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1.
Neurology ; 49(1 Suppl 1): S58-62, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9222275

ABSTRACT

The use of dopamine agonists as monotherapy or in combination with levodopa in the treatment of Parkinson's disease (PD) allows for reduction or limitation of the levodopa dose, potentially delaying the onset or reducing the severity of late motor complications. Ropinirole is a new nonergoline dopamine agonist that binds specifically to D2-like receptors with a selectivity similar to that of dopamine (D3 > D2 > D4). The chemical structure of ropinirole has the potential to maintain a structure-activity relationship similar to that of dopamine and other effective dopamine agonists without producing ergot-related adverse effects. Ropinirole has demonstrated efficacy in two standard preclinical models of PD and has shown a very low propensity to induce dyskinesia in these studies. This latter property is of potential clinical importance for pharmacotherapy of early PD. This article will present the importance of pharmacologic specificity of dopamine agonists along with the basic pharmacologic characteristics of ropinirole that may contribute to its efficacy in the treatment of PD.


Subject(s)
Antiparkinson Agents/therapeutic use , Dopamine Agonists/therapeutic use , Indoles/therapeutic use , Parkinson Disease/drug therapy , Animals , Humans
2.
J Neurosci Methods ; 72(2): 147-51, 1997 Apr 04.
Article in English | MEDLINE | ID: mdl-9133578

ABSTRACT

In vitro receptor autoradiography is a widely used technique for determining the distribution of radioligand binding sites. By using this technique it is possible to investigate alterations in receptor number and affinity caused by trauma or a disease state. To date, however, the largest sections prepared for in vitro autoradiography have been from single human hemispheres, with the adjacent hemisphere being used for neuropathological investigations. Therefore, a method for cutting large cryosections of human whole brain tissue is described. Whole brains obtained less than 2 days postmortem were frozen at -80 degrees C. 1.5-2 cm coronal slices were cut from the brain and embedded and frozen in a carboxymethylcellulose solution. Sections 40 microm in size were sliced from the frozen block at -16 degrees C in a whole body cryostat. The sections were lifted by means of a nylon membrane backing material and subsequently incubated with tritiated ligand to produce autoradiograms of each whole brain coronal section. [(3)H]paroxetine was used in the present study as an example.


Subject(s)
Autoradiography/methods , Brain Chemistry , Microtomy/methods , Tissue Embedding/methods , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Paroxetine , Radioligand Assay , Selective Serotonin Reuptake Inhibitors , Tritium
3.
Neuropharmacology ; 33(12): 1581-8, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7760981

ABSTRACT

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT2C/5-HT2B receptors was assessed using a putative in vivo model of 5-HT2C/5-HT2B receptor function, mCPP-induced hypolocomotion. mCPP (2, 4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily x 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily x 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o. daily x 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT2C/5-HT2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.


Subject(s)
Norepinephrine/metabolism , Receptors, Serotonin/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Clomipramine/pharmacology , Desipramine/pharmacology , Fluoxetine/pharmacology , Male , Motor Activity/drug effects , Paroxetine/pharmacology , Piperazines/metabolism , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/physiology , Time Factors
4.
Pharmacol Biochem Behav ; 49(2): 281-5, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7824539

ABSTRACT

The effects of short- and long-term administration of the selective serotonin reuptake inhibitor paroxetine were investigated in a rat social interaction test. A single administration of paroxetine at oral doses of 0.3, 1, 3 and 10 mg/kg had no effect on social interaction between pairs of male rats under bright light (high anxiety) conditions. After 21 days of daily administration, paroxetine given orally at 3 mg/kg significantly (p < 0.01) increased the time spent in social interaction by pairs of rats tested under the same conditions, with no effect on locomotor activity, indicating an anxiolytic-like effect. The magnitude of increase (+97%) was comparable to that seen after a single dose of chlordiazepoxide (4 mg/kg orally). Although there was also an increase in time spent in social interaction after 21 days of repeated oral administration of paroxetine at 0.3, 1, and 10 mg/kg (+44, +56, and +54% increases, respectively), statistical significance was not achieved. These results indicate that in the long term paroxetine has an anxiolytic action, and thus support the clinical evidence for its therapeutic use in the treatment of anxiety disorders in addition to its established role as an antidepressant.


