Biomedical subjects

Mark J Millan

Publications and source records attributed to Mark J Millan.

At least 19 recordsLinked to original sources

PubMed2006

Dopamine D3 receptor agonists for protection and repair in Parkinson's disease.

Parkinson's disease is a severe, age-related neurodegenerative disorder in which a loss of substantia nigra-derived dopaminergic pathways to the striatum triggers profound motor perturbation, as well as cognitive, sensory and mood deficits. Although the dopamine precursor, L-dopa, is effective in the short-term in relieving motor dysfunction, it does not stop the progressive disappearance of dopaminergic neurons, encouraging interest in alternative therapeutic strategies. Dopaminergic agonists, such as pramipexole, appear to have neuroprotective and neurorestorative actions based on clinical and, most convincingly, experimental work. The role of specific dopaminergic receptor subtypes is an important issue, especially with respect to new drug development. Of particular interest, dopamine D3 receptors contribute to the beneficial influence of dopaminergic agonists for the protection and restoration of dopaminergic pathways in Parkinson's disease.

Animals↗

PubMed2006

Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats: a characterization with alpha/beta-adrenoceptor subtype selective ligands, antidepressants, and antagonists at neuropeptide receptors.

Although little information is available concerning discriminative stimulus (DS) properties of antidepressants, rats can be trained to recognize the selective norepinephrine (NE) reuptake inhibitor, reboxetine (2.5 mg/kg i.p.). By analogy to reboxetine (effective dose50, 1.1), 'full' (80%) substitution dose50 was obtained with the NE reuptake inhibitors, nisoxetine (4.9), nomifensine (0.5) and BW1555,U88 (1.0). Full substitution was also attained with the NE/serotonin (5-HT) reuptake inhibitors, S33005 (0.3), venlafaxine (4.8) and duloxetine (26.8), and the tricyclics, imipramine (2.5) and clomipramine (2.9). In contrast, the 5-HT reuptake inhibitors, citalopram, sertraline and paroxetine (all >2.5), and the 5-HT reuptake inhibitors/5-HT2 receptor antagonists, nefazodone and trazodone (both >10.0), did not substitute for reboxetine. The 'atypical' antidepressants, mirtazapine (>10.0) and mianserin (>2.5), similarly failed to substitute. DS properties of reboxetine were dose-dependently blocked by the alpha1-adrenoceptor (AR) antagonists, prazosin (inhibitory dose50, 0.3) and WB4101 (0.5), but resistant to the alpha2-AR antagonists, atipamezole (>0.63), idazoxan (>2.5) and RX821,002 (>0.08), and to the beta1-AR and beta2-AR antagonists, betaxolol (>2.5) and ICI118,551 (>10.0). Interestingly, the neurokinin-1 receptor antagonist, GR205,171, stereospecifically substituted for reboxetine (1.1) compared to its less active isomer, GR226,206 (>10.0). The corticotrophin-releasing factor-1 antagonists, DMP695 (>40), CP154,526 (>10.0) and SN003 (>40.0), and the melanin-concentrating hormone-1 antagonist, SNAP-7941 (>40.0), failed to substitute for reboxetine. In conclusion, DS properties of reboxetine are mimicked by antidepressants recognizing NE transporters, and require functionally intact alpha1-ARs for their expression. The neurokinin-1 antagonist, GR205,171, mimics the interoceptive properties of reboxetine, possibly reflecting its elevation of extracellular levels of NE in corticolimbic structures.

Adrenergic Uptake Inhibitors↗

PubMed2006

Discriminative stimulus properties of S32504, a novel D3/D2 receptor agonist and antiparkinson agent, in rats: attenuation by the antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine, and by selective antagonists at dopamine D2 but not D3 receptors.

