John Paul Redrobe

The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y.

This review aims to give a brief overview of NPY receptor distribution and physiology in the brain and summarizes series of studies, test by test and region by region, aimed at identification receptor subtypes and neuronal circuitry mediating anxiolytic-like effects of NPY. We conclude that from four known NPY receptor subtypes in the rat (Y(1), Y(2), Y(4), Y(5)), only the NPY Y(1) receptor can be linked to anxiety-regulation with certainty in the forebrain, and that NPY Y(2) receptor may have a role in the pons. Microinjection studies with NPY and NPY receptor antagonists support the hypothesis that the amygdala, the dorsal periaqueductal gray matter, dorsocaudal lateral septum and locus coeruleus form a neuroanatomical substrate that mediates anxiolytic-like effects of NPY. The release of NPY in these areas is likely phasic, as NPY receptor antagonists are silent on their own. However, constant NPY-ergic tone seems to exist in the dorsal periaqueductal gray, the only brain region where NPY Y(1) receptor antagonists had anxiogenic-like effects. We conclude that endogenous NPY has an important role in reducing anxiety and serves as a physiological stabilizer of neural activity in circuits involved in the regulation of arousal and anxiety.

The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test

The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY) in the mouse forced swimming test, an animal model widely used for the screening of potential antidepressant drugs. In addition, experiments were performed, using agonists and selective antagonists, to assess the potential role of NPY Y1 and Y2 receptor subtypes in this model. Complementary studies were performed in an open field apparatus to rule out any changes in locomotor activity that might have interfered with the interpretation of data from the mouse forced swimming test. Intracerebroventricular injections (0.03 nmole-3 nmole) of NPY, [Leu31Pro34]PYY (Y1 agonist), NPY13-36 (Y2 agonist), BIBP3226, BIBO3304 (Y1 antagonists) and BIIE0246 (Y2 antagonist) were performed 30 min prior to testing in the mouse forced swimming test and open field. NPY administration significantly reduced immobility time in a dose dependent manner (p < .01 vs. control group), as did [Leu31Pro34]PYY (p < .01 vs. control group) and BIIE0246 (p < .05 vs. control group). In contrast, BIBO3304, BIBP3226 and NPY13-36 did not display any activity at the doses tested. However, pretreatment with BIBO3304 or BIBP3226 significantly blocked the anti-immobility effects of NPY. Data from the open field demonstrated that BIIE0246 increased horizontal ambulation at the dose found to be active in the forced swimming test. Taken together, our results demonstrate that NPY displays antidepressant-like activity in the mouse forced swimming test, and suggest that this activity is mediated by the NPY Y1 receptor subtype.

Multiple receptors for neuropeptide Y in the hippocampus: putative roles in seizures and cognition

Neuropeptide Y (NPY) is widely distributed throughout the central nervous system (CNS) and is one of the most conserved peptides in evolution, suggesting an important role in the regulation of basic physiological functions, including learning and memory. In addition, experimental studies have suggested that NPY, together with its receptors, may have a direct implication in several pathological disorders, including epilepsy/seizure. NPY-like immunoreactivity and NPY receptors have been shown to be present throughout the brain, but is concentrated in the hippocampus. The hippocampal formation has been repeatedly implicated in the modulation of cognition, as well as the pathogenesis of seizure. This review will concentrate on the hippocampal distribution of NPY, its receptors and the putative role played by this peptide in seizure, together with the regulation of cognitive function associated with learning and memory.

Partial role of 5-HT2 and 5-HT3 receptors in the activity of antidepressants in the mouse forced swimming test

The present study was designed to evaluate the roles of 5-HT2 and 5-HT3 receptors in the mouse forced swimming test, by using selective agonists and antagonists of 5-HT(2A/C) and 5-HT3 receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Pretreatment with (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) (4 mg/kg, i.p.) or 2-methyl-5-HT (4 mg/kg, i.p.) had no effect on the anti-immobility effects of any antidepressant tested. Prior administration of ritanserin (4 mg/kg, i.p.) or ketanserin (8 mg/kg, i.p.), on the other hand, potentiated the effects of sub-active doses of imipramine (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.) but not of maprotiline (8 mg/kg, i.p.), fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). Pretreatment with ondansetron (1 X 10(-5) mg/kg, i.p.) enhanced the antidepressant-like effects of sub-active doses of the selective serotonin reuptake inhibitors. The results of the present study suggested that, in the forced swimming test, the selective serotonin reuptake inhibitors act partially through 5-HT3 receptor sites, whereas the tricyclic antidepressants exert effects at 5-HT(2A/C) receptor sites. Anti-immobility effects of the selective noradrenaline reuptake inhibitor, maprotiline, do not seem to be mediated by 5-HT(2A/C) or 5-HT3 receptor function.

Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity

Abstract The present study was undertaken to investigate thoroughly the preclinical psychopharmacological profile of venlafaxine, testing a wide range of doses in animal models indicative of antidepressant-like effects. Venlafaxine was found to be active in mouse forced swimming test (at 8, 16, 32 and 64 mg/kg) and to increase spontaneous locomotor activity (at 16, 32 and 64 mg/kg). Venlafaxine antagonised apomorphine-induced (16 mg/kg) hypothermia (at 2, 4, 8, 16, 32 and 64 mg/kg). Pretreatment with PCPA significantly attenuated the anti-immobility effects of venlafaxine (8 and 16 mg/kg; P < 0.01) in the mouse forced swimming test. Venlafaxine at a dose of 32 mg/kg remained active, despite PCPA pretreatment. DSP-4 significantly attenuated the anti-immobility effects of venlafaxine (16 mg/kg; P < 0.05), whereas venlafaxine at 32 mg/kg remained active, despite DSP-4 pretreatment. Venlafaxine was active in the forced swimming test when administered at sub-effective doses in combination with (±) pindolol (venlafaxine: 1 and 2 mg/kg), RU 24969 (venlafaxine: 1, 2 and 4 mg/kg), 8-OH-DPAT (venlafaxine: 4 mg/kg), clonidine (venlafaxine: 1, 2 and 4 mg/kg), lithium (venlafaxine: 1, 2, and 4 mg/kg) and quinine (venlafaxine: 1 and 2 mg/kg). Prior administration with NAN-190 antagonised the anti-immobility effects of venlafaxine (8, 16 and 32 mg/kg). Interaction studies did not induce changes in locomotor activity. The results of the present study indicated that, at low doses, venlafaxine inhibited serotonin reuptake, while at higher doses it inhibited both serotonin and noradrenaline reuptake.

The role of 5-HT1A and 5-HT1B receptors in antidepressant drug actions in the mouse forced swimming test

The forced swimming test is a behavioural model developed to predict the efficacy of antidepressant drugs. Few studies have been aimed at evaluating the mechanism of action of antidepressants in the forced swimming test. The present study was designed in order to further evaluate the mode of action of antidepressants in the forced swimming test, by using selective agonists and antagonists at 5-HT1A and 5-HT1B receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) induced anti-immobility effects with the tricyclic antidepressant imipramine (8 mg/kg, i.p.) and noradrenaline uptake inhibitors maprotiline (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.), but not with fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). These effects were antagonised by prior administration of 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazine) (NAN 190) (0.5 mg/kg, i.p.). On the other hand, pretreatment with (+/-)-pindolol (32 mg/kg, i.p.) potentiated the effects of the selective serotonin reuptake inhibitors and was devoid of any activity with imipramine (8 mg/kg, i.p.), maprotiline (8 mg/kg, i.p.) or desipramine (16 mg/kg, i.p.). Prior administration of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) enhanced the antidepressant-like effects of the selective serotonin reuptake inhibitors and imipramine (8 mg/kg, i.p.) in the forced swimming test. The anti-immobility effects of the selective serotonin reuptake inhibitors in the forced swimming test seem to be mediated by presynaptic 5-HT1A receptors as well as postsynaptic 5-HT1B receptors. Antidepressant-like effects of the noradrenaline uptake inhibitors seem, on the other hand, to be mediated by postsynaptic 5-HT1A receptors. Considering the variety of 5-HT receptors, it is possible that other subtypes may participate in the anti-immobility effects of antidepressants in the forced swimming test.

Neuropeptide Y (NPY) Y2 receptors mediate behaviour in two animal models of anxiety: evidence from Y2 receptor knockout mice

The behavioural phenotype of mice lacking neuropeptide Y (NPY) Y(2)-type receptors was assessed in two well documented animal models of anxiety: namely, the elevated plus maze and the open field. NPY Y(2)-/- mice made more entries into, and spent significantly more time on, the open arms of the elevated plus maze when compared to their wild-type Y(2)+/+ controls (P<0.001). This effect was not due to non-specific changes in locomotor activity as the number of closed arm entries did not differ between groups. In addition, NPY Y(2)-/- mice displayed increased preference for the central area of the open field when compared to Y(2)+/+ animals (P<0.01), whereas total entries did not differ between groups. This study suggests that NPY Y(2) receptors may play an inhibitory role and supports the hypothesis that Y(2) receptors are involved in the regulation of anxiety-like behaviours by NPY.

Neuropeptide Y (NPY) and depression: From animal studies to the human condition

Neuropeptide Y (NPY) is widely distributed throughout the central nervous system (CNS) and is one of the most conserved peptides in evolution, suggesting an important role in the regulation of basic physiological functions. In addition, both pre-clinical and clinical evidence have suggested that NPY, together with its receptors, may have a direct implication in several psychiatric disorders, including depression and related illnesses. NPY-like immunoreactivity and NPY receptors are expressed throughout the brain, with varying concentrations being found throughout the limbic system. Such brain structures have been repeatedly implicated in the modulation of emotional processing, as well as in the pathogenesis of depressive disorders. This review will concentrate on the distribution of NPY, its receptors, and the putative role played by this peptide in depressive illness based on both pre-clinical and clinical evidence.

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.

Characterization of neuropeptide Y, Y(2) receptor knockout mice in two animal models of learning and memory processing.

Neuropeptide Y (NPY) and, in particular, the Y2 receptor subtype, has been suggested to be involved in learning and memory processing. However, the precise role of Y2 receptors in learning and memmory remains unclear. In the present study, mice lacking NPY Y2-type receptors were assessed in two animal models of learning and memory processing. We found that NPY Y2−/− mice displayed a deficit on the probe trial in the Morris water maze task, whereas acquisition performance, swim speed, and visible platform performance did not differ significantly between groups. In addition, NPY Y2−/− mice exhibited a marked deterioration in object memory 6 h, but not 1 h, following initial exposure in the object recognition test. Both groups of mice showed similar locomotor activity profiles in a low-stress, open field test. These data support the hypothesis that Y2 receptors are involved in the regulation of learning and memory processing.