Subject(s)
Anti-Anxiety Agents/pharmacology , Interpersonal Relations , Paroxetine/pharmacology , Animals , Chlordiazepoxide/pharmacology , Male , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Time Factors
5.
J Clin Psychiatry ; 53 Suppl: 7-12, 1992 Feb.
Article in English | MEDLINE | ID: mdl-1531829

ABSTRACT

Paroxetine is a highly potent and selective inhibitor of serotonin reuptake, being more potent in vitro than fluoxetine, fluvoxamine, and sertraline. In contrast to the tricyclic antidepressants, paroxetine has little affinity for catecholaminergic or histaminergic systems. Paroxetine is well absorbed from the gastrointestinal tract and undergoes first-pass metabolism that is partially saturable. Unlike the metabolites of fluoxetine and sertraline, the metabolites of paroxetine are pharmacologically inactive in vivo. Steady-state paroxetine plasma concentrations are generally achieved within 4 to 14 days of commencing therapy and remain stable thereafter. The pharmacokinetics of paroxetine are also consistent with once-daily dosing. This pharmacologic and pharmacokinetic profile, taken together with extensive clinical data, indicates that paroxetine is a valuable addition to the physician's armamentarium for the treatment of depression.


Subject(s)
Piperidines/pharmacology , Serotonin Antagonists/pharmacology , 1-Naphthylamine/analogs & derivatives , 1-Naphthylamine/pharmacokinetics , 1-Naphthylamine/pharmacology , 1-Naphthylamine/therapeutic use , Depressive Disorder/drug therapy , Fluoxetine/pharmacokinetics , Fluoxetine/pharmacology , Fluoxetine/therapeutic use , Fluvoxamine/pharmacokinetics , Fluvoxamine/pharmacology , Fluvoxamine/therapeutic use , Humans , In Vitro Techniques , Neurotransmitter Uptake Inhibitors/pharmacokinetics , Neurotransmitter Uptake Inhibitors/pharmacology , Neurotransmitter Uptake Inhibitors/therapeutic use , Paroxetine , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/therapeutic use , Sertraline
6.
J Psychopharmacol ; 5(3): 187-95, 1991 Jan.
Article in English | MEDLINE | ID: mdl-22282554

ABSTRACT

The α(2)-adrenoceptor antagonists idazoxan and RX811059 induced reciprocal forepaw treading, a component of the 5-HT-behavioural syndrome in rats. This response is independent of 'non-α(2)-adrenoceptor idazoxan binding sites' (NAIBS) at which RX811059 is inactive. Idazoxan pre-treatment, in rats, enhanced forepaw treading, head weaving and tremor induced by the 5-HT agonist 5-methoxy-N,N dimethyltryptamine (5-MeODMT), increased head twitches (but decreased hindlimb abduction) induced by the 5-HT releaser p- chloroamphetamine (pCA), but did not clearly alter head twitches induced by the 5-HT precursor L-5-hydroxytryptophan in mice. The α(1)-antagonist prazosin did not alter behaviour induced by either 5-MeODMT or pCA in rats. The α( 2)-agonist, guanoxabenz, did not alter 5-MeODMT-induced behaviour in rats. St587, an α(1)-agonist, selectively potentiated tremor induced by 5-MeODMT, but no other behaviour. A possible mechanism for these interactions could be through enhanced, α(2)-adrenoceptor-mediated, 5-HT release in specific brain areas. Other possibilities, e.g. direct action at subtypes of 5-HT receptors and the importance of these NA-5-HT interactions in the treatment of resistant depression, are discussed.