RATIONALE: Drug-discrimination studies have proven instructive in the characterization of psychotropic agents, a procedure applied herein to the novel antiparkinson agent, S32504. This highly selective agonist at dopamine D(3) and (less potently) D(2) receptors displays potent antiparkinson, neuroprotective and antidepressant properties (Millan et al., J Pharmacol Exp Ther 309:936-950, 2004a; Millan et al., J Pharmacol Exp Ther 309:903-920, 2004b; Millan et al., J Pharmacol Exp Ther 309:921-935, 2004c). OBJECTIVES: To generate a discriminative stimulus (DS) with S32504 and undertake substitution/antagonism studies with diverse antiparkinson and antipsychotic agents. MATERIALS AND METHODS: Using a two-lever, fixed-ratio 10 schedule, rats were trained to recognize S32504 (0.04 mg/kg, s.c.) from saline. RESULTS: S32504 displayed dose-dependent and stereospecific substitution in comparison to its less active racemic form, (+/-) S31411, and to its inactive (-) distomer, S32601. Apomorphine, and the selective D(3)/D(2) receptor agonists, ropinirole, PD128,907, 7-OH-DPAT and CGS15855A, fully (=80%) substituted for S32504, whereas D(4) and D(1)/D(5) receptor agonists were ineffective. The selective D(3) vs D(2) receptor partial agonist, BP897, did not substitute for S32504 and the selective D(3) receptor antagonists, S33084, SB277,011, GR218,231, PNU99194A and S14297, did not block its DS properties. By contrast, S32504 lever selection was blocked by the preferential D(2) vs D(3) receptor antagonists, L741,626 and S23199, and by the D(2)/D(3) antagonists, raclopride and haloperidol. The D(2)/D(3) receptor partial agonists and antipsychotics, aripiprazole, bifeprunox, N-desmethylclozapine and preclamol did not substitute for S32504: indeed, they dose-dependently attenuated its DS properties. CONCLUSION: The antiparkinson agent, S32504, displays DS properties principally mediated by high-efficacy activation of D(2) receptors Antipsychotics known to act as partial agonists at D(2)/D(3) receptors attenuate DS properties of S32504, actions reflecting their low efficacy at these sites.

Animals↗

PubMed2006

Activation of dopamine D1 receptors enhances cholinergic transmission and social cognition: a parallel dialysis and behavioural study in rats.

Although dopaminergic mechanisms are known to modulate cognitive function and cholinergic transmission, their pharmacological characterization remains incomplete. Herein, the role of D1 sites was evaluated employing neurochemical and behavioural approaches. By analogy to the acetylcholinesterase inhibitor, galantamine (0.0025-0.63 mg/kg s.c.), the selective and high efficacy D1 receptor agonist, SKF 82958, dose-dependently (0.0025-0.63), robustly and potently enhanced extracellular levels of acetylcholine (ACh) in the frontal cortex and hippocampus of freely moving rats. A further agonist, SKF 81297 (0.04-0.63), mimicked this action whereas the selective antagonist, SCH 23390 (0.00063-0.63), decreased levels of ACh. In the presence of SCH 23390 (0.08), the facilitatory influence of SKF 82958 (0.04) upon ACh levels was abolished. In a model of social memory (recognition of a juvenile by an adult rat), galantamine (0.04-0.63), SKF 82958 (0.01-0.16) and SKF 81297 (0.001-0.16) dose-dependently abrogated amnesic effects of the muscarinic receptor antagonist scopolamine (1.25). Further, under conditions of spontaneous loss of recognition, mimicking the effects of galantamine (0.04-2.5), SKF 82958 (0.01-0.16) and SKF 81297 (0.04-1.25) dose-dependently and specifically facilitated social recognition. Conversely, SCH 23390 (0.0025-0.04) exerted a modest negative influence upon social recognition and, in its presence, the pro-cognitive properties of SKF 82958 were blocked. In conclusion, D1 receptors exert a tonic, facilitatory influence upon cholinergic transmission and social recognition. Although the relationship between these actions awaits further clarification, these data underpin the relevance of D1 receptors to CNS disorders in which cholinergic transmission and social cognition are disrupted.

Acetylcholine↗

PubMed2006

Actions at sites other than D(3) receptors mediate the effects of BP897 on l-DOPA-induced hyperactivity in monoamine-depleted rats.

