The alpha1A antagonist tamsulosin impairs memory acquisition, consolidation and retrieval in a novel object recognition task in mice.

Tamsulosin is an α1-adrenoceptor antagonist used to treat benign prostatic hyperplasia. This drug exhibits high affinity for α1A- and α1D-adrenoceptor subtypes, which are also expressed in the brain. While dementia symptoms have been reported after administration of tamsulosin in humans, studies on its effects on the rodent brain are still rare. The present study investigated the effects of tamsulosin (and biperiden, an amnesic drug) on cognitive performance in the object recognition task (ORT). Tamsulosin (0.001-0.01 mg/kg) was orally administrated in mice at three distinct time points: pre-training, post-training and pre-test session. Tamsulosin 0.01 mg/kg impaired object recognition regardless of when it was injected, whereas at lower doses did not affect mouse performance in the ORT. Biperiden also impaired acquisition and consolidation of object recognition in mice. Furthermore, the effects of tamsulosin on locomotion, motivation and anxiety were excluded as potential confounding factors. At all doses tested, tamsulosin did not alter distance moved, time spent exploring objects in the ORT, and anxiety-related behaviors in the elevated plus-maze test. By contrast, diazepam evoked a significant reduction of anxiety-like behaviours. In conclusion, tamsulosin impaired memory acquisition, consolidation and retrieval in an object recognition task in mice, thus affecting memory performance in a non-specific phase manner. These findings contribute to our understanding of the potential adverse effects of tamsulosin, and shed light on the role played by α1-adrenoceptors, particularly α1A- subtype, in cognitive processes.

Activation of NOP receptor increases vulnerability to stress: role of glucocorticoids and CRF signaling.

RATIONALE: Recently, we demonstrated that the activation of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) signaling facilitates depressive-like behaviors. Additionally, literature findings support the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal (HPA) axis. OBJECTIVES: Considering that dysfunctional HPA axis is strictly related to stress-induced psychopathologies, we aimed to study the role of the HPA axis in the pro-depressant effects of NOP agonists. METHODS: Mice were treated prior to stress with the NOP agonist Ro 65-6570, and immobility time in the forced swimming task and corticosterone levels were measured. Additionally, the role of endogenous glucocorticoids and CRF was investigated using the glucocorticoid receptor antagonist mifepristone and the CRF1 antagonist antalarmin in the mediation of the effects of Ro 65-6570. RESULTS: The NOP agonist in a dose-dependent manner further increased the immobility of mice in the second swimming session compared to vehicle. By contrast, under the same conditions, the administration of the NOP antagonist SB-612111 before stress reduced immobility, while the antidepressant nortriptyline was inactive. Concerning in-serum corticosterone in mice treated with vehicle, nortriptyline, or SB-612111, a significant decrease was observed after re-exposition to stress, but no differences were detected in Ro 65-6570-treated mice. Administration of mifepristone or antalarmin blocked the Ro 65-6570-induced increase in the immobility time in the second swimming session. CONCLUSIONS: Present findings suggest that NOP agonists increase vulnerability to depression by hyperactivating the HPA axis and then increasing stress circulating hormones and CRF1 receptor signaling.

Tamsulosin facilitates depressive-like behaviors in mice: Involvement of endogenous glucocorticoids.

The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α1-adrenoceptor blocker widely prescribed for BPH. Beyond the common adverse effects of tamsulosin, increased diagnosis of dementia after prescription was observed. Importantly, a clinical study suggested that tamsulosin may exert antidepressant effects in BPH patients. Considering the expression of α1-adrenoceptors in the brain, this study aimed to investigate the effects of tamsulosin in the forced swimming and open field tests in mice. For this, tamsulosin (0.001-1 mg/kg) was orally administered subacutely (1, 5 and 23 hr) and acutely (60 min) before tests. Mifepristone (10 mg/kg), a glucocorticoid receptor antagonist, and aminoglutethimide (10 mg/kg), a streoidogenesis inhibitor, were intraperitoneally injected before tamsulosin to investigate the role of the hypothalamic-pituitary-adrenal axis in the mediation of tamsulosin-induced effects. Subacute and acute administrations of tamsulosin increased the immobility time in the first exposition to an inescapable stressful situation. In the re-exposition to the swim task, controls displayed a natural increase in the immobility time, and the treatment with tamsulosin further increased this behavioral parameter. Tamsuslosin did not affect spontaneous locomotion neither in naïve nor in stressed mice. Our findings also showed that mifepristone and aminoglutethimide prevented the tamsulosin-induced increase in the immobility time in the first and second swimming sessions, respectively. In conclusion, tamsulosin may contribute to increased susceptibility to depressive-like behaviors, by facilitating the acquisition of a passive stress-copying strategy. These effects seem to be dependent on endogenous glucocorticoids.

