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Biomedical subjects

M J Millan

Publications and source records attributed to M J Millan.

At least 73 records · Page 4Linked to original sources
PubMed2000

S18616, a highly potent, spiroimidazoline agonist at alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine.

S18616 ((S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4, 2'-(8'-chloro-1',2',3',4'-tetrahydronaphthalene)]) displayed high affinity at native rat alpha(2)-adrenoceptors (AR)s (pK(i), 9.8), native human (h)alpha(2A)-ARs (9.6), and cloned halpha(2A)- (9.5), halpha(2B)- (9.2), and halpha(2C)- (9.0) ARs. It showed 40-fold lower affinity for halpha(1A)-ARs (8.4) and >/=100-fold lower affinity for rat alpha(1)-ARs (7.1), halpha(1B)-ARs (7.7), halpha(1D)-ARs (7.6), imidazoline(1) (7.4), and imidazoline(2) (7.4) sites and >100-fold lower affinity for all other (>50) sites. At halpha(2A)-ARs, in guanosine-5'-O-(3-[(35)S]thio)triphosphate binding studies, S18616 was a potent (partial) agonist: log effective concentration (pEC(50)), 9.3/maximal effect, 51%. This observation was corroborated employing a halpha(2A)-Gi1alpha fusion protein/GTPase assay (9.0/40%) in which the actions of S18616 were blocked by pertussis toxin. Employing guanosine-5'-O-(3-[(35)S]thio)triphosphate binding assays, S18616 was also a partial agonist at halpha(2C)-ARs (8.2/63%) but a full agonist (8.4/124%) at halpha(2B)-ARs. At halpha(2A)-, halpha(2B)-, and halpha(2C)-ARs, the selective alpha(2)-AR antagonist, atipamezole, abolished the actions of S18616: pK(b) values of 9.1, 9. 1, and 9.4, respectively. As determined by depletion of membrane-bound [(3)H]phosphatidyl inositols, S18616 behaved as a (less potent) agonist (7.8/79%) at halpha(1A)-ARs, an action abolished by prazosin (pK(b), 8.9). Reflecting alpha(2)-AR agonist properties, S18616 potently (>/=1 microg/kg, s.c.) and dose dependently elicited hypothermia and antinociception (nine diverse models) in rodents. These actions were dose dependently inhibited by chemically diverse alpha(2)- versus alpha(1)-AR antagonists, atipamezole, idazoxan, RX821,002, and BRL44418 (a preferential alpha(2A)-AR ligand). In contrast, the actions of S18616 were unaffected by the alpha(1)-AR antagonists, ARC239 and prazosin (which preferentially block alpha(2B/2C)- versus alpha(2A)-ARs). Although the affinity of dexmedetomidine at alpha(2)-ARs was lower than S18616; it displayed a similar receptor and functional profile. Clonidine displayed lower efficacy than S18616, was substantially less potent, and had marked affinity for imidazoline(1) sites and alpha(1)-ARs. In conclusion, S18616 is a novel, selective, and highly potent agonist at alpha(2)-ARs.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2000

S18616, a highly potent spiroimidazoline agonist at alpha(2)-adrenoceptors: II. Influence on monoaminergic transmission, motor function, and anxiety in comparison with dexmedetomidine and clonidine.