7.
J Psychopharmacol ; 4(2): 90-9, 1990 Jan.
Article in English | MEDLINE | ID: mdl-22282933

ABSTRACT

The behavioural effects of the specific and selective α(2)-adrenoreceptor antagonists, idazoxan, efaroxan and RX811059, have been investigated in the rat. All three drugs induced periods of behavioural activation characterized by increased locomotion and exploration (rearing and hole dipping). However, these effects were only apparent in animals which were fully habituated to their environments and thus displayed low baseline activity. The behaviour observed lay within the normal range of activity and was not apparent under conditions when exploration was stimulated such as in a novel environment. α( 2)-Adrenoreceptor antagonist- induced activation was a weak response when compared with the intense and prolonged hyperactivity, in both novel and non-novel environments, induced by the amine releaser D- amphetamine. Possible mechanisms involving a direct action of noradrenaline at postsynaptic α( 1)-adrenoreceptors (subsequent to enhanced presynaptic α(2)-receptor feedback blockade) or an indirect action of α(2)-antagonists on dopamine function in mesolimbic pathways are discussed.

8.
J Med Chem ; 32(7): 1627-30, 1989 Jul.
Article in English | MEDLINE | ID: mdl-2567783

ABSTRACT

A 1,4-dioxane analogue (1) of the alpha 2-adrenoreceptor partial agonist clonidine (2) has previously been shown to possess an interesting but complex pharmacological profile. In this study, from a series of other heterocyclic analogues of clonidine, the 1,4-oxazines 6 and 12 were found to resemble 1 in that they are partial alpha 2-agonists in the periphery and are excluded from the central nervous system. However, when given directly into the brain, they behave as pure alpha 2-antagonists.


Subject(s)
Adrenergic alpha-Agonists , Clonidine/analogs & derivatives , Clonidine/pharmacology , Heterocyclic Compounds/pharmacology , Animals , Brain/drug effects , Male , Rats , Vas Deferens/drug effects
9.
Neuroscience ; 29(2): 463-70, 1989.
Article in English | MEDLINE | ID: mdl-2498761

ABSTRACT

The behaviours evoked by the intrathecal injection of thyrotrophin-releasing hormone and a variety of analogues (RX77368, CG3509 and CG3703) were examined in conscious rats and the spread of injectate at the peak of the behavioural response was determined using 14C-labelled RX77368. The number of wet-dog shakes observed following intrathecal injection of thyrotrophin-releasing hormone, RX77368, CG3509 and CG3703 was linearly related to log10 dose (0.01-200 micrograms) in the first 6 min with the relative potencies being 1:7:10:60 respectively. The thyrotrophin-releasing hormone analogues also produced a marked forepaw-licking behaviour, but this did not increase with dose. Intrathecal or intraperitoneal pretreatment with prazosin (0.5 microgram and 1 or 2 mg/kg, respectively) attenuated both the wet-dog shake and forepaw-licking behaviours normally produced by the thyrotrophin-releasing hormone peptides. Following intrathecal [14C]RX77368 the radioactivity was principally restricted to the spinal cord with only limited amounts rostral to the rhombencephalon. These results imply that a tonically active bulbospinal noradrenergic pathway facilitates both thyrotrophin-releasing hormone-induced behaviours via alpha 1-adrenoceptors.


Subject(s)
Behavior, Animal/drug effects , Motor Activity/drug effects , Thyrotropin-Releasing Hormone/analogs & derivatives , Thyrotropin-Releasing Hormone/pharmacology , Animals , Dose-Response Relationship, Drug , Injections, Spinal , Male , Prazosin/pharmacology , Pyrrolidonecarboxylic Acid/analogs & derivatives , Rats , Rats, Inbred Strains
10.
J Med Chem ; 31(1): 7-11, 1988 Jan.
Article in English | MEDLINE | ID: mdl-3336034

ABSTRACT

Two different structural types of 2-aryl-1,3,4-thiadiazole amidines were synthesized and evaluated for anticonvulsant activity. Enhancement of the inherent anticonvulsant activity therein and separation of this activity from the accompanying sedative action of these compounds were attempted. The most potent compounds occurred in the 2-(trifluoromethyl)phenyl series of type 3 amidines, but they also possessed a relatively high level of neurotoxicity and sedation as demonstrated in the rotorod test.