The role of D(3) receptors in the antiparkinsonian actions of l-DOPA and l-DOPA-induced dyskinesia (LID) remains unclear. The D(3) receptor partial agonist BP897 attenuates LID in primates without affecting the antiparkinsonian actions of l-DOPA, suggesting that "normalization" of D(3) activity is antidyskinetic [Bezard, E., Ferry, S., Mach, U., Stark, H., Leriche, L., Boraud, T., Gross, C., and Sokoloff, P., 2003. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D(3) receptor function. Nat. Med. 9, 762-767]. However, subsequent studies have questioned these findings [Hsu, A., Togasaki, D.M., Bezard, E., Sokoloff, P., Langston, J.W., Di Monte, D.A., and Quik, M., 2004. Effect of the D(3) dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on l-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys. J. Pharmacol. Exp. Ther. 311, 770-777]. The D(3) receptor antagonist S33084 is not antidyskinetic yet enhances the antiparkinsonian actions of l-DOPA, suggesting that stimulation of D(3) receptors is not involved in LID. Here, we address the possibility that in vivo BP897 acts via mechanisms in addition to attenuation of D(3) signaling. l-DOPA (125 mg/kg) elicits hyperkinesia in reserpine-treated rats, the vertical component of which (rearing) is attenuated by agents with antidyskinetic actions in MPTP-lesioned primates and Parkinson's disease (PD) [Johnston, T.H., Lee, J., Gomez-Ramirez, J., Fox, S.H., and Brotchie, J.M., 2005. A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease. Exp. Neurol. 191, 243-250]. BP897 (0.1, 0.3, 1.0 and 3 mg/kg) reduced l-DOPA-induced rearing by 0%, 44%, 86% and 57% respectively. In contrast, S33084 had no effect on l-DOPA-induced rearing (0.1 mg/kg, 115%; 0.3 mg/kg, 94%, 1 mg/kg, 134%; 3 mg/kg, 100%, of vehicle, all P > 0.05). Furthermore, S33084 failed to antagonize the effects of BP897 on l-DOPA-induced rearing. The influence of BP897 on l-DOPA-induced rearing was, however, mimicked by the selective D(2) antagonist L741,626. Finally, BP897 attenuated l-DOPA-induced horizontal activity, an action attenuated by S33084 and mimicked by L741,626. Thus, while BP897 may reduce LID, we raise the possibility that receptors other than D(3) receptors might be involved in this action.

Adrenergic Uptake Inhibitors↗

PubMed2006

Discriminative stimulus properties of the selective and highly potent alpha2-adrenoceptor agonist, S18616, in rats: mediation by the alpha2A subtype, and blockade by the atypical antidepressants, mirtazapine and mianserin.

The novel spiroimidazoline, S18616, a potent and efficacious agonist at alpha2-adrenoceptors (ARs), shows>100-fold selectivity versus alpha1-ARs, imidazoline receptors and all other sites examined. Herein, we characterized its discriminative stimulus (DS) properties in rats trained to recognise S18616 (0.01 mg/kg, s.c.) from saline. S18616 dose-dependently (0.0063-0.01) and "fully" (>or=80% "S18616" lever selection) substituted for itself. Full substitution was also acquired for the agonist, UK14,304 (0.04-0.16), while the partial agonist, clonidine (0.01-0.08), yielded sub-maximal substitution (67%). Guanfacine (0.16-1.25) and guanabenz (0.00063-0.04), preferential agonists at alpha2A-ARs, revealed full substitution for S18616. In contrast, the alpha1-AR agonists, cirazoline and ST587 (both 0.04-0.63), did not substitute. The alpha2-AR antagonists, RX821,002, atipamezole (both 0.0025-0.04) and idazoxan (0.04-0.63) blocked the S18616 DS, whereas the alpha1-AR antagonists, prazosin (0.16-0.63) and WB4101 (0.04-0.63), were inactive. Prazosin is also a preferential antagonist at alpha2B/2C- versus alpha2A-ARs and a further preferential alpha2B/2C-AR antagonist, BRL41,992 (0.63-2.5), was likewise ineffective. In contrast, the alpha2A-AR antagonist, BRL44,408 (0.04-0.16), dose-dependently abolished the S18616 DS. Finally, the "atypical" antidepressants, mirtazapine (0.16-10.0) and mianserin (0.63-10.0), which behave as antagonists at alpha2A-ARs, dose-dependently blocked the S18616 DS. In conclusion, S18616 elicits a robust DS in rats that principally reflects engagement of alpha2A-ARs. This novel procedure should prove useful in the characterisation of psychoactive drugs which interact with alpha2-ARs.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2006

Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.