Neuropeptide S Receptor as an Innovative Therapeutic Target for Parkinson Disease.

Parkinson disease (PD) is a neurodegenerative disease mainly characterized by the loss of nigral dopaminergic neurons in the substantia nigra pars compacta. Patients suffering from PD develop severe motor dysfunctions and a myriad of non-motor symptoms. The treatment mainly consists of increasing central dopaminergic neurotransmission and alleviating motor symptoms, thus promoting severe side effects without modifying the disease's progress. A growing body of evidence suggests a close relationship between neuropeptide S (NPS) and its receptor (NPSR) system in PD: (i) double immunofluorescence labeling studies showed that NPSR is expressed in the nigral tyrosine hydroxylase (TH)-positive neurons; (ii) central administration of NPS increases spontaneous locomotion in naïve rodents; (iii) central administration of NPS ameliorates motor and nonmotor dysfunctions in animal models of PD; (iv) microdialysis studies showed that NPS stimulates dopamine release in naïve and parkinsonian rodents; (v) central injection of NPS decreases oxidative damage to proteins and lipids in the rodent brain; and, (vi) 7 days of central administration of NPS protects from the progressive loss of nigral TH-positive cells in parkinsonian rats. Taken together, the NPS/NPSR system seems to be an emerging therapeutic strategy for alleviating motor and non-motor dysfunctions of PD and, possibly, for slowing disease progress.

Novel Mixed NOP/Opioid Receptor Peptide Agonists.

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.

Nociceptin/orphanin FQ receptor system blockade as an innovative strategy for increasing resilience to stress.

The ability to successfully cope with stress is known as 'resilience', and resilient individuals are less prone to develop psychopathologies. Understanding the neurobiological mechanisms of resilience may be instrumental to improve current therapies and benefit high-risk subjects. This review summarizes the complex interplay that exists between physiological and pathological responses to stressful events and the nociceptin/orphanin FQ (N/OFQ) - N/OFQ receptor (NOP) system, including: the effects of stress in regulating N/OFQ release and NOP expression; the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal axis; behavioral studies; and evidence in humans correlating this peptidergic system with psychopathologies. Available findings support the view that N/OFQ signaling stimulates the hypothalamic-pituitary-adrenal axis, thus increasing stress circulating hormones and corticotropin-releasing factor signaling. Additionally, activation of the NOP receptor inhibits monoamine transmission, including 5-HT, and this may contribute to maladaptive outcomes of stress. Ultimately, the N/OFQ system seems to have an important role in stress vulnerability, and blockade of NOP signaling may provide an innovative strategy for the treatment of stress related psychopathologies.

Blockade of nociceptin/orphanin FQ signaling facilitates an active copying strategy due to acute and repeated stressful stimuli in mice.

The role of stress in the etiology of depression has been largely reported. In this line, exogenous glucocorticoids are employed to mimic the influence of stress on the development of depression. The N/OFQ-NOP receptor system has been implicated in the modulation of stress and emotional behaviors. In fact, the blockade of NOP receptors induces antidepressant effects and increases resilience to acute stress. This study investigated the effects of the NOP receptor blockade on dexamethasone-treated mice exposed to acute and prolonged swimming stress. Swiss and NOP(+/+) and NOP(-/-) mice were treated with dexamethasone, and the protective effects of the NOP antagonist SB-612111 (10 mg/kg, ip) or imipramine (20 mg/kg, ip) were investigated in three swimming sessions. The re-exposure to swim stress increased immobility time in Swiss and NOP(+/+), but not in NOP(-/-) mice. Acute and repeated dexamethasone administration induced a further increase in the immobility time, and facilitated body weight loss in Swiss mice. Single administration of SB-612111, but not imipramine, prevented swimming stress- and dexamethasone-induced increase in the immobility time. Repeated administrations of SB-612111 prevented the deleterious effects of 5 days of dexamethasone treatment. Imipramine also partially prevented the effects of repeated glucocorticoid administration on the immobility time, but did not affect the body weight loss. NOP(-/-) mice were more resistant than NOP(+/+) mice to inescapable swimming stress, but not dexamethasone-induced increase in the immobility time and body weight loss. In conclusion, the blockade of the NOP receptor facilitates an active stress copying response and attenuates body weight loss due to repeated stress.

Effects of non-peptide nociceptin/orphanin FQ receptor ligands on methylphenidate-induced hyperactivity in mice: Implications for bipolar disorders.

Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment adherence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to investigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65-6570 (0.01-1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001-0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1-10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP(-/-)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP(-/-) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder.

Blockade of NOP receptor modulates anxiety-related behaviors in mice exposed to inescapable stress.

