The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds.

Gray AM, Spencer PS, Sewell RD.

Division of Pharmacology, The Welsh School of Pharmacy, UWC, Cardiff, Wales.

1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

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Schild regression analysis of antidepressant and bicuculline antagonist effects at the GABAA receptor.

Malatynska E, Crites G, Yochum A, Kopp R, Giroux ML, Dilsaver SC.

Department of Pharmacology and Toxicology, Indiana University, School of Medicine, Evansville, Ind., USA.

We showed previously that antidepressants inhibit GABA-stimulated 36Cl- uptake in rat cerebral cortex. In this study Schild analysis was used to determine if antidepressants are competitive antagonists or allosteric modulators at GABAA receptors. GABA concentration-response curves for 36Cl- uptake in rat cerebral cortex were generated in the absence or presence of different concentrations of the following antidepressants: amitriptyline, amoxapine, mianserin, and also the GABAA receptor antagonist, bicuculline. The pA2 values for amitriptyline, amoxapine, mianserin, and bicuculline were 4.2 +/- 0.2, 5.5 +/- 0.3, 4.4 +/- 0.1 and 6.2 +/- 0.6, respectively. The respective Schild slope values were 0.7 +/- 0.1, 0.6 +/- 0.03, 0.7 +/- 0.2 and 1.0 +/- 0.3. All slope values for antidepressants differed from unity. The maximum effect produced by GABA to stimulate chloride influx was decreased by both antidepressants and bicuculline. It is concluded that neither the antidepressants studied nor bicuculline are pure competitive GABA antagonists at the GABAA receptor-chloride-ionophore complex in the rat cerebral cortex.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9691231&dopt=Abstract antidepressant




[Prospective evaluation of antidepressant discontinuation]

[Article in French]

Mourad I, Lejoyeux M, Ades J.

Hopital Louis Mourier, Colombes.

The authors prospectively assessed symptoms induced by the interruption of antidepressants in 16 patients (11 women and 5 men), aged from 33 to 85 years (mean = 52.4 +/- 16.4), treated with antidepressants since at least two weeks. All patients were free of alcohol abuse or dependence disorder and of other dependence to psychoactive substances. None of them presented medical illness. Diagnosis were made by separate evaluations by two authors and confirmed with a semistructered assessment instrument: the Schedule for Affective Disorders and Schizophrenia (Lifetime Version). All patients were submitted to a brutal discontinuation of their antidepressant agent. Patients were assessed twice, before the interruption of the antidepressant, and 72 hours later. Effects of antidepressant interruption were assessed by several means. Modification of anxiety and depression were evaluated using the Montgomery Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Scale. Symptoms of withdrawal were assessed with Cassano and al.'s scale SESSH including an evaluation of anxiety, agitation, irritability, anergy, difficulty on concentrating, depersonalization, sleep and appetite disorders, muscle pains, nausea, tremor, sweating, altered taste, hyperosmia, paresthesias, photophobia, motor incoordination, dizziness, hyperacousia pain, delirium. Fourteen of the 16 patients (87.5%) presented modifications of their somatic or psychic state 3 days after the interruption of the antidepressant treatment. Most frequent symptoms were: increase in anxiety (31%), increase in irritability (25%), sleep disorders (19%), decrease of anergia and fatigue (19%). Mean scores of anxiety and depression were not significantly modified by the withdrawal. Following TCAs interruption (7 patients) most frequent symptoms were sleep disorders; increase in anxiety, nausea. Among patients withdrawn from SSRIs (6 patients), most frequent symptoms were increase in anxiety, increase in irritability, headache. Patients also presented a decrease of nausea, and of anorexia.

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Effect of antidepressant drugs administered repeatedly on the dopamine D3 receptors in the rat brain.

Maj J, Dziedzicka-Wasylewska M, Rogoz R, Rogoz Z.

Institute of Pharmacology, Department of Pharmacology, Polish Academy of Sciences, Krakow.

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.

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Effects of antidepressant drugs on rats bred for low activity in the swim test.

West CH, Weiss JM.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.

To determine responsivity to antidepressant medication of Sprague-Dawley rats bred for low activity in the swim test [Swim Low-Active (SwLo) rats], these animals were given different antidepressant drugs via subcutaneously implanted minipumps for 1, 12, or 26 days, and then were tested for activity in the swim test and 2 days later in the open field. Antidepressant drugs given were amitriptyline, imipramine, desipramine (tricyclics), phenelzine (monoamine oxidase inhibitor (MAOI)], fluoxetine [selective serotonin reuptake inhibitor (SSRI)], venlafaxine, and bupropion (atypical). To assess specificity of response, the nonantidepressant drugs amphetamine, caffeine, and haloperidol were also tested. For comparison, several drugs were also tested in rats bred for high activity in the swim test [Swim High-Active (SwHi) rats]. When administered for 14 and/or 28 days (but not for 1 day), imipramine, desipramine, venlafaxine, phenelzine, and bupropion significantly increased struggling behavior of SwLo rats in swim test. No nonantidepressant drug significantly elevated struggling activity. Long-term administration of phenelzine and bupropion also significantly decreased floating behavior in the swim test, although amphetamine also had this effect at all times of administration. No significant effects of antidepressants were seen in SwHi rats. Amitriptyline and fluoxetine were ineffective in altering either struggling or floating in SwLo rats; however, a high dose of an SSRI (sertraline) did reduce floating, but this type of effect is probably not indicative of antidepressant action. Behavior in the open field was not consistently affected by any drug type. It is concluded that, based on pharmacological response profile in the swim test, SwLo rats represent depression that is responsive to potent norepinephrine reuptake-blocking antidepressants and also MAOIs; atypical depression may fit this profile.