Organic cation transporters (OCTs) are polyspecific carriers implicated in low-affinity, corticosteroid-sensitive extraneuronal catecholamine uptake in peripheral tissues. The three main OCT subtypes, OCT1, OCT2 and OCT3, are also present in the brain, but their central role remains unclear. In the present study, we investigated by comparative in situ hybridization analysis the regional distribution of these transporters in rat brain and compared their functional properties in stably transfected HEK293 cells expressing human or rat OCTs. In rat brain, OCT2 and OCT3 mRNAs are expressed predominantly in regions located at the brain-cerebrospinal fluid border, with OCT3 mRNA expression extending to regions that belong to monoaminergic pathways such as raphe nuclei, striatum and thalamus. After normalization with MPP+ uptake, OCT2 and OCT3 subtypes share a similar monoamine preference profile, with higher transport efficacies for epinephrine and histamine than for the other monoamines. Interestingly, a significant level of epinephrine transport, previously only shown for rOCT2, is achieved by most OCTs subtypes. Finally, another novel finding was that OCTs are sensitive to 3,4-methylenedioxymetamphetamine (MDMA), phencyclidine (PCP), MK-801 and ketamine. Altogether, all our results suggest a functional specialization of OCT subtypes, based both on their intrinsic properties and their differential regional expression pattern in the brain.

Amphetamine↗

PubMed2006

The corticotropin-releasing factor (CRF)(1) receptor antagonists CP154,526 and DMP695 inhibit light-induced phase advances of hamster circadian activity rhythms.

The circadian activity of corticotropin releasing factor (CRF) and the hypothalamic-pituitary-adrenal axis is controlled by the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus. However, the reciprocal influence of CRF and the hypothalamic-pituitary-adrenal axis upon the circadian pacemaker is less well established. Therefore, in the present study, we tested two nonpeptidergic antagonists at CRF(1) receptors for their ability to modulate photic resetting of pacemaker time (phase). CP154,526 dose dependently and significantly inhibited light-induced phase advances in hamster circadian activity rhythms late in the subjective night by approximately 60% at a maximally effective dose of 20 mg/kg delivered intraperitoneally. Likewise, a further CRF(1) receptor antagonist, DMP695, inhibited phase advances by approximately 40% at a dose of 10 mg/kg. The attenuation of phase shifts by CP154,526 was specific to phase advances as light-induced phase delays of the circadian pacemaker achieved early in the subjective night were not affected by CP154,526 (20 mg/kg). We also tested one of the CRF(1) receptor antagonists for its potential ability to reset the pacemaker in the absence of light and found that CP154,526 did not elicit a nonphotic phase shifts in circadian activity rhythms at circadian times (CT) 2, 8, 14, 18, or 22. In conclusion, CRF(1) receptor antagonists selectively modulate the effect of light on the circadian pacemaker late at night. These novel data emphasize the suspected critical link between CRF and the hypothalamic-pituitary-adrenal axis, on the one hand, and stress (including stress caused by jet-lag) and depression on the other. These results also suggest that CRF(1) antagonists may not only improve affect but also counter the circadian disruption associated with depression and other stress-related disorders.

Animals↗

PubMed2006

Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.

Major depression is a debilitating and recurrent disorder with a substantial lifetime risk and a high social cost. Depressed patients generally display co-morbid symptoms, and depression frequently accompanies other serious disorders. Currently available drugs display limited efficacy and a pronounced delay to onset of action, and all provoke distressing side effects. Cloning of the human genome has fuelled expectations that symptomatic treatment may soon become more rapid and effective, and that depressive states may ultimately be "prevented" or "cured". In pursuing these objectives, in particular for genome-derived, non-monoaminergic targets, "specificity" of drug actions is often emphasized. That is, priority is afforded to agents that interact exclusively with a single site hypothesized as critically involved in the pathogenesis and/or control of depression. Certain highly selective drugs may prove effective, and they remain indispensable in the experimental (and clinical) evaluation of the significance of novel mechanisms. However, by analogy to other multifactorial disorders, "multi-target" agents may be better adapted to the improved treatment of depressive states. Support for this contention is garnered from a broad palette of observations, ranging from mechanisms of action of adjunctive drug combinations and electroconvulsive therapy to "network theory" analysis of the etiology and management of depressive states. The review also outlines opportunities to be exploited, and challenges to be addressed, in the discovery and characterization of drugs recognizing multiple targets. Finally, a diversity of multi-target strategies is proposed for the more efficacious and rapid control of core and co-morbid symptoms of depression, together with improved tolerance relative to currently available agents.