The alpha(2)-adrenoceptor (AR) agonist, S18616 ((S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(8'-chloro-1' , 2',3',4'-tetrahydronaphthalene)] accompanying article), suppressed electrical activity of adrenergic neurons in the locus ceruleus, an action reversed by the alpha(2)-AR antagonist, idazoxan, which itself enhanced their firing rate. Electrical activity of serotonergic neurons in the dorsal raphe nucleus was similarly suppressed, an action likewise blocked by idazoxan, which did not, itself, influence firing. In freely moving rats, S18616 decreased extracellular levels of norepinephrine (NE), serotonin (5-HT), and dopamine (DA) in frontal cortex and hippocampus. The selective alpha(2)- versus alpha(1)-AR antagonists, atipamezole and BRL-44408 (a preferential alpha(2A)-AR antagonist), elevated levels of NE and DA but not 5-HT. In their presence, the influence of S18616 on frontocortical levels of NE, DA, and 5-HT was blocked. In contrast, prazosin, a selective alpha(1)- versus alpha(2)-AR antagonist (which also preferentially blocks alpha(2B/2C)-ARs) dose dependently decreased levels of 5-HT, but not NE and DA, and failed to modify the actions of S18616. Ultrasonic vocalizations elicited by rats in an aversive environment were inhibited by S18616, which also suppressed aggressive and marble-burying behaviors in mice. Furthermore, S18616 (biphasically) enhanced punished responses in the Vogel conflict test and active social interaction tests in rats. At higher doses, S18616 displayed sedative/hypnotic properties. Both anxiolytic and motor actions of S18616 were inhibited by atipamezole and BRL-44408 but not prazosin. Dexmedetomidine mimicked the actions of S18616 at higher doses except for more potent sedative/hypnotic properties. Clonidine also mimicked S18616, but only at markedly higher doses. In conclusion, via activation of alpha(2)-ARs, S18616 potently inhibits corticolimbic adrenergic, serotonergic, and (frontocortical) dopaminergic transmission in parallel with the expression of its anxiolytic and sedative properties.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1999

The 5HT(1A) receptor ligand, S15535, antagonises G-protein activation: a [35S]GTPgammaS and [3H]S15535 autoradiography study.

4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine (S15535) is a highly selective ligand at 5-HT(1A) receptors. The present study compared its autoradiographic labelling of rat brain sections with its functional actions, visualised by guanylyl-5'-[gamma-thio]-triphosphate ([35S]GTPgammaS) autoradiography, which affords a measure of G-protein activation. [3H]S15535 binding was highest in hippocampus, frontal cortex, entorhinal cortex, lateral septum, interpeduncular nucleus and dorsal raphe, consistent with specific labelling of 5-HT(1A) receptors. In functional studies, S15535 (10 microM) did not markedly stimulate G-protein activation in any brain region, but abolished the activation induced by the selective 5-HT(1A) agonist, (+)-8-hydroxy-dipropyl-aminotetralin ((+)-8-OH-DPAT, 1 microM), in structures enriched in [3H]S15535 labelling. S15535 did not block 5-HT-stimulated activation in caudate nucleus or substantia nigra, regions where (+)-8-OH-DPAT was ineffective and [3H]S15535 binding was absent. Interestingly, S15535 attenuated (+)-8-OH-DPAT and 5-HT-stimulated G-protein activation in dorsal raphe, a region in which S15535 is known to exhibit agonist properties in vivo [Lejeune, F., Millan, M.J., 1998. Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)(1A) receptors: WAY100,635-reversible actions of the highly selective ligands, flesinoxan and S15535. Synapse 30, 172-180.]. The present data show that (i) [3H]S15535 labels pre- and post-synaptic populations of 5-HT(1A) sites in rat brain sections, (ii) S15535 exhibits antagonist properties at post-synaptic 5-HT(1A) receptors in corticolimbic regions, and (iii) S15535 also attenuates agonist-stimulated G-protein activation at raphe-localised 5-HT(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Citalopram elicits a discriminative stimulus in rats at a dose selectively increasing extracellular levels of serotonin vs. dopamine and noradrenaline.

Citalopram (2.5 mg/kg, i.p.) increased (+145-+180%) extracellular levels of serotonin (5-hydroxytryptamine, 5-HT) in the frontal cortex, nucleus accumbens and striatum of freely-moving rats, whereas dopamine and noradrenaline were unaffected. At this dose, employing a two-lever, food-reinforced, drug discrimination procedure, citalopram generated reliable recognition and fully (> 80%) generalized to itself with an Effective Dose50 (ED50) of 0.1 mg/kg, s.c. Two further selective 5-HT reuptake inhibitors, sertraline and paroxetine, fully generalized with ED50s of 0.01 and 0.04 mg/kg, s.c., respectively. In contrast, the anxiolytic, diazepam (0.63), and the antipsychotic, clozapine (2.5), did not (< or = 20%) generalize. In conclusion, the selective 5-HT reuptake inhibitor, citalopram, elicits a pharmacologically-specific discriminative stimulus in rats at a dose selectively elevating extracellular concentrations of 5-HT.

