protein (Arc) is an effector immediate early gene that plays a fundamental role in activity-dependent neural plasticity in corticolimbic brain regions and has been implicated in the modulation of several functions known to be profoundly perturbed in depressive states. In the present study, we investigated transcriptional and translational changes of Arc in response to acute or chronic treatment with the novel antidepressant duloxetine. Although a limited increase of Arc messenger RNA (mRNA) levels was found in some structures after acute antidepressant administration, a marked up-regulation of its gene expression was found after chronic treatment, primarily at the level of frontal cortex. The changes observed after prolonged duloxetine administration strongly correlates with those previously reported on brain-derived neurotrophic factor mRNA levels Calabrese et al. (Neuropsychopharmacol 32:2351-2359, 2007). In addition, we found an anatomical-specific influence of chronic duloxetine on stress-dependent Arc modulation, which was limited to the frontal cortex. We suggest that these neuroadaptive changes, among others, might contribute to the normalization of neuroplastic defects associated with mood disorders.

Abnormal temporal difference reward-learning signals in major depression

Anhedonia is a core symptom of major depressive disorder (MDD), long thought to be associated with reduced dopaminergic function. However, most antidepressants do not act directly on the dopamine system and all antidepressants have a delayed full therapeutic effect. Recently, it has been proposed that antidepressants fail to alter dopamine function in antidepressant unresponsive MDD. There is compelling evidence that dopamine neurons code a specific phasic (short duration) reward-learning signal, described by temporal difference (TD) theory. There is no current evidence for other neurons coding a TD reward-learning signal, although such evidence may be found in time. The neuronal substrates of the TD signal were not explored in this study. Phasic signals are believed to have quite different properties to tonic (long duration) signals. No studies have investigated phasic reward-learning signals in MDD. Therefore, adults with MDD receiving long-term antidepressant medication, and comparison controls both unmedicated and acutely medicated with the antidepressant citalopram, were scanned using fMRI during a reward-learning task. Three hypotheses were tested: first, patients with MDD have blunted TD reward-learning signals; second, controls given an antidepressant acutely have blunted TD reward-learning signals; third, the extent of alteration in TD signals in major depression correlates with illness severity ratings. The results supported the hypotheses. Patients with MDD had significantly reduced reward-learning signals in many non-brainstem regions: ventral striatum (VS), rostral and dorsal anterior cingulate, retrosplenial cortex (RC), midbrain and hippocampus. However, the TD signal was increased in the brainstem of patients. As predicted, acute antidepressant administration to controls was associated with a blunted TD signal, and the brainstem TD signal was not increased by acute citalopram administration. In a number of regions, the magnitude of the abnormal signals in MDD correlated with illness severity ratings. The findings highlight the importance of phasic reward-learning signals, and are consistent with the hypothesis that antidepressants fail to normalize reward-learning function in antidepressant-unresponsive MDD. Whilst there is evidence that some antidepressants acutely suppress dopamine function, the long-term action of virtually all antidepressants is enhanced dopamine agonist responsiveness. This distinction might help to elucidate the delayed action of antidepressants. Finally, analogous to recent work in schizophrenia, the finding of abnormal phasic reward-learning signals in MDD implies that an integrated understanding of symptoms and treatment mechanisms is possible, spanning physiology, phenomenology and pharmacology.

Effects of acute fluoxetine, paroxetine and desipramine on rats tested on the elevated plus-maze

Antidepressants are usually prescribed for the treatment of depression but more recently have also been recommended for the treatment of anxiety disorders. The purpose of this study was to investigate the anxiogenic- or anxiolytic-like effects of an acute administration of antidepressants (serotonergic and noradrenergic compounds) in male Wistar rats submitted to the elevated plus-maze. Fluoxetine (2.5, 5, 10, 15 mg/kg), paroxetine (0.1, 0.5, 3, 12 mg/kg) and desipramine (2.5, 5, 10 mg/kg) or their vehicles were administered intraperitoneally 30 min prior to testing. Diazepam (0.5, 1.5, 2.5 mg/kg) was used as a positive comparator for anxiolytic effect. In comparison with control animals, the percentage of time the rats treated with fluoxetine (5 and 10 mg/kg) and paroxetine (3 and 12 mg/kg) spent in the open arms decreased. The percent of inactive time spent in the open arms also decreased in rats given fluoxetine (5 and 10 mg/kg) and paroxetine (12 mg/kg). Desipramine was inactive on all these parameters. In conclusion, acute treatment with fluoxetine and paroxetine, but not with desipramine, produced a pattern of anxiety behavior. Thus, the pharmacological mechanism appears to be due more to serotonergic than adrenergic neurotransmission. The elevated plus-maze exhibits good sensitivity for detecting anxiogenic effects of antidepressant drugs and the conventional parameters are sufficient and reliable for detecting such effects.