RATIONALE: Depression and anxiety frequently co-occur, and this has important clinical implications. Previous studies showed that activation of the nociceptin/orphanin FQ receptor (NOP) elicits anxiolytic effects, while its blockade promotes consistent antidepressant actions. NOP antagonists are effective in reversing footshock-induced depressive-like behaviors, but their effects on stress-induced anxiety are still unclear. OBJECTIVE: This study aimed to investigate the effects of the NOP antagonist SB-612111 on footshock stress-induced anxiety behaviors. METHODS: Male Swiss mice were exposed to inescapable electric footshock stress, and behavioral phenotype was screened based on the ability to escape from footshock (i.e., helpless or non-helpless). Animals were then treated with diazepam (1 mg/kg) and SB-612111 (0.1-10 mg/kg), and their behavior was assessed in the elevated plus-maze (EPM) and open field test. RESULTS: When compared with non-stressed mice, helpless, but not non-helpless, animals displayed significant reductions in the time spent in and entries into open arms in the EPM. Diazepam significantly increased open arms exploration in helpless, non-helpless, and non-stressed mice. However, treatment with the NOP antagonist SB-612111 was inactive in naive mice, while it reversed anxiogenic-related behaviors in helpless mice and increased anxiety states in non-helpless mice. No effects on locomotion were observed. CONCLUSION: Helpless mice displayed increased anxiety compared to non-stressed and non-helpless animals, thus supporting use of this approach as an animal model to investigate anxiety/depression comorbidity. Additionally, SB-612111 modulated anxiety-like behaviors in male mice depending on individual stress susceptibility. Ultimately, NOP antagonists could be useful for treating anxiety in depressed patients.

Prenatal restraint stress impairs recognition memory in adult male and female offspring.

OBJECTIVE: Accumulating evidence from preclinical and clinical studies indicates that prenatal exposure to stress impairs the development of the offspring brain and facilitates the emergence of mental illness. This study aims to describe the impact of prenatal restraint stress on cognition and exploration to an unfamiliar environment at adulthood in an outbred strain of mice. METHODS: Late pregnant mice were exposed to restraint stress and adult offspring (60 days of age) behaviours were assessed in the object recognition task and open field test. FINDINGS: Prenatal stress (PNS) impaired new object recognition in male and female mice. Importantly, the learning deficits in female PNS mice were linked to their estrous cycle. Actually, PNS females in metestrus/diestrus but not in proestrus/estrus phases displayed recognition deficits compared to controls. Concerning locomotion in an unfamiliar environment, male but not female PNS mice displayed significant increase, but showed no differences in the distance travelled within the centre zone of the arena. CONCLUSION: Present findings support the view that maternal restraint-stress during late pregnancy impairs recognition memory in both male and female offspring, and in females, this cognitive deficit is dependent on the estrous cycle phase. Ultimately, these data reinforce that PNS is an aetiological component of psychiatric disorders associated with memory deficits.

Dopamine D1 and D2 receptors mediate neuropeptide S-induced antinociception in the mouse formalin test.

Neuropeptide S (NPS) is the endogenous ligand of a G-protein coupled receptor named NPS receptor. The NPS system controls several biological functions, including anxiety, wakefulness, locomotor activity, food intake, and pain transmission. A growing body of evidence supports facilitatory effects for NPS over dopaminergic neurotransmission. The present study was aimed to investigate the role of dopamine receptors signaling in the antinociceptive effects of NPS in the mouse formalin test. The following dopamine receptor antagonists were employed: SCH 23390 (selective dopamine D1 antagonist, 0.05 mg/kg, ip), haloperidol (non-selective dopamine D2-like receptor antagonist; 0.03 mg/kg, ip), and sulpiride (selective dopamine D2-like receptor antagonist; 25 mg/kg, ip). Mice were pretreated with dopamine antagonists before the supraspinal administration of NPS (0.1 nmol, icv). Morphine (5 mg/kg, sc) and indomethacin (10 mg/kg, ip) were used as positive controls to set up the experimental conditions. Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was only active at phase 2. Central NPS significantly reduced formalin-induced nociception during both phases. The systemic administration of SCH 23390 slightly blocked the effects of NPS only during phase 2. Haloperidol prevented NPS-induced antinociceptive effects. Similar to haloperidol, sulpiride also counteracted the antinociceptive effects of NPS in both phases of the formalin test. In conclusion, the present findings suggest that the analgesic effects of NPS are linked with dopaminergic neurotransmission mainly through dopamine D2-like receptor signaling.

Modulation of the NOP receptor signaling affects resilience to acute stress.

BACKGROUND: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear. AIMS: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. METHODS: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. RESULTS: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. CONCLUSIONS: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.

NOP agonist action of cebranopadol counteracts its liability to promote physical dependence.