Adrenergic Uptake Inhibitors↗

PubMed2006

Antiparkinsonian effects of the novel D3/D2 dopamine receptor agonist, S32504, in MPTP-lesioned marmosets: Mediation by D2, not D3, dopamine receptors.

L-dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D3/D2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D2 vs. D3 receptors, an issue we addressed with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned nonhuman primate model of Parkinson's disease. In L-dopa-primed animals, S32504 (0.16-2.5 mg/kg p.o.) dose-dependently enhanced locomotor activity. This action was abolished by the D2 antagonist, L741,626 (2.5 mg/kg), but potentiated by the D3 antagonist, S33084 (0.63 mg/kg). Both antagonists were inactive alone. In drug-naive animals, a maximally effective dose of S32504 (2.5 mg/kg p.o.) displayed pronounced antiparkinsonian properties from the third day of administration, and its actions were expressed rapidly and durably. Thus, on day 33, antiparkinsonian properties of S32504 were apparent within 5 minutes and present for > 4 hours. Moreover, they were associated with neither wearing off nor significant dyskinesia. In conclusion, the novel D3/D2 agonist S32504 may offer advantages over L-dopa in the treatment of newly diagnosed parkinsonian patients. Its actions are expressed primarily by activation of D2, not D3, receptors.

Analysis of Variance↗

PubMed2006

Antidepressant-like properties of the anti-Parkinson agent, piribedil, in rodents: mediation by dopamine D2 receptors.

The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.

Aggression↗

PubMed2005

The selective tachykinin neurokinin 1 (NK1) receptor antagonist, GR 205,171, stereospecifically inhibits light-induced phase advances of hamster circadian activity rhythms.

Circadian rhythms in mammals are generated by master pacemaker cells located within the suprachiasmatic nucleus of the hypothalamus. In hamsters, the suprachiasmatic nucleus contains a small collection of cells immunoreactive for substance P, the endogenous ligand of tachykinin neurokinin 1 (NK1) receptors. In addition, two other nuclei which form part of the circadian system, the intergeniculate leaflet of the thalamus and the raphe nuclei, also contain fibers and/or cell bodies immunoreactive for substance P. In light of these observations, we evaluated the influence of the selective tachykinin NK1 receptor antagonist, GR 205,171, upon circadian activity rhythms in the hamster. Systemic injection of GR 205,171 dose-dependently (2.5-40.0 mg/kg, i.p.) inhibited light-induced phase advances in hamster circadian wheel running activity rhythms by approximately 50%. In contrast, GR 226,206, the less active enantiomer of GR 205,171, failed to affect light-induced phase advances. In addition, we examined the potential ability of GR 205,171 to induce non-photic phase shifts in hamster wheel running rhythms when injected at mid-day to late night circadian times. However, GR 205,171 (40 mg/kg) did not elicit non-photic phase shifts at these times indicating that tachykinin NK1 receptor antagonists are only effective when a light stimulus is applied to the pacemaker. Although GR 205,171 may, in theory, activate several sites within the circadian system, we suggest that GR 205,171 acts in the raphe nuclei to increase inhibitory serotonergic input to pacemaker cells in the suprachiasmatic nuclei, thereby suppressing photic modulation of the pacemaker. These findings have important implications for the use of tachykinin NK1 receptor antagonists in the treatment of depression and other central nervous system disorders.

Activity Cycles↗

PubMed2005

Stereoselective and region-specific induction of immediate early gene expression in rat parietal cortex by blockade of neurokinin 1 receptors.