Comparison of Alterations in c-fos and Egr-1 (zif268) Expression Throughout the Rat Brain Following Acute Administration of Different Classes of Antidepressant Compounds

The majority of immediate-early gene (IEG) studies focus on a few key brain regions associated with the class of psychoactive compound being studied. Recently, using a meta-analysis of the c-fos literature, we demonstrated the utility of c-fos profiling to classify such compounds. The present study examined acute delivery of a range of antidepressant classes; fluoxetine, imipramine, LiCl, and mirtazapine. The dual aims were to study the IEG profiles of these varying classes of antidepressants throughout the rat brain and to compare the utility of c-fos or Egr-1 as IEGs to classify clinically efficacious antidepressants. All antidepressants increased c-fos mRNA in the central amygdala, as previously shown, while c-fos was also increased in the anterior insular cortex and significantly decreased within the septum. Although acute antidepressant administration altered c-fos expression in a number of brain regions, Egr-1 expression was only significantly altered in the central amygdala, suggesting that Egr-1 may not be as useful a marker to investigate acute antidepressant treatment. The fact that these drugs, including the previously unclassified antidepressant mirtazapine, share a number of common loci of activation, which are implicated by human and animal studies in depression, adds further support to the use of IEG mapping to classify psychoactive compounds.

Are there gender differences in the temperature profile of mice after acute antidepressant administration and exposure to two animal models of depression?

Numerous studies have reported gender differences in the rates of depression in humans, but few behavioural observations of antidepressant drug effects have been investigated in female mice. The forced swimming test (FST) is widely used as a predictor of antidepressant activity in rodents, as is the tail suspension test (TST), where immobility is objectively measured and in this last test, no hypothermia is induced by immersion in cold water. The present study investigated gender differences in the temperature profile of mice after acute antidepressant administration (imipramine and paroxetine) and exposure to two animal models of depression. Imipramine and paroxetine were active at 32 mg/kg in male mice in the FST, whereas they were active at 8, 16 and 32 mg/kg in female mice. In the TST, for both antidepressants immobility duration was reduced at a dose of 16 and 32 mg/kg in male mice and at 32 mg/kg in female mice. No significant difference was observed between male and female mice for immobility duration. Imipramine administration, but not paroxetine, decreased the temperature at the higher dose (32 mg/kg) in male and female mice in the FST. The body temperature was reduced in male and female mice for all treatment groups after FST challenge. Imipramine (16 and 32 mg/kg in male and 32 mg/kg in female mice), paroxetine (4, 16 and 32 mg/kg in male and 4 to 32 mg/kg in female mice) attenuated the reduction in temperature due to the FST. In the TST, imipramine tends to decrease the temperature in male and female mice, even though only imipramine at a dose of 32 mg/kg in female mice significantly decreases the temperature. Paroxetine had no effect on temperature. The TST enhanced the body temperature in male and female mice. In mice, there was no difference between the sexes after imipramine or paroxetine administration in the FST and TST. Both tests can be used to predict the activity of antidepressants as the decrease or enhancement of temperature is not correlated with a reduction in immobility duration.

Effect of antidepressant drugs administered repeatedly on the dopamine D 3 receptors in the rat brain

Previous studies have indicated that antidepressant drugs displaying different pharmacological profiles, administered repeatedly, increase the locomotor hyperactivity induced by various dopaminomimetics, among others by quinpirole. As this drug, according to a recent study, shows high affinity not only for dopamine D 2 but also for dopamine D 3 receptors, the question arises if dopamine D 3 receptors are involved in the increase in quinpirole-elicited locomotor hyperactivity induced by repeated treatment with antidepressant drugs. In the present study we administered imipramine, amitriptyline, citalopram and mianserin (in a dose of 10 mg/kg p.o., twice a day, 14 days) to male Wistar rats and then (±)-7-OH-DPAT (7-hydroxy-dipropylaminotetralin), a dopamine D 3 receptor agonist, was given (3 mg/kg s.c.). Hyperlocomotion induced by (±)-7-OH-DPAT was significantly increased by repeated administration of antidepressant drugs. The receptor autoradiography technique with [ 3 H ]7-OH-DPAT as a radioligand was applied to measure the effects of antidepressant drugs treatment on the dopamine D 3 receptors in the islands of Calleja and in the shell of the nucleus accumbens septi, which are brain regions with highly selective expression of dopamine D 3 receptors. The biochemical studies indicated that in both examined brain regions there was an increase in the binding of [ 3 H ]7-OH-DPAT following the repeated administration of antidepressant drugs. In some cases this increase was also observed after the acute administration of antidepressants. The results obtained in the present study indicate that antidepressant drugs administered repeatedly enhance the responsiveness of dopamine D 3 receptors, probably via an increase in the density of these receptors. This mechanism is probably similar to that observed already in the case of dopamine D 2 receptors. Therefore it is hypothesized that dopamine D 3 receptors are also involved in the increased responsiveness to dopamine D 3 receptor agonists observed after antidepressants.