Animals↗
PubMed1999

Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors.

Roxindole is a potential antidepressant agent. The present study determined its affinity and agonist efficacy at recombinant human (h) dopamine hD2, hD3 and hD4 and serotonin (5-HT) h5-HT1A, h5-HT1B and h5-HT1D receptors. Roxindole exhibited high affinity at hD3 as well as at hD2 (short isoform) and hD4 (4-repeat isoform) receptors (pKi values 8.93, 8.55 and 8.23, respectively). Further, it displayed high affinity at hS-HT1A receptors (pKi = 9.42) but modest affinity at 5-HT1B and 5-HT1D receptors (pKi values 6.00 and 7.05, respectively). In [35S]GTPgammaS binding experiments, roxindole was >20-fold more potent in stimulating [35S]GTPgammaS binding at hD3 than at hD2 or hD4 receptors (pEC50 = 9.23 vs. 7.88 and 7.69). However, whereas roxindole exhibited partial agonist activity at hD3 and hD4 sites (Emax = 30.0% and 35.1%, respectively, relative to dopamine = 100%), it only weakly activated hD2 receptors (Emax = 10.5%). Roxindole potently blocked dopamine-stimulated [35S]GTPgammaS binding at hD2 receptors (pkappaB = 9.05). In comparison, the dopamine receptor agonist, (-)quinpirole, acted as a partial agonist at hD3 and hD4 sites (Emax = 67.4% and 66.3%, respectively) but surpassed the efficacy of dopamine at hD2 receptors (Emax = 132%). At h5-HT1A receptors, roxindole behaved as a high affinity (pKi = 9.42) partial agonist (Emax = 59.6%, relative to 5-HT = 100%), whereas (-)quinpirole had negligible activity. The selective 5-HT1A antagonist, WAY 100,635, blocked roxindole (100 nM)-stimulated [35S]GTPgammaS binding at h5-HT1A receptors in a concentration-dependent manner (pkappaB = 9.28). Roxindole only weakly stimulated [35S]GTPgammaS binding at 5-HT1B and 5-HT1D receptors (Emax = 27.1% and 13.7%). The present data suggest that roxindole activates mainly D3 vs. D2 or D4 receptors and 5-HT1A vs. 5-HT1B or 5-HT1D receptors. Activation of D3 and/or 5-HT1A receptors may thus contribute to its potential antidepressant properties.

Adenylyl Cyclase Inhibitors↗
PubMed1999

5-HT2C receptors are involved in the discriminative stimulus effects of citalopram in rats.

Rats were trained on a fixed ratio 10, food-reinforced schedule to recognize a discriminative stimulus (DS) elicited by the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram (2.5 mg/kg, IP). The preferential, high efficacy agonist at 5-HT2C receptors, Ro60-0175, dose-dependently generalized to citalopram with an ED50 of 0.3 mg/kg, IP. Further, the selective 5-HT2C receptor antagonist, SB242,084, dose-dependently (ED50=0.1 mg/kg, IP) blocked the citalopram DS. These data suggest that 5-HT2C receptors are involved in the DS properties of the SSRI, citalopram, in rats. They do not, however, exclude a potential role of other 5-HT receptor types.

Animals↗
PubMed1999

Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats.