Antagonists at neurokinin 1 (NK1) receptors are attracting attention as potential treatments for depressive states in light of their actions in behavioural models predictive of antidepressant properties, their modulation of corticolimbic monoaminergic transmission, and their influence upon neural plasticity. Here, we evaluated the influence of NK1 receptor blockade upon two immediate early genes, Arc and c-fos, implicated in mechanisms of synaptic plasticity. Administration of the selective NK1 receptor antagonist, GR 205,171 (40, but not 1, 5 or 10 mg/kg i.p.), elicited a pronounced elevation in mRNA encoding Arc in both outer and inner layers of the parietal cortex of rat brain. This action was region-specific inasmuch as Arc expression did not change in other cortical territories examined including frontal cortex, nor in CA1, CA3 and the dentate gyrus of the hippocampus. In comparison to GR 205,171, its less active isomer GR 226,206 (1-40 mg/kg) did not significantly modify Arc gene expression in parietal cortex or other cortical areas. GR 205,171 (40 mg/kg) also increased the abundance of c-fos mRNA in outer and inner parietal cortex and caused a corresponding increase in c-fos immunoreactivity in this region. GR 226,206 (40 mg/kg i.p.) had no effect on either c-fos mRNA or protein in parietal cortex. In conclusion, administration of GR 205,171 elicits a stereospecific increase in Arc and c-fos expression in rat parietal cortex but not in other cortical regions. These data suggest that the parietal cortex plays a role in the central actions of NK1 receptor antagonists.

Animals↗

PubMed2005

Acute administration of the novel serotonin and noradrenaline reuptake inhibitor, S33005, markedly modifies sleep-wake cycle architecture in the rat.

RATIONALE: The interrelationship between depressive states and sleep-wake cycle architecture is characterised by a decreased latency to the first paradoxical sleep (PS) episode, together with an enhancement of PS during the first part of the night. Conversely, slow-wave sleep (SWS) is decreased and intermittent awakenings increased. Notably, antidepressant treatment is generally associated with a diminution of PS. OBJECTIVES: In light of these observations, we examined the influence of acute administration of the novel mixed serotonin-noradrenaline reuptake blocker, (-)1-(1-dimethylaminomethyl 5-methoxybenzocyclobutan-1-yl)-cyclohexanol HCl (S33005), upon sleep-wake architecture in rats. METHODS: Animals were injected with vehicle or incremental doses of S33005 at the onset of either the dark or light periods. Digitised polygraphic recordings were performed, and changes evoked by S33005 were determined over 24-h recording periods, i.e., number and duration of sleep-wake episodes, latencies to PS and SWS, power band spectra of the electroencephalogram (EEG) and circadian changes. RESULTS: At 0.04 mg/kg, S33005 was inactive, whereas at 0.63 mg/kg, it modestly increased PS latencies and diminished PS duration during the light period. At 10 mg/kg, S33005 reduced markedly PS duration for about 4-h when injected prior to both light and dark periods. Latency to PS was prolonged, and the circadian acrophase was delayed. These effects are in keeping with previous studies of monoamine reuptake inhibitors, but, notably, SWS duration was increased when S33005 was injected at the onset of the light phase (+4%). These changes occurred without marked modifications in circadian rhythmicity or EEG spectral band power. Finally, even at the highest dose of S33005, only a limited rebound of SWS (+5%) and PS (+10%) was apparent. Amongst antidepressant to date examined, this is an original profile of influence upon sleep patterns. CONCLUSIONS: These results demonstrate a pattern of influence of S33005 upon sleep-wake architecture in rats which is globally consistent with antidepressant properties, but with a distinctive enhancement of restorative slow-wave sleep.

Adrenergic Agonists↗

PubMed2005

Dopamine D3 receptor antagonists as therapeutic agents.

The behavioral and pathophysiological role of the dopamine D(3) receptor, which was deduced from anatomical, lesion and drug treatment studies in the ten years following cloning of the receptor, indicated that its functions differed from those of the D(2) receptor. There is increasingly strong evidence that D(3) receptor antagonists will be effective antipsychotic agents. In this regard, an amelioration of the negative and cognitive symptoms of schizophrenia holds the most promise for D(3) receptor antagonists, a concept currently under clinical evaluation. In addition, D(3) receptors could be involved in behavioral sensitization and the potential application of D(3) receptor antagonists in the treatment of drug abuse is undergoing intensive experimental investigation.

Animals↗

PubMed2005

N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives.