Subject(s)
Amidines/chemical synthesis , Anticonvulsants/chemical synthesis , Thiadiazoles/chemical synthesis , Amidines/pharmacology , Animals , Electroshock , Indicators and Reagents , Male , Mice , Mice, Inbred Strains , Pentylenetetrazole , Seizures/physiopathology , Structure-Activity Relationship , Thiadiazoles/pharmacology
11.
Psychopharmacology (Berl) ; 96(4): 521-7, 1988.
Article in English | MEDLINE | ID: mdl-2907662

ABSTRACT

The importance of dopamine (DA) in mediating locomotor, exploratory and stereotyped behaviour in rodents is well established. Evidence also indicates a modulatory role for noradrenaline (NA) although, due to nonspecificity. of previously available agents, a precise role remains undefined. The effects of the specific and selective alpha-adrenoreceptor antagonists idazoxan (alpha 2) and prazosin (alpha 1) on behaviour induced by amphetamine and apomorphine have been investigated in the rat. d-Amphetamine (2 mg/kg) induced hyperactive locomotion and exploration. Pretreatment with prazosin (1 mg/kg) markedly reduced these responses. In contrast, pretreatment with idazoxan (20 mg/kg) only marginally altered d-amphetamine hyperactivity. Apomorphine (0.5 mg/kg) induced biphasic locomotor and exploratory activity. Neither alpha-antagonist affected the initial burst of activity (60 min), although prazosin inhibited whereas idazoxan potentiated the secondary phase (90-180 min). At higher dosage, amphetamine (6 mg/kg) and apomorphine (2 mg/kg) induced stereotyped behaviours. Prazosin pretreatment enhanced stereotyped gnawing and decreased sniffing and locomotion, whereas idazoxan increased locomotion and decreased amphetamine-induced mouth movements. These data indicate that DA-induced locomotor and stereotyped behaviours are differentially influenced (in opposite directions) by both alpha1- and alpha 2-adrenoreceptor antagonists. NA may thus modulate the expression and character of behaviour by influencing DA function in certain brain areas.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Apomorphine/pharmacology , Dextroamphetamine/pharmacology , Motor Activity/drug effects , Stereotyped Behavior/drug effects , Animals , Dioxanes/pharmacology , Idazoxan , Male , Prazosin/pharmacology , Rats , Rats, Inbred Strains , Time Factors
12.
J Med Chem ; 30(5): 951-4, 1987 May.
Article in English | MEDLINE | ID: mdl-3572984

ABSTRACT

The synthesis and anticonvulsant activity of a number of 2-aryl-5-guanidino-1,3,4 thiadiazoles are described. The unsubstituted guanidine 2a was found to possess potent anticonvulsant properties; considerable reduction or loss of activity however was observed with the majority of the substituted guanidines. Incorporation of the guanidine group into an imidazoline ring also resulted in a loss of activity. Secondary pharmacological evaluation confirmed the anticonvulsant properties of 2a but also revealed that the compound exhibited a considerable degree of sedative activity.


Subject(s)
Guanidines/therapeutic use , Seizures/drug therapy , Thiadiazoles/therapeutic use , Animals , Chemical Phenomena , Chemistry , Electroshock , Guanidines/chemical synthesis , Guanidines/toxicity , Mice , Pentylenetetrazole , Rats , Seizures/etiology , Thiadiazoles/chemical synthesis , Thiadiazoles/toxicity
13.
J Med Chem ; 29(11): 2273-80, 1986 Nov.
Article in English | MEDLINE | ID: mdl-3783589

ABSTRACT

The synthesis and anticonvulsant activity of a series of 2-aryl-5-hydrazino-1,3,4-thiadiazoles are described. The combination of preferred aromatic substituents in the 2-position coupled with alkyl substitution on the hydrazine moiety led to a number of potent compounds lacking sedation, ataxia, or lethality. 5-(2-Biphenylyl)-2-(1-methylhydrazino)-1,3,4-thiadiazole (4m) represents a new class of anticonvulsant agent and compares favorably with the standard drugs phenytoin, phenobarbital, and carbamazepine.