The 5-HT2 receptor agonist, DOI, dose-dependently (0.16-10.0 mg/kg, s.c.) increased dialysate levels of dopamine (DA) and noradrenaline (NA), but not 5-HT, in the frontal cortex (FCX) of freely-moving rats. This action was abolished by the selective 5-HT2A antagonist, MDL100,907 (0.04), which did not, itself, modify levels of DA and NA. In contrast, the selective 5-HT2B/2C antagonist, SB206,553 (0.63), increased levels of DA and NA additively with DOI. Thus, in contrast to a tonic, inhibitory influence of 5-HT2C receptors (see Millan, M.J., Dekeyne, A., Gobert, A., 1998. Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NAD), but not 5-HT, release in the FCX in vivo. Neuropharmacology 37, 953-955), 5-HT2A receptors exert a phasic, facilitatory influence upon FCX levels of DA and NA.

Amphetamines↗
PubMed1999

Discriminative stimulus properties of the novel serotonin (5-HT)2C receptor agonist, RO 60-0175: a pharmacological analysis.

Employing a Fixed-Ratio 10, food-reinforced protocol, rats were trained to recognize the discriminative stimulus (DS) properties of the novel, potent, 5-HT2C agonist, Ro 60-0175 (2.5 mg/kg, i.p.). This schedule generated appropriate drug versus vehicle responding after 50 + 5 training sessions and Ro 60-0175 elicited full (100%) drug selection with an effective dose50 (ED50) of 0.6 mg/kg, i.p.. The 5-HT2C receptor agonists, mCPP and MK 212, fully generalized to Ro 60-0175 with ED50s of 0.8 and 0.4 mg/kg, s.c., respectively, whereas the preferential 5-HT2B agonist, BW 723C86 ( > 10.0 mg/kg, s.c.) and the 5-HT2A agonist, DOI ( > 2.5 mg/kg, s.c.), were ineffective. The 5-HT2A/2B/2C receptor antagonist, mianserin, dose-dependently blocked the DS properties of Ro 60-0175 with an ED50 of 0.7 mg/kg, s.c. This action was mimicked by the novel, 5-HT2B/2C antagonist, SB 206,553 (ED50 = 0.3 mg/kg, s.c.), whereas the selective 5-HT2A antagonist, MDL 100,907 ( > 0.63 mg/kg, s.c.), was ineffective. Further, the selective 5-HT2C antagonist, SB 242,084, dose-dependently and fully blocked drug selection (ED50 = 0.2 mg/kg, i.p.), whereas the selective 5-HT2B antagonist, SB 204,741, was not active ( > 0.63 mg/kg, i.p.). In conclusion, these data demonstrate that Ro 60-0175 generates a robust DS and suggest that activation of 5-HT2C receptors is the principal mechanism underlying its DS properties.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

(-)-Pindolol increases dialysate concentrations of dopamine and noradrenaline, but not serotonin, in the frontal cortex of freely-moving rats.

(-)-Pindolol (2.5-20.0 mg/kg, s.c.) markedly increased extracellular levels of dopamine (DA) and noradrenaline (NA) in single dialysate samples of the frontal cortex (FCX) of freely-moving rats. This action was specific inasmuch as serotonin (5-HT) levels were not significantly modified. In contrast, (-)-propranolol (2.5) did not modify FCX dialysate levels of DA, NA (or 5-HT) alone and abolished the facilitatory influence of (-)-pindolol (10.0) upon levels of DA, though not NA. In contrast to (-)-propranolol, (-)-pindolol exerts, a facilitatory influence upon frontocortical dopaminergic and adrenergic, but not serotonergic, transmission.

Animals↗
PubMed1999

The induction of pain: an integrative review.