RATIONALE: Activation of "co-agonist" N-methyl-D-aspartate (NMDA) and Glycine(B) sites is mandatory for the operation of NMDA receptors, which play an important role in the control of mood, cognition and motor function. OBJECTIVES: This article outlines the complex regulation of activity at Glycine(B)/NMDA receptors by multiple classes of endogenous ligand. It also summarizes the evidence that a hypoactivity of Glycine(B)/NMDA receptors contributes to the pathogenesis of psychotic states, and that drugs which enhance activity at these sites may possess antipsychotic properties. RESULTS: Polymorphisms in several genes known to interact with NMDA receptors are related to an altered risk for schizophrenia, and psychotic patients display changes in levels of mRNA encoding NMDA receptors, including the NR1 subunit on which Glycine(B) sites are located. Schizophrenia is also associated with an overall decrease in activity of endogenous agonists at Glycine(B)/NMDA sites, whereas levels of endogenous antagonists are elevated. NMDA receptor "open channel blockers," such as phencyclidine, are psychotomimetic in man and in rodents, and antipsychotic agents attenuate certain of their effects. Moreover, mice with genetically invalidated Glycine(B)/NMDA receptors reveal similar changes in behaviour. Finally, in initial clinical studies, Glycine(B) agonists and inhibitors of glycine reuptake have been found to potentiate the ability of "conventional" antipsychotics to improve negative and, albeit modestly, cognitive and positive symptoms. In contrast, therapeutic effects of clozapine are not reinforced, likely since clozapine itself enhances activity at NMDA receptors. CONCLUSIONS: Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at Glycine(B) sites may be of use as adjuncts to other classes of antipsychotic agent. However, there is an urgent need for broader clinical evaluation of this possibility, and, to date, there is no evidence that stimulation of Glycine(B) sites alone improves psychotic states.

Animals↗

PubMed2005

[Dopamine D3 receptors as a novel target for improving the treatment of schizophrenia].

Schizophrenia is a complex and serious disorder which affects some 0.5-1.0% of the population. The disease generally begins in adolescence. This early onset, together with the progressive and often irreversible nature of schizophrenia, account for its high social cost. Positive symptoms, such as hallucinations, are generally well-controlled by antipsychotics, whereas cognitive and deficit symptoms are poorly-treated. All antipsychotic agents, irrespective of their overall receptor-binding profiles, interact with dopaminergic mechanisms that are known to be perturbed in schizophrenic patients. Dopamine exerts its actions via five classes of receptor, offering a broad palette of targets for the conception of novel antipsychotic agents. The present article focuses on the relevance of dopamine D3 receptors to the aetiology and treatment of schizophrenia. Experimental studies suggest that, as compared to other drugs, antipsychotic agents which preferentially block D3 receptors may possess therapeutic advantages, notably in the control of cognitive symptoms. The first clinical studies for the evaluation of this hypothesis have recently got underway.

Humans↗

PubMed2004

Quantification and pharmacological characterization of dialysate levels of noradrenaline in the striatum of freely-moving rats: release from adrenergic terminals and modulation by alpha2-autoreceptors.

Information concerning striatal levels of noradrenaline (NA) remains inconsistent. Here we have addressed this issue using a sensitive method of HPLC coupled to amperometric detection. The NA reuptake-inhibitor, reboxetine, selectively elevated levels of NA versus dopamine (DA), and NA levels were also selectively elevated by the alpha2-adrenoceptor (AR) antagonist, atipamezole. The actions of atipamezole were mimicked by the preferential alpha2A-AR antagonist, BRL44408, while JO-1 and prazosin, preferential antagonists at alpha2C-ARs, caused less marked elevations in NA levels. In contrast to antagonists, the alpha2-AR agonist, S18616, decreased NA levels and likewise suppressed those of DA. Unilateral lesions of the substantia nigra with 6-hydroxydopamine depleted DA levels without affecting those of NA. Further, the D3/D2 receptor agonist, quinelorane, decreased levels of DA without modifying those of NA. However, the D3/D2 receptor antagonists, haloperidol and raclopride, and the DA reuptake-inhibitor, GBR12935, elevated levels of both DA and NA. Levels of 5-HT (but not of NA or DA) were increased only by the 5-HT reuptake-inhibitor, citalopram. They were decreased by S18616 and prazosin, reflecting the inhibitory and excitatory influence of alpha2- and alpha1-ARs, respectively, upon serotonergic pathways. In conclusion, NA in the striatum is derived from adrenergic terminals. Its release is subject to tonic, inhibitory control by alpha2-ARs, possibly involving both alpha2A- and alpha2C-AR subtypes, though their respective contribution requires clarification. A role of dopaminergic terminals in the reuptake of NA likely explains the elevation in its levels elicited by DA reuptake-inhibitors and D3/D2 receptor antagonists.

Adrenergic Uptake Inhibitors↗