Cebranopadol is a mixed NOP/opioid receptor agonist currently under development as innovative analgesic. In this study the liability of cebranopadol to produce opioid-type physical dependence has been evaluated in comparison with morphine in wild type mice and in mice knockout for the NOP receptor gene (NOP(-/-)). Mice were treated twice a day for 5 days with increasing doses of cebranopadol or morphine (cumulative doses 10.2 and 255 mg/kg, respectively) and the number of jumping in response to naloxone 10 mg/kg were measured after 2 h from the last injection. In wild type mice naloxone evoked a similar withdrawal jumping behavior in animal pretreated with morphine or cebranopadol. In NOP(-/-) mice morphine treatment produced the same signs of withdrawal as in NOP(+/+) animals, while cebranopadol treatment elicited a stronger withdrawal syndrome in NOP(-/-) than of NOP(+/+) mice. These results demonstrated that the activation of the NOP receptor reduces the liability of cebranopadol to produce opioid-like physical dependence. Thus, the simultaneous activation of NOP and opioid receptors can be an effective pharmacological strategy to counteract physical dependence to opioid drugs.

NOP Ligands for the Treatment of Anxiety and Mood Disorders.

Many studies point toward the nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP) as targets for the development of innovative drugs for treating anxiety- and mood-related disorders. Evidence supports the view that the activation of NOP receptors with agonists elicits anxiolytic-like effects, while its blockade with NOP antagonists promotes antidepressant-like actions in rodents. Genetic studies showed that NOP receptor knockout mice display an antidepressant-like phenotype, and NOP antagonists are inactive in these animals. In contrast, the genetic blockade of NOP receptor signaling generally displays an increase of anxiety states in the elevated plus-maze test. In this chapter we summarized the most relevant findings of NOP receptor ligands in the modulation of anxiety and mood disorders, and the putative mechanisms of action are discussed.

NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine.

RATIONALE: Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of a Gi protein-coupled receptor named NOP. Both N/OFQ and NOP receptor are widely expressed in brain areas involved in the control of emotional processes. Clinical and preclinical studies support antidepressant effects due to the blockade of NOP receptor signaling. By contrast, NOP receptor activation did not evoke any change in behavioral despair tests. OBJECTIVES: The present study aimed to investigate the effects of the co-administration of NOP agonists and classic antidepressant drugs in the forced swimming test (FST) and learned helplessness model (LH) in mice. METHODS: Male Swiss mice were co-administered with NOP agonists (N/OFQ and Ro 65-6570) and antidepressants (nortriptyline, fluoxetine, and R-ketamine) or SB-612111 (NOP antagonist) and the behavioral effects were assessed in the FST and LH tests. RESULTS: Fluoxetine, nortriptyline, R-ketamine and the NOP antagonist SB-612111 displayed antidepressant-like effects in the FST. The administration of the NOP agonists N/OFQ and Ro 65-6570 did not induce any behavioral change. However, co-administration of NOP agonists blocked the antidepressant effects of SB-612111, fluoxetine, and nortriptyline, but not R-ketamine in the FST. Similarly, in the LH, the systemic injection of SB-612111, nortriptyline, and R-ketamine reversed helplessness. The co-administration of Ro 65-6570 blocked the antidepressant-like effects of SB-612111 and nortriptyline, but not R-ketamine. CONCLUSIONS: NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.

Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness.

RATIONALE: Pharmacological and genetic evidence support antidepressant-like effects elicited by the blockade of the NOP receptor. The learned helplessness (LH) model employs uncontrollable and unpredictable electric footshocks as a stressor stimulus to induce a depressive-like phenotype that can be reversed by classical antidepressants. OBJECTIVES: The present study aimed to evaluate the action of NOP receptor antagonists in helpless mice. METHODS: Male Swiss mice were subjected to the three steps of the LH paradigm (i.e., (1) induction, (2) screening, and (3) test). Only helpless animals were subjected to the test session. During the test session, animals were placed in the electrified chamber and the latency to escape after the footshock and the frequency of escape failures were recorded. The effect of the following treatments administered before the test session were evaluated: nortriptyline (30 mg/kg, ip, 60 min), fluoxetine (30 mg/kg, ip, four consecutive days of treatment), and NOP antagonists SB-612111 (1-10 mg/kg, ip, 30 min) and UFP-101 (1-10 nmol, icv, 5 min). To rule out possible biases, the effects of treatments on controllable stressful and non stressful situations were assessed. RESULTS: In helpless mice, nortriptyline, fluoxetine, UFP-101 (3-10 nmol), and SB-612111 (3-10 mg/kg) significantly reduced escape latencies and escape failures. No effects of drug treatments were observed in mice subjected to the controllable electric footshocks and non stressful situations. CONCLUSIONS: Acute treatment with NOP antagonists reversed helplessness similarly to the classical antidepressants. These findings support the proposal that NOP receptor antagonists are worthy of development as innovative antidepressant drugs.