The highly disagreeable sensation of pain results from an extraordinarily complex and interactive series of mechanisms integrated at all levels of the neuroaxis, from the periphery, via the dorsal horn to higher cerebral structures. Pain is usually elicited by the activation of specific nociceptors ('nociceptive pain'). However, it may also result from injury to sensory fibres, or from damage to the CNS itself ('neuropathic pain'). Although acute and subchronic, nociceptive pain fulfils a warning role, chronic and/or severe nociceptive and neuropathic pain is maladaptive. Recent years have seen a progressive unravelling of the neuroanatomical circuits and cellular mechanisms underlying the induction of pain. In addition to familiar inflammatory mediators, such as prostaglandins and bradykinin, potentially-important, pronociceptive roles have been proposed for a variety of 'exotic' species, including protons, ATP, cytokines, neurotrophins (growth factors) and nitric oxide. Further, both in the periphery and in the CNS, non-neuronal glial and immunecompetent cells have been shown to play a modulatory role in the response to inflammation and injury, and in processes modifying nociception. In the dorsal horn of the spinal cord, wherein the primary processing of nociceptive information occurs, N-methyl-D-aspartate receptors are activated by glutamate released from nocisponsive afferent fibres. Their activation plays a key role in the induction of neuronal sensitization, a process underlying prolonged painful states. In addition, upon peripheral nerve injury, a reduction of inhibitory interneurone tone in the dorsal horn exacerbates sensitized states and further enhance nociception. As concerns the transfer of nociceptive information to the brain, several pathways other than the classical spinothalamic tract are of importance: for example, the postsynaptic dorsal column pathway. In discussing the roles of supraspinal structures in pain sensation, differences between its 'discriminative-sensory' and 'affective-cognitive' dimensions should be emphasized. The purpose of the present article is to provide a global account of mechanisms involved in the induction of pain. Particular attention is focused on cellular aspects and on the consequences of peripheral nerve injury. In the first part of the review, neuronal pathways for the transmission of nociceptive information from peripheral nerve terminals to the dorsal horn, and therefrom to higher centres, are outlined. This neuronal framework is then exploited for a consideration of peripheral, spinal and supraspinal mechanisms involved in the induction of pain by stimulation of peripheral nociceptors, by peripheral nerve injury and by damage to the CNS itself. Finally, a hypothesis is forwarded that neurotrophins may play an important role in central, adaptive mechanisms modulating nociception. An improved understanding of the origins of pain should facilitate the development of novel strategies for its more effective treatment.

Animals↗
PubMed1999

Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin1A receptors and blockade of alpha2-adrenergic receptors underlie its actions.

The serotonin1A receptor partial agonist, buspirone, also displays antagonist properties at D2 receptors and is metabolized to the alpha2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine). Herein, we examined mechanisms underlying the influence of buspirone alone, and in association with the serotonin reuptake inhibitor, fluoxetine, upon extracellular levels of serotonin, dopamine and noradrenaline simultaneously quantified in the frontal cortex of freely moving rats. Buspirone (0.01-2.5 mg/kg, s.c.) dose-dependently decreased dialysate levels of serotonin (-50%), and increased those of dopamine (+100%) and noradrenaline (+140%). The reduction by buspirone of serotonin levels was abolished by the serotonin1A receptor antagonist, WAY 100,635 (0.16), which did not, however, modify its influence upon dopamine and noradrenaline. In contrast to buspirone, the serotonin reuptake inhibitor, fluoxetine (10.0), increased frontocortical levels of serotonin (+ 120%), dopamine (+55%) and noradrenaline (+90%). Buspirone dose-dependently (0.01-2.5) decreased the induction by fluoxetine of serotonin levels yet potentiated (three-fold) its elevation of dopamine and noradrenaline levels. The serotonin1A agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (0.16), mimicked the action of buspirone in reducing resting levels of serotonin (-60%) and in enhancing those of dopamine (+135%) and noradrenaline (+165%). Like buspirone, it attenuated the influence of fluoxetine upon serotonin levels, yet facilitated its influence upon dopamine and noradrenaline levels. In contrast, WAY 100,635 selectively potentiated the increase in levels of serotonin (two-fold) versus dopamine and noradrenaline elicited by fluoxetine. Further, WAY 100,635 abolished the inhibitory influence of buspirone upon fluoxetine-induced serotonin release, but only partly interfered with its potentiation of fluoxetine-induced increases in dopamine and noradrenaline levels. The D2/D3 receptor antagonist, raclopride (0.16), increased basal dopamine (+60%) levels but little influenced those of serotonin and noradrenaline, and failed to modify the action of fluoxetine. The alpha2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine) (2.5), which did not modify resting levels of serotonin, markedly increased those of dopamine (+90%) and noradrenaline (+190%) and potentiated (two-fold) the increases in dialysate levels of dopamine, noradrenaline and serotonin provoked by fluoxetine. Further, the alpha2-adrenergic receptor agonist, S18616, attenuated the enhancement by buspirone of the fluoxetine-induced increase in levels of dopamine and noradrenaline. In conclusion, the inhibitory influence of buspirone upon resting and fluoxetine-stimulated serotonin levels reflects its agonist properties at serotonin1A autoreceptors. The facilitatory influence of buspirone upon resting and fluoxetine-stimulated dopamine and noradrenaline levels may also involve its serotonin1A properties. However, its principal mechanism of action in this respect is probably the alpha2-adrenergic antagonist properties of its metabolite, 1-(2-pyrimidinyl-piperazine). The present observations are of significance to experimental and clinical studies of the influence of buspirone upon depressive states, alone and in association with antidepressant agents.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Inverse agonists and serotonergic transmission: from recombinant, human serotonin (5-HT)1B receptors to G-protein coupling and function in corticolimbic structures in vivo.