Subject(s)
Anticonvulsants/chemical synthesis , Hydrazines/chemical synthesis , Animals , Anticonvulsants/pharmacology , Anticonvulsants/toxicity , Hydrazines/pharmacology , Hydrazines/toxicity , Male , Rats , Rats, Inbred Strains , Structure-Activity Relationship
14.
J Med Chem ; 29(10): 2000-3, 1986 Oct.
Article in English | MEDLINE | ID: mdl-2876101

ABSTRACT

The resolution of three 2-substituted derivatives of idazoxan is described. The enantiomers show large separations in activity in a variety of in vitro and in vivo tests, and the active isomers are all potent and selective antagonists at the alpha 2-adrenoreceptor. The significance of these results in relation to those published on the enantiomers of idazoxan and to those on optically active alpha 2-adrenoreceptor agonists is discussed.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Dioxanes/pharmacology , Dioxins/pharmacology , Animals , Idazoxan , Rats , Stereoisomerism , Structure-Activity Relationship
15.
Br J Pharmacol ; 83(3): 707-12, 1984 Nov.
Article in English | MEDLINE | ID: mdl-6150739

ABSTRACT

Four 2-alkyl (methyl, ethyl, n-propyl and isopropenyl) analogues of idazoxan (RX 781094) have been synthesized and assessed in terms of their central alpha 2/alpha 1-adrenoceptor selectivity and alpha 2-adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat. In cortical binding assays using [3H]-idazoxan and [3H]-prazosin, idazoxan had a 5 times greater alpha 2/alpha 1-selectivity than yohimbine. The 2-alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than yohimbine for [3H]-idazoxan binding sites. In terms of central antagonist potency in vivo, the most favourable substitutions were 2-ethyl (RX 811033) and 2-n-propyl (RX 811054). Compared with yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of guanoxabenz-induced mydriasis in the pentobarbitone-anaesthetized rat. All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine. The results indicate that introduction of alkyl groups in the 2-position of idazoxan greatly increases the alpha 2/alpha 1-adrenoceptor selectivity as measured in binding studies. Improved alpha 2-adrenoceptor affinity and antagonist potency were particularly associated with the 2-ethyl and 2-n-propyl analogues.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Dioxanes/pharmacology , Dioxins/pharmacology , Receptors, Adrenergic, alpha/drug effects , Adrenergic alpha-Antagonists/metabolism , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dioxanes/metabolism , Idazoxan , In Vitro Techniques , Kinetics , Male , Prazosin/pharmacology , Quinolizines/pharmacology , Rats , Rats, Inbred Strains , Yohimbine/pharmacology
16.
Regul Pept ; 9(4): 305-15, 1984 Nov.
Article in English | MEDLINE | ID: mdl-6441196

ABSTRACT

Thyrotrophin-releasing hormone (TRH) and its stable analogues CG3509 and RX77368 were injected directly into the nucleus accumbens, septum and striatum of the rat and locomotor activity was recorded. TRH (5-20 micrograms) caused a dose-dependent increase in locomotor activity when injected into the nucleus accumbens. TRH (20 micrograms) also increased locomotor activity after administration into the septum but not when put into the striatum. Both the TRH analogues (0.1 and 1.0 microgram) produced closely related increases in activity when injected into either the nucleus accumbens or septum but CG3509 was more potent with a longer lasting effect. Also, in contrast with TRH (20 micrograms), both TRH analogues stimulated locomotor activity when injected into the striatum at a dose of 1 microgram but the effect was less marked and delayed in onset compared to the nucleus accumbens and septum response. Dopamine (100 micrograms) injected into the accumbens or septum also produced significant increases in locomotor activity. The locomotor effects of the peptides are discussed in relation to a possible dopamine-mediated mechanism which contrasts with the actions of TRH and the analogues on barbiturate anaesthesia.


Subject(s)
Motor Activity/drug effects , Thyrotropin-Releasing Hormone/analogs & derivatives , Thyrotropin-Releasing Hormone/pharmacology , Animals , Corpus Striatum/drug effects , Dopamine/pharmacology , Male , Nucleus Accumbens/drug effects , Pyrrolidonecarboxylic Acid/analogs & derivatives , Rats , Rats, Inbred Strains , Septal Nuclei/drug effects
17.
Neuropharmacology ; 23(3): 339-48, 1984 Mar.
Article in English | MEDLINE | ID: mdl-6145113

