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Biomedical subjects

M Briley

Publications and source records attributed to M Briley.

At least 19 recordsLinked to original sources
PubMed2001

The role and histological classification of needle core biopsy in comparison with fine needle aspiration cytology in the preoperative assessment of impalpable breast lesions.

AIMS: To investigate the role of needle core biopsy (NCB) in the preoperative assessment of impalpable breast lesions, mainly derived from the NHS Breast Screening Programme (NHSBSP) and to assess our own modifications to a suggested system for the classification of breast NCBs. METHODS: The NCB, fine needle aspiration cytology (FNAC), and radiology scores from 298 women with non-palpable breast lesions presenting between January 1997 and December 1998, together with the open biopsy results (where available) were collated and analysed. RESULTS: The mean follow up period was 15.8 months (range, 5-28). The 298 NCB specimens were categorised as follows: unsatisfactory/non-representative (B1; n = 61; 20.5%), benign but uncertain whether representative (B2r; n = 52; 17.4%), benign (B2; n = 103; 34.6%), lesions possibly associated with malignancy but essentially benign (B3a; n = 9; 3.0%), atypical epithelial proliferations (B3b; n = 10; 3.4%), suspicious of malignancy (B4; n = 7; 2.3%), and malignant (B5; n = 56; 18.7%). Excision biopsy was performed in 43 cases within the B1 (n = 19), B2r (n = 8), B2 (n = 8), and the B3a (n = 8; data unavailable in one case) categories, revealing malignancy in 18 (42.8%) cases and in 65 cases within the B3b, B4, and B5 categories, revealing malignancy in 64 cases (98.5%). The sensitivity of NCB for malignancy was 87.7%, with a specificity and positive predictive value of 99.3% and 98.5%, respectively. FNAC had an inadequacy rate of 58.7%, a complete sensitivity of 34.5% and a specificity of 47.6%. CONCLUSIONS: This study confirms the value of NCB in the preoperative assessment of impalpable breast lesions. Two new categories are suggested for the NCB classification; category B2r for benign breast tissue where representativeness is uncertain, and the subdivision of category B3 into B3a for benign lesions potentially associated with malignancy (for example, radial scars and intraduct papillomas) and B3b for more worrisome atypical epithelial proliferations. These will aid the accurate audit of NCB and identify more clearly the intellectual pathway leading to a particular assessment.

Aged↗
PubMed2001

Where are the new therapies for anxiety and obsessive-compulsive disorders?

The benzodiazepines have monopolized the acute anxiety market for about 40 years, but their potential for tolerance and dependency has stimulated an interest in alternative anxiolytics. Until recently, however, attention has focused on existing drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors. The 5-HT1A partial agonist, buspirone (Bristol-Myers-Squibb), is one of the few compounds developed principally as an anxiolytic since the benzodiazepines. The challenge for the future is not only to find efficacious treatments with a rapid onset of action and an acceptable side effect profile but also to determine the optimal compounds for each of the different anxiety disorders.

Journal Article↗
PubMed2000

The possible role of 5-HT(1B/D) receptors in psychiatric disorders and their potential as a target for therapy.

Serotonin (5-hydroxytryptamine, 5-HT) is implicated in several psychiatric diseases. Is this also true for 5-HT(1B/D) receptors? These receptors are found in high density in substantia nigra, globus pallidus, striatum and basal ganglia and in other brain regions. This ubiquity makes 5-HT(1B/D) receptors responsible for many physiological and behavioural functions. This review focuses on the role of 5-HT(1B) receptors in the regulation of 5-HT release and synthesis. Microdialysis experiments performed on freely moving animals are an interesting in vivo model to study the function of the terminal 5-HT(1B) autoreceptor. Synthesis of 5-HT, estimated by the measurement of the accumulation of 5-hydroxytryptophan (5-HTP) ex vivo or in vitro, is modulated by the 5-HT(1B) autoreceptors. Many reports have shown that chronic administration with selective serotonin reuptake inhibitors leads to the desensitisation of the terminal 5-HT(1B) autoreceptors. With the help of some animal models of depression and anxiety and with some data from clinical studies it has been hypothesised that 5-HT(1B) receptors may be supersensitive in depression, anxiety and obsessive compulsive disorder. Thus, since the dysfunction of 5-HT(1B) receptors may be involved in some pathological states, particularly in the psychiatric field, these receptors represent important potential targets for drugs to treat mental diseases.

Animals↗
PubMed2000

Pharmacodynamics of milnacipran in young and elderly volunteers.

AIMS: To investigate the pharmacodynamics of milnacipran in healthy young and elderly volunteers. METHODS: Randomized double-blind crossover designs were employed and a standardized psychometric battery was administered pre and post dose for both studies. In the first study 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose. The second study compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo for 3 days' dosing in healthy volunteers aged over 65 years. The test battery was administered at baseline and at 2, 10 and 24 h post dose. The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short-term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ). RESULTS: Milnacipran produced no significant dose related effects in the young volunteers. For the elderly, milnacipran significantly (P<0.05) raised CFF scores compared with placebo but had no significant effects on any of the other measures used. Amitriptyline, in contrast, significantly (P<0. 05) lowered CFF threshold, lengthened CRT and increased error on the CTT. On the subjective variables, LARS and LSEQ, amitriptyline increased ratings both of sedation and of difficulty in waking from sleep. CONCLUSIONS: The results showed that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from disruptive effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers, where it seemingly improves performance on CFF. In contrast, the tricyclic antidepressant amitriptyline, used here as a positive internal control, significantly impaired performance in the elderly on the majority of psychometric measures used in this study. This finding not only validated the sensitivity of this current test battery but also indicates the potential behavioural toxicity of amitriptyline in clinical use in the elderly.

Adult↗
PubMed1998

The role of transvaginal ultrasound in the investigation of women with post-menopausal bleeding.

One-hundred and eighty-two women with post menopausal bleeding were examined with transvaginal ultrasound (TVUS) over a 16-month period. The imaging findings were correlated with the pathological specimens. One-hundred and forty had pipelle aspiration cytology and 35 hysteroscopy, dilatation and currettage and seven a hysterectomy. Endometrial thickness on TVUS was classified as either thin (equal to or less than 5 mm), thick (greater than 5 mm), or not seen. A thin endometrium was noted in 87 patients, in whom no pathological abnormality was found in 84 (negative predictive value 95%). There were three cases of hyperplasia or polyps but no carcinomas occurred in this group (negative predictive value for carcinoma 100%). A thickened endometrium was noted in 82 patients. In this group there were five carcinomas, nine polyps and eight cases of endometrial hyperplasia (positive predictive value 29%). In five patients the endometrium could not be identified. One carcinoma occurred in this group. There were an additional eight patients who were taking tamoxifen who were grouped separately. If a clear symmetrical endometrial stripe measuring less than or equal to 5 mm in thickness on TVUS is seen the probability of malignancy is extremely low and endometrial biopsy can probably be avoided in this group particularly in the context of an isolated episode of postmenopausal bleeding. If the endometrium