The concept of inverse agonism, whereby "antagonists" exert actions opposite to those of agonists at constitutively active receptors, has been documented both at receptor-modulated ion channels as well as at G-protein-coupled receptors (GPCR) in recombinant expression systems. However, it remains unclear whether physiologically or therapeutically relevant inverse agonists actions at GPCRs occur in the CNS in vivo. The present overview discusses our recent observations concerning 5-HT1B receptors, and focuses on the relationship between actions at heterologous Chinese hamster ovary (CHO) expression systems compared with native CNS populations of receptors. To this end, we have exploited several novel and selective ligands, notably the inverse agonist and neutral antagonist at 5-HT1B receptors, SB224,289 and S18127, respectively. Like 5-HT itself, the agonist, GR46611, markedly increases the binding of [35S]-GTP gamma S binding to h5-HT1B receptors expressed in CHO cells, while the "antagonist", GR127,935, modestly stimulates binding suggesting partial agonist properties. However, SB224,289 markedly suppresses binding at these sites. S18127, which does not alter [35S]GTP gamma S binding alone, abolishes the actions of both GR46611 and SB224,289. Nevertheless, in quantitative autoradiographical studies, S18127 and SB224,289 cannot be distinguished as concerns modulation of [35S]-GTP gamma S binding at substantia nigra and caudate nucleus-localized 5-HT1B receptors, inasmuch as they each block the action of the 5-HT1B agonist, CP93129, yet fail to modify binding alone. Further, S18217 and SB224,289, as well as GR127,935, all abolish the inhibitory influence of GR46611 upon dialysis levels of 5-HT in the frontal cortex of freely moving rats without themselves modifying release. Moreover, they all block the hypothermic actions of GR46611 without themselves modifying core temperature. Thus, differences in intrinsic activity of S18127, SB224,289 and GR127,935 seen at cloned, h5-HT1B receptors cannot be detected in vivo. Most notably, no evidence for opposite actions of the inverse agonist, SB224,289, as compared to 5-HT1B agonists is apparent. These data suggest that in vitro observations of inverse agonist actions cannot necessarily be extrapolated to intact systems in vivo.

Animals↗
PubMed1999

Modulation of dialysate levels of dopamine, noradrenaline, and serotonin (5-HT) in the frontal cortex of freely-moving rats by (-)-pindolol alone and in association with 5-HT reuptake inhibitors: comparative roles of beta-adrenergic, 5-HT1A, and 5-HT1B receptors.