ABSTRACT

The effect of intracerebral injection of TRH and several biologically stable TRH analogues in the pentobarbitone anaesthetized rat was examined. Bilateral injection of TRH (5.0 micrograms total dose) and the analogues RX 77368 (0.01-1.0 microgram), CG 3509 (0.1-1.0 microgram), DN-1417 (1.0 microgram) and MK-771 (1.0 microgram) into the nucleus accumbens reduced the pentobarbitone-induced sleeping time. The TRH metabolite DKP (5 micrograms) had no effect on the sleeping time following intra-accumbens injection. Intra-septal injection of TRH (1.0-5.0 micrograms), RX 77368 (0.1-1.0 microgram) and CG 3509 (0.1-1.0 microgram) also reversed the pentobarbitone-induced sleeping time. In contrast, TRH (5 micrograms) injected into the striatum had no effect on the pentobarbitone-induced sleeping time, and CG 3509 (0.1 microgram) and RX 77368 (0.1 microgram) had weaker effects following intrastriatal injection compared to injection of these analogues into the nucleus accumbens and septum. Measurements of core temperature and respiration rate in rats following intra-accumbens or septal injection of TRH, CG 3509 and RX 77368 showed these peptides to reverse pentobarbitone-induced hypothermia and stimulate respiration rate. However, while intrastriatal injections of CG 3509 and RX 77368 caused an increase in respiration rate they had no effect on core temperature. These results suggest a close association between peptide-induced respiratory stimulation and reversal of pentobarbitone-induced anaesthesia. Since intra-accumbens and septal injection of dopamine (20-100 micrograms) failed to reverse anaesthesia, it is unlikely that the peptide-induced responses are mediated via dopamine release.


Subject(s)
Central Nervous System Stimulants/pharmacology , Pentobarbital/pharmacology , Sleep/drug effects , Thyrotropin-Releasing Hormone/analogs & derivatives , Thyrotropin-Releasing Hormone/pharmacology , Anesthesia , Animals , Body Temperature/drug effects , Corpus Striatum/physiology , Male , Pyrrolidonecarboxylic Acid/analogs & derivatives , Rats , Rats, Inbred Strains , Respiration/drug effects , Septum Pellucidum/physiology , Thyrotropin-Releasing Hormone/administration & dosage
18.
Br J Pharmacol ; 80(1): 155-61, 1983 Sep.
Article in English | MEDLINE | ID: mdl-6140052

ABSTRACT

Seven alpha 2-adrenoceptor antagonists with diverse chemical structures have been examined for their effects at alpha 2-adrenoceptors in the vas deferens and central nervous system of the rat. Antagonist potency assessed against the presynaptic alpha 2-adrenoceptor agonist action of clonidine in the isolated vas deferens (RX 781094 greater than Wy 26703 greater than yohimbine greater than rauwolscine greater than piperoxan greater than mianserin greater than RS 21361) was highly correlated with the ability of these drugs to displace saturable [3H]-RX 781094 binding from cerebral cortex membranes. Similarly, antagonist potency in the vas deferens was highly correlated with antagonist activity in reversing the centrally-mediated mydriasis induced by the selective alpha 2-adrenoceptor agonist, guanoxabenz, in pentobarbitone-anaesthetized rats. The results indicate that the presynaptic alpha 2-adrenoceptors in the vas deferens are pharmacologically similar to characterized these alpha 2-adrenoceptors in the central nervous system of the rat.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Receptors, Adrenergic/drug effects , Vas Deferens/drug effects , Animals , Cerebral Cortex/drug effects , Male , Rats , Rats, Inbred Strains , Receptors, Adrenergic/metabolism
19.
Neuropharmacology ; 22(6): 729-37, 1983 Jun.
Article in English | MEDLINE | ID: mdl-6136932

