Jesper T. Andreasen

Cognitive deficits in the rat chronic mild stress model for depression: Relation to anhedonic-like responses

The chronic mild stress (CMS) protocol is widely used to evoke depressive-like behaviours in laboratory rats. The aim of the present study was to examine the effects of chronic stress on cognitive performance. About 70% of rats exposed to 7 weeks of chronic mild stress showed a gradual reduction in consumption of a sucrose solution, indicating an anhedonic-like state. The remaining rats did not reduce their sucrose intake, but appeared resilient to the stress-induced effects on sucrose intake. Cognitive profiling of the CMS rats revealed that chronic stress had a negative effect on performance in the spontaneous alternation test, possibly reflecting a deficit in working memory. This effect was independent of whether the stressed rats were anhedonic-like or stress-resilient as measured by their sucrose intake. CMS did not influence performance in passive avoidance and auditory cued fear conditioning, however, in rats displaying an anhedonic-like profile, CMS increased freezing behaviour in contextual fear conditioning.

Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests

Abstract Current literature suggests involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. However, it is controversial whether the antidepressant-like effect of nAChR modulation is induced by activation, desensitization or inhibition of central nAChRs. In addition, the specific nAChR subtype/s involved remains unknown. In this study, we systematically compared the effects of non-selective and selective nicotinic agonists and antagonists in two different tests for antidepressant effects in mice: the tail suspension test and the forced swim test. Compounds: nicotine, RJR-2403 (α4β2-selective agonist), PNU-282987 (α7-selective agonist), mecamylamine (non-selective antagonist), dihydro-β-erythroidine (DHβE; α4β2-selective antagonist), methyllycaconitine (MLA; α7-selective antagonist) and hexamethonium (non-brain-penetrant non-selective antagonist). All compounds were tested in a locomotor activity paradigm to rule out non-specific stimulant effects. The data show that blockade of nAChRs with mecamylamine, or selective antagonism of α4β2 or α7 nAChRs with DHβE or MLA, respectively, has antidepressant-like effects. These effects were not confounded by motor stimulation. Hexamethonium did not show antidepressant-like activity, supporting the involvement of central nAChRs. At the dose levels tested, none of the nAChR agonists displayed antidepressant-like profiles. In conclusion, antagonism of central α4β2 and/or α7 nAChRs induced antidepressant-like effects in mice. A strategy involving antagonism of central nAChRs could potentially lead to the development of novel antidepressant therapeutics.

Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.

Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.

Antidepressant-like effects of nicotine and mecamylamine in the mouse forced swim and tail suspension tests: role of strain, test and sex.

Clinical and preclinical evidence suggest a role of nicotinic acetylcholine receptors in major depression. In humans, both nicotine and the nonselective nicotinic acetylcholine receptor antagonist mecamylamine ameliorate depressive symptoms. Similarly, both drugs produce antidepressant-like effects in rodents. In rats, the most consistent finding is antidepressant-like effects of nicotine, but not mecamylamine. Conversely, in mice, several studies show antidepressant-like effects of mecamylamine, whereas nicotine has shown modest or no effects. These contradictory results might be because of genetic differences. Here, we compared the effects of nicotine and mecamylamine in females and males of NMRI, C57BL/6J and BALB/c mice using the mouse forced swim (mFST) and tail suspension tests (mTST). In the mFST, mecamylamine, but not nicotine, increased swim distance in NMRI mice. In contrast, nicotine, but not mecamylamine, increased swim distance in C57BL/6J mice. Both drugs increased swim distance in BALB/c mice. Effects in the mFST were independent of sex. In the mTST, mecamylamine decreased immobility in NMRI mice only, independent of sex. Nicotine was devoid of effects in the mTST, except in female C57BL/6J mice, where it increased immobility. We hypothesize that nicotine and mecamylamine produce antidepressant-like effects through partially different mechanisms.