Adenosinergic nature of antidepressant-induced antinociception in mice

The antinociceptive activity of the antidepressant agents imipramine, maprotiline and amitriptyline and their interactions with morphine and aminophylline were evaluated using the acetic acid writhing test of mouse. All the antidepressants induced a dose-dependent antinociceptive activity with a rank of potency was amitriptyline > maprotiline > imipramine. Antinociception was blocked by the pretreatment with 10 mg/kg of aminophylline, suggesting an interaction of these agents with adenosine receptors, which may cause the release of adenosine at neuronal level and depression of neuronal activity by inhibition of neurotransmitter release. Isobolographic analysis demostrated that the simultaneous administration of imipramine or maprotiline plus morphine (10:1 and 4.5:1 respectively) produced a supra-additive interaction, but the combination of amitriptyline and morphine (1:1) resulted in simple additivity. These effects were not antagonized by 1 or 10 mg/kg of aminophylline. The interaction between morphine and antidepressants seems to be due to an upregulated neuronal activity (i.e. indirect antagonism of the effect of the tricyclic agents) which could be dependent on the pharmacological profile of antidepressants with respect to their inhibition of bioamines uptake. Since antinociception was induced by acute administration of antidepressants, this action seems to be independent of antidepressive properties, which are obtained only after chronical administration. © 1997 John Wiley & Sons, Ltd.

ANTIDEPRESSANT DRUGS AND EXPERIMENTAL INFLAMMATION

There are strong indications from this brief survey that the anti-inflammatory action of antidepressant drugs is involved in their well documented analgesic effect. In particular, the experimental data reported here contribute to explain the reduction of pain observed after the acute administration of antidepressants in clinical conditions. A better understanding of the mechanisms underlined should lead to improved therapies for pain, and to new compounds for the treatment of inflammation.

Differential responsiveness of inbred strains of rats to antidepressants in the forced swimming test: are Wistar Kyoto rats an animal model of subsensitivity to antidepressants?

In three experiments we have studied the effects of acute administration of various doses (5, 10, 15 and 25 mg/kg) of desipramine (DMI) and two doses (0.5 and 2 mg/kg) of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5HT1A receptor agonist, on behaviour of five inbred strains of rats in the holeboard and the forced swimming test (FST). The strains were Brown-Norway (BN), Fischer 344 (FIS), Lewis (LEW), Spontaneously Hypertensive Rats (SHR) and Wistar-Kyoto (WKY). In drug-free conditions, the strains showed striking differences in their activity in the holeboard and in the FST, the WKY rats being the most passive in both tests. The dose of 15 mg/kg DMI caused a profound inhibitory effect on locomotor/exploration activity in all strains. In the FST, this dose of DMI increased struggling and reduced immobility in BN, FIS and LEW rats, but did not exert any effect in SHR and WKY rats. The lack of marked strain-dependent differences in the sensitivity to the inhibitory effects of DMI on locomotor activity or exploration rule out a major role of changes in the metabolism of drug among strains as an explanation for differential response to DMI in the FST. In further experiments three strains were used: BN (responsive), WKY (non-responsive) and the outbred Sprague Dawley (SD) rats. In the FST, both DMI and 8-OH-DPAT, at all doses, decreased immobility and increased struggling in BN and SD rats. However, WKY rats responded only to a very high dose of DMI (25 mg/kg). Hence, WKY rats are not only passive in the FST, but are also subsensitive to acute antidepressant administration. The present data indicate that the levels of activity of animals in the FST in drug-free conditions are not predictive of their response to antidepressants, and that inbred strains might be useful for studying the biological basis of subsensitivity to antidepressants and depressive-like behaviour.