ABSTRACT

Several neuropharmacological effects of RX 781094, a new selective alpha 2-adrenoceptor antagonist, have been investigated in rodents. In rats, RX 781094 (0.1-1.0 mg kg-1, i.v.) produced a rapid dose-related reversal of cortical EEG synchronisation and behavioural sedation, induced by clonidine or the more selective alpha 2-adrenoceptor agonist, guanoxabenz. The alpha 2-adrenoceptor antagonists yohimbine and mianserin were also effective in blocking guanoxabenz-induced EEG synchronisation but had a lower potency than did RX 781094. In specificity experiments, RX 781094 (1.0 mg kg-1, i.v.) failed to antagonise the EEG synchronisation and pronounced behavioural sedation induced by the CNS depressant sodium pentobarbitone (15 mg kg-1, i.v.). In mice, pretreatment (i.v. or p.o.) with RX 781094 inhibited in a dose-dependent way both guanoxabenz-induced behavioural hypoactivity and clonidine-induced hypothermia. By itself, RX 781094 had no effect on the temperature of normal mice. In sleep-waking studies in rats, RX 781094 (0.1 and 1.0 mg kg-1, i.v.) had no measurable stimulant or depressant effect on the CNS, in contrast to (+)-amphetamine (1.0 mg kg-1, i.v.) which elicited marked CNS stimulation. These results support the conclusion that RX 781094 is a potent antagonist at central alpha 2-adrenoceptors.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Cerebral Cortex/physiology , Dioxins/pharmacology , Receptors, Adrenergic, alpha/physiology , Receptors, Adrenergic/physiology , Animals , Antihypertensive Agents/pharmacology , Cerebral Cortex/drug effects , Clonidine/pharmacology , Drug Antagonism , Electroencephalography , Guanabenz/analogs & derivatives , Guanabenz/pharmacology , Idazoxan , Male , Parietal Lobe/drug effects , Parietal Lobe/physiology , Rats , Rats, Inbred Strains , Receptors, Adrenergic, alpha/drug effects , Sleep/drug effects , Wakefulness/drug effects
20.
Br J Pharmacol ; 78(3): 507-15, 1983 Mar.
Article in English | MEDLINE | ID: mdl-6132641

ABSTRACT

1 The effects of intravenous administration of the selective alpha 2-adrenoceptor agonists clonidine, UK 14,304 and guanoxabenz on rat pupil diameter were investigated. 2 In rats anaesthetized with pentobarbitone, each agonist produced a marked dose-related increase in pupil diameter; the rank order of potency was: clonidine greater than UK 14,304 greater than guanoxabenz. 3 Pretreatment with the selective alpha 2-adrenoceptor antagonist, RX 781094 (0.5 mg/kg, i.v.), produced a parallel 30-40 fold shift to the right of the dose-pupil dilator response curves for the three agonists. Yohimbine (1.5 mg/kg, i.v.) produced about a 10 fold rightward shift of the dose-response curve for guanoxabenz. In contrast, the alpha 1-selective antagonist, prazosin (0.5 mg/kg, i.v.), failed to affect the dose-response relation for guanoxabenz. 4 Several antagonists of varying selectivities towards alpha 1- and alpha 2-adrenoceptors were tested for their ability to reverse the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). The rank order of potency of the antagonists producing a 50% reversal of this effect was: RX 781094 greater than yohimbine greater than piperoxan = rauwolscine greater than mianserin greater than RS 21361. Neither corynanthine nor prazosin reversed the guanoxabenz-induced mydriasis. 5 Topical application of RX 781094 (0.1 to 3% w/v solutions) onto one eye produced a slow reversal of guanoxabenz-induced mydriasis; the time course and degree of reversal were virtually the same in both eyes. 6 Intracerebroventricular administration of RX 781094 (1.25-15 micrograms total dose) caused a rapid dose-related reversal of the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). 7 Guanoxabenz (0.3 and 1.0 mg/kg, i.v.) did not produce any dilation of the physostigmine-constricted undamaged pupil of the pithed rat. Intravenous adrenaline was found to produce a small mydriatic effect, while atropine completely antagonized the effects of physostigmine in this preparation. 8 These results indicate that alpha 2-adrenoceptor agonists induce mydriasis in the rat through a central alpha 2-adrenoceptor mechanism. However, the site of action within the central nervous system remains to be determined.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Brain/drug effects , Mydriatics , Adrenergic alpha-Antagonists/pharmacology , Animals , Atropine/pharmacology , Dioxins/pharmacology , Epinephrine/pharmacology , Guanabenz/analogs & derivatives , Guanabenz/pharmacology , Idazoxan , Injections, Intraventricular , Male , Physostigmine/pharmacology , Pupil/drug effects , Rats , Rats, Inbred Strains
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