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Combining pindolol and paroxetine in an animal model of chronic antidepressant action--can early onset of action be detected?

Cryan JF, McGrath C, Leonard BE, Norman TR.

Department of Psychiatry, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.

The realisation that pindolol may accelerate the effects of some antidepressant drugs in clinical trials has added extra impetus to the search for faster acting antidepressants. Currently, no animal model of depression can identify potential faster acting antidepressant drugs or drug combinations. In this study, we investigate the effects of combining pindolol (2 mg/kg, s.c., bid) with the antidepressant paroxetine (2.5 mg/kg, i.p., bid) in the olfactory bulbectomised rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in separate groups of rats, following 3, 7 and 14 days of treatment. Further, we simultaneously study adaptive changes in 5-HT1A receptor function, utilising alterations in the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Pindolol in combination with paroxetine attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days with a full reversal evident following 7 days, whereas paroxetine alone did so after 14 days only. Likewise, paroxetine alone reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an 'antidepressant' response in this model. However, the group treated with both paroxetine and pindolol failed to reverse the hyperactive response. This suggests that a factor intrinsic to pindolol antagonises the behavioural effects of paroxetine in the olfactory bulbectomised rat. It also demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioural syndrome is insensitive to the potential faster onset of antidepressant action induced by pindolol. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT much faster further emphasises the role of the 5-HT1A receptor in the mechanism of action of antidepressants and as a target for the development of faster acting antidepressants. However, an animal model sensitive to the effects of any such compound and the actions of pindolol remains elusive.

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Course of antidepressant treatment drug type, and prescriber's specialty.

Fairman KA, Drevets WC, Kreisman JJ, Teitelbaum F.

Health Management Services Department of Express Scripts/ValueRx, Inc., Maryland Heights, MO, USA.

OBJECTIVE: The study examined whether the relationship between the course of antidepressant treatment and the type of prescriber-psychiatrist or nonpsychiatrist-varied by whether a tricyclic antidepressant or a selective serotonin reuptake inhibitor (SSRI) was prescribed. METHODS: Pharmacy claims from a nationwide database were analyzed retrospectively. A total of 3,101 adults who did not have a prescription for antidepressants for nine months and who were then given a prescription for a tricyclic or an SSRI antidepressant were followed for 13 to 16 months after the initial prescription. Outcome measures were rates of treatment termination before one month and subtherapeutic dosing, defined as having received no prescribed daily dosages at or above commonly cited thresholds. RESULTS: Among tricyclic-treated patients, psychiatrists' patients were significantly more likely than nonpsychiatrists' patients to continue in treatment for more than one month (72 percent versus 62 percent). Among patients taking tricyclics for at least three months, those with at least one prescription from a psychiatrist had a significantly higher rate of therapeutic dosing than those with all prescriptions from a nonpsychiatrist (70 percent versus 25 percent). For SSRI-treated patients, rates of termination and therapeutic dosing did not differ significantly by prescriber type. In multivariate equations that controlled for selected differences, effects of drug type and prescriber type were independent when persistence in treatment was analyzed, and interactive when subtherapeutic dosing was analyzed. CONCLUSIONS: Policy making about antidepressant pharmacotherapy should include assessments of the relationships between drug selection and patient outcome across a variety of clinical settings.

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Indorenate produces antidepressant-like actions in the rat forced swimming test via 5-HT1A receptors.

Martinez-Mota L, Estrada-Camarena E, Lopez-Rubalcava C.

Subdireccion de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatria Ramon de la Fuente Muniz, Calzada Mexico-Xochimilco 101, San Lorenzo Huipulco, Tlalpan, Mexico 14370, D.F. lucia imp.edu.mx

RATIONALE: Indorenate has been proposed to possess antihypertensive, anorectic, stimulus control and anxiolytic-like actions. This compound has affinity mainly for the serotonergic(1A/1B) receptors, hence it could possess antidepressant-like activity. OBJECTIVES: The general purpose of this study was to explore the possible antidepressant-like effects of the serotonergic compound indorenate in the forced swimming test (FST). METHODS: In a first approach, a comparison of the actions of several doses of indorenate (2.5, 5.0, 10 mg/kg) with those of other 5-HT(1A) agonists, buspirone (5.0, 10.0 mg/kg) and 8-OH-DPAT (0.25, 0.50, 1.0 mg/kg), was performed in the FST. Secondly, in order to determine the serotonergic receptors that are participating in indorenate's action, different doses of serotonergic antagonists were administered. The compounds used were the 5-HT(1A/1B) and beta-adrenergic antagonist pindolol (2.5, 5.0 mg/kg), the 5-HT(1B)receptor antagonist GR 55562 (0.75, 1.5, 3.0 mg/kg), the 5-HT(1A) antagonist WAY 100635 (0.25, 0.5, 1.0 mg/kg) and the 5-HT(2) antagonist ketanserin (1.0, 2.0, 4.0 mg/kg). RESULTS: Indorenate (10 mg/kg), 8-OH-DPAT (1.0 mg/kg) and buspirone (5.0 and 10.0 mg/kg) reduced immobility behaviour in the FST, considered as an antidepressant-like effect. Both doses of pindolol (2.5 and 5.0 mg/kg) and WAY 100635 (0.5 and 1.0 mg/kg) antagonised the antidepressant-like effect of indorenate. Neither 5-HT(1B) (GR55562) nor 5-HT(2)(ketanserin) antagonists produced changes in the effect of indorenate in the FST. CONCLUSIONS: Indorenate produces antidepressant-like actions in the FST that are mediated by the stimulation of 5-HT(1A) receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12474119&dopt=Abstract antidepressant