Nicotine, but not mecamylamine, enhances antidepressant-like effects of citalopram and reboxetine in the mouse forced swim and tail suspension tests

Current literature suggests that nicotinic acetylcholine receptors (nAChRs) are involved in major depression. In rodents, antidepressant-like effects of both nicotine and the non-selective nAChR antagonist mecamylamine have been reported. Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. Thus, we hypothesise that nicotine may enhance the behavioural effects of serotonin (e.g., citalopram) and/or noradrenaline (e.g., reboxetine) reuptake inhibitors. Here, we tested if nicotine enhanced the activity of citalopram or reboxetine in the mouse forced swim test (mFST) and the mouse tail suspension test (mTST). The potential for mecamylamine to augment antidepressant drug action was also investigated. Sub-threshold and threshold doses of citalopram (3 and 10mg/kg) or reboxetine (3, 10 and 20mg/kg) were tested alone and in combination with nicotine (0.3 and 1.0mg/kg) and mecamylamine (1 and 3mg/kg). Locomotor activity experiments were performed to rule out non-specific stimulant effects. Nicotine (1.0mg/kg) enhanced the effect of 10mg/kg citalopram and 20mg/kg reboxetine in the mFST. Similarly, nicotine (1.0mg/kg) enhanced the effect of 3 and 10mg/kg citalopram and 3 and 10mg/kg reboxetine in the mTST. No concomitant locomotor stimulation was observed at the tested dose combinations. Mecamylamine was effective on its own in some tests, but did not augment the effects of citalopram or reboxetine at the doses tested. The data show that nicotine enhances the effects of both serotonin and noradrenaline reuptake inhibitors, possibly reflecting nicotines facilitating effects on the release of these two neurotransmitters, and indicating that nicotine may enhance antidepressant action.

Nicotine reverses anhedonic-like response and cognitive impairment in the rat chronic mild stress model of depression: comparison with sertraline.

Smoking rates among depressed individuals are higher than is observed in the background population, and nicotine alleviates depressive symptoms. In rodents, nicotine shows antidepressant-like effects in the forced swim and learned helplessness paradigms. Clinical depression is associated with both anhedonia and cognitive impairments. In rats, chronic mild stress (CMS) decreases voluntary sucrose intake, reflecting an anhedonic-like state, and impairs performance in the spontaneous alternation behaviour (SAB) test, suggesting impaired cognitive function. Here, we examine the effect of chronic treatment of nicotine (0.4 mg/kg/day) and sertraline (5 mg/kg/day) on CMS-induced anhedonic-like behaviour and impairment in the SAB test. Nicotine and sertraline administered individually or in combination show significant and equally efficacious reversal of the CMS-induced decrease in sucrose intake, implying there is no additive or synergistic effect of the nicotine + sertraline combination. In the SAB test, nicotine, but not sertraline or nicotine + sertraline, reversed the CMS-induced impairment. The present results show that the effect of nicotine on a CMS-induced anhedonic-like state in rats is similar to that of a standard antidepressant drug. Moreover, the data suggest that nicotine alleviates CMS-induced cognitive disturbance. A treatment strategy involving the targeting of nicotinic acetylcholine receptors may prove beneficial for emotional and cognitive disturbances associated with depression.

Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: a comparison of SSR180711 and PNU-282987.

Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5-HT) release has been shown to depend on α7 nAChR activation. The α7 nAChR agonist PNU-282987 shows no antidepressant-like activity when tested alone in the mouse forced swim (mFST) or tail suspension tests (mTST). However, in combination with a sub-active dose of the selective 5-HT reuptake inhibitor citalopram, inducing ~50% 5-HT reuptake inhibition, PNU-282987 has shown marked antidepressant-like effects in the mFST. SSR180711 is a recently described α7 nAChR agonist that has shown antidepressant-like activity in the rat forced swim test. To address the possibility that 5-HT reuptake inhibition contributes to the antidepressant-like profile of SSR180711, we compared the behavioural and biochemical profiles of PNU-282987 and SSR180711. In the mFST and mTST, SSR180711 (3-30 mg/kg, s.c.) showed dose-dependent antidepressant-like activity, while PNU-282987 (3-30 mg/kg, s.c.) showed no significant effect. The ED(50) to displace [³H]α-bungarotoxin binding was 1.7 and 5.5 mg/kg for SSR180711 and PNU-282987, respectively, suggesting that both compounds produce near-maximal α7 nAChR occupancy at the highest dose. While PNU-282987 did not affect ex vivo [³H]5-HT uptake, SSR180711 inhibited [³H]5-HT uptake with an ED₅₀ of 30 mg/kg. This degree of inhibition is similar to that observed with a citalopram dose of ~2.4 mg/kg, a dose that is normally not active in the mFST or mTST. This suggests that the antidepressant-like activity of SSR180711 may involve partial 5-HT reuptake inhibition. SSR180711 therefore represents a compound displaying the synergistic effect of α7 nAChR agonism combined with partial 5-HT reuptake inhibition previously described. The addition of α7 nAChR agonism to classical monoamine-based mechanisms may represent a novel option for the improved treatment of major depression.

Subtype-selective nicotinic acetylcholine receptor agonists enhance the responsiveness to citalopram and reboxetine in the mouse forced swim test

Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. Accordingly, nicotine enhances antidepressant-like actions of reuptake inhibitors selective for serotonin or noradrenaline in the mouse forced swim test and the mouse tail suspension test. Both high-affinity α4β2 and low-affinity α7 nicotinic acetylcholine receptor subtypes are implicated in nicotine-mediated release of serotonin and noradrenaline. The present study therefore investigated whether selective agonism of α4β2 or α7 nicotinic acetylcholine receptors would affect the mouse forced swim test activity of two antidepressants with distinct mechanisms of action, namely the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine. Subthreshold and threshold doses of citalopram (3 and 10 mg/kg) or reboxetine (10 and 20 mg/kg) were tested alone and in combination with the novel α4β2-selective partial nicotinic acetylcholine receptor agonist, NS3956 (0.3 and 1.0 mg/kg) or the α7-selective nicotinic acetylcholine receptor agonist, PNU-282987 (10 and 30 mg/kg). Alone, NS3956 and PNU-282987 were devoid of activity in the mouse forced swim test, but both 1.0 mg/kg NS3956 and 30 mg/kg PNU-282987 enhanced the effect of citalopram and also reboxetine. The data suggest that the activity of citalopram and reboxetine in the mouse forced swim test can be enhanced by agonists at either α4β2 or α7 nicotinic acetylcholine receptors, suggesting that both nicotinic acetylcholine receptor subtypes may be involved in the nicotine-enhanced action of antidepressants.

Design, Synthesis, and Biological Evaluation of Erythrina Alkaloid Analogues as Neuronal Nicotinic Acetylcholine Receptor Antagonists

The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.

Low maternal care exacerbates adult stress susceptibility in the chronic mild stress rat model of depression

In the present study we report the finding that the quality of maternal care, in early life, increased the susceptibility to stress exposure in adulthood, when rats were exposed to the chronic mild stress paradigm. Our results indicate that high, as opposed to low maternal care, predisposed rats to a differential stress-coping ability. Thus rats fostered by low maternal care dams became more prone to adopt a stress-susceptible phenotype developing an anhedonic-like condition. Moreover, low maternal care offspring had lower weight gain and lower locomotion, with no additive effect of stress. Subchronic exposure to chronic mild stress induced an increase in faecal corticosterone metabolites, which was only significant in rats from low maternal care dams. Examination of glucocorticoid receptor exon 17 promoter methylation in unchallenged adult, maternally characterized rats, showed an insignificant tendency towards higher total cytosine methylation in rats from low maternal care dams. Assessment of methylation in the resilient versus anhedonic-like rat phenotypes, revealed only minor differences. Thus, maternal care status seems to be a strong predictor or trait marker for the behavioural phenotype.