(-)-Pindolol, which possesses significant affinity for 5-HT1A, 5-HT1B, and beta 1/2-adrenergic receptors (AR)s, dose-dependently increased extracellular levels of dopamine (DA) and noradrenaline (NAD) versus 5-HT, in dialysates of the frontal cortex (FCX), but not accumbens and striatum, of freely-moving rats. In distinction, the preferential beta 1-AR antagonist, betaxolol, and the preferential beta 2-AR antagonist, ICI118,551, did not increase basal levels of DA, NAD, or 5-HT. Further, they both dose-dependently and markedly blunted the influence of (-)-pindolol upon DA and NAD levels. The selective 5-HT1A receptor antagonist, WAY100,635, slightly attenuated the (-)-pindolol-induced increase in DA and NAD levels, while the selective 5-HT1B antagonist, SB224,289, was ineffective. These data suggest that (-)-pindolol facilitates frontocortical dopaminergic (and adrenergic) transmission primarily by activation of beta 1/2-ARs and, to a lesser degree, by stimulation of 5-HT1A receptors, whereas 5-HT1B receptors are not involved. (-)-Pindolol potentiated the increase in FCX levels of 5-HT elicited by the 5-HT reuptake inhibitors, fluoxetine and duloxetine, and also enhanced their ability to elevate FCX levels of DA--though not of NAD. In contrast to (-)-pindolol, betaxolol and ICI118,551 did not affect the actions of fluoxetine, whereas both WAY100,635 and SB224,289 potentiated the increase in levels of 5-HT--but not DA or NAD levels--elicited by fluoxetine. In conclusion, (-)-pindolol modulates, both alone and together with 5-HT reuptake inhibitors, dopaminergic, adrenergic, and serotonergic transmission in the FCX via a complex pattern of actions at beta 1/2-ARs, 5-HT1A, and 5-HT1B receptors. These findings have important implications for clinical studies of the influence of (-)-pindolol upon the actions of antidepressant agents.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Contrasting EEG profiles elicited by antipsychotic agents in the prefrontal cortex of the conscious rat: antagonism of the effects of clozapine by modafinil.

1. Power spectra (0-30 Hz) were recorded from transcortical electrodes implanted in prefrontal and sensorimotor cortex in conscious rats. For each animal, the spectra in the presence of a drug were divided by the spectra in the presence of vehicle to give a drug-related differential display of the power spectra, the profile of EEG effects. 2. The profiles of a range of antipsychotic agents of different classes were compared. Haloperidol (0.5 mg kg-1 and 1 mg kg-1 s.c., peak 8 - 12 Hz), chlorpromazine (0.5 mg kg-1, i. p., peak 8 Hz), levomepromazine (1 mg kg-1, i.p., peak 8 Hz), quetiapine (2.5 mg kg-1, s.c., peak 9 - 12 Hz), sertindole (2.5 mg kg-1, s.c., peak 6 - 14 Hz), risperidone (0.5 and 1 mg kg-1 i.p., peak 9 Hz), clozapine (0.1, 0.2, 0.3 and 5 mg kg-1, s.c., peak 8 Hz) and MDL100907 (0.01 mg kg-1 s.c. peak 2 Hz) synchronized the EEG, increasing the power spectra between 2 and 30 Hz, although there were marked differences between the individual profile of EEG effects for each drug. 3. In contrast, the benzamides, sulpiride (7.5 and 15 mg kg-1 i.p.), and amisulpiride (1 and 15 mg kg-1 i.p.) caused marked asynchronous changes in the EEG. Raclopride (2.5 mg kg-1 i.p.), caused an initial peak at 9 Hz, but the effects of raclopride desynchronized over a 3 h time period. 4 Modafinil and apomorphine, administered alone, decreased the power spectra at frequencies higher than 4. Hz. Modafinil (62.4 mg kg-1, i.p.) selectively antagonized the effects of clozapine, but did not antagonize the effects of raclopride. 5. Different pharmacological classes of antipsychotic show synchronization or desynchronization of the EEG in the prefrontal cortex, with the benzamides showing a distinctive spectrum. There appears to be a specific interaction between modafinil and clozapine. Thus, modulation of prefrontal cortical function, perhaps by thalamic gating, may be important for antipsychotic activity.

Animals↗
PubMed1999

Changes in EEG spectral power in the prefrontal cortex of conscious rats elicited by drugs interacting with dopaminergic and noradrenergic transmission.

1. The electroencephalographic (EEG) effects of drugs interacting with dopaminergic and noradrenergic systems were studied in conscious rats. Power spectra (0 - 30 Hz) were recorded from electrodes implanted bilaterally in the prefrontal cortex. Drug effects on EEG power were calculated as the spectral power following drug administration divided by the spectral power after vehicle administration. 2. Dopaminergic agonists at low doses, (apomorphine 0. 01 mg kg-1 s.c., quinpirole 0.01 mg kg-1 i.p.) and dopaminergic antagonists (haloperidol 1 mg kg-1 i.p., raclopride 2.5 mg kg-1 s.c. ), which decrease dopaminergic transmission, induced an increase of EEG power. Conversely, dopaminergic agonists at higher doses (apomorphine 0.5 mg kg-1 s.c., quinpirole 0.5 mg kg-1 i.p.) which increase activation of postsynaptic D2 and D3 receptors, induced a decrease of EEG power. 3. The alpha1-adrenoceptor antagonists (phenoxybenzamine 0.64 mg kg-1 s.c., prazosin 0.32 mg kg-1 s.c.) and the alpha2-adrenoceptor agonists (UK 14304 0.05 mg kg-1 s.c., clonidine 0.025 mg kg-1 i.p.), which decrease noradrenergic transmission, induced an increase of EEG power. Conversely, the alpha1-adrenoceptor agonist, cirazoline (0.05 mg kg-1 s.c.), the adrenergic agent modafinil (250, 350 mg kg-1 i.p.) and alpha2-adrenoceptor antagonists (RX 821002 0.01 mg kg-1 s.c., yohimbine 0.5 mg kg-1 i.p.), which increase noradrenergic transmission, induced a decrease of EEG power. The effects of prazosin (0.64 mg kg-1 s.c.) were dose-dependently antagonized by co-administration with modafinil and cirazoline, but not by apomorphine. 4. In conclusion, pharmacological modulation of dopaminergic and noradrenergic transmission may result in consistent EEG changes: decreased dopaminergic or noradrenergic activity induces an increase of EEG spectral power; while increased dopaminergic or noradrenergic activity decreases EEG spectral power.

Adrenergic Agents↗
PubMed1999

S 15535, a benzodioxopiperazine acting as presynaptic agonist and postsynaptic 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal scopolamine.

1 The effect of S 15535 (4-benzodioxan-5-yl)1-(indan-2-yl)piperazine), an agonist at presynaptic and antagonist at postsynaptic 5-HT1A receptors, on the impairment of spatial learning caused by intrahippocampal scopolamine in a two-platform spatial discrimination task was studied. 2 Scopolamine (4.0 microg microl-1), injected bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, impaired choice accuracy with no effect on choice latency and errors of omission. 3 Administered subcutaneously 30 min before each training session, S 15535 1.0 (but not 0.3) mg kg-1 did not modify choice accuracy but prevented its impairment by intrahippocampal scopolamine. 4 WAY 100635, a 5-HT1A receptor antagonist, injected into the dorsal raphe at 1.0 microg 0.5 microl-1 5 min before scopolamine, had no effect on choice accuracy and latency or errors of omission and did not modify the effect of scopolamine but completely antagonized the effect of S 15535 (1.0 mg kg-1) on scopolamine-induced impairment of choice accuracy. 5 The results confirm a previous report (Carli et al., 1998) that stimulation of presynaptic 5-HT1A receptors in the dorsal raphe counteracts the deficit caused by intrahippocampal scopolamine, probably by facilitating the transfer of facilitatory information from the entorhinal cortex to the hippocampus. 6 Drugs that stimulate action on presynaptic 5-HT1A receptors, such as S 15535 and other partial 5-HT1A receptors agonists, may be useful in the symptomatic treatment of human memory disturbances associated with loss of cholinergic innervation to the hippocampus.

Animals↗
PubMed1999

Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites for PCP-induced locomotion in the rat.

In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP-induced locomotion (PLOC) was potently blocked by the selective serotonin (5-HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra-accumbens PCP, but not intra-accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.

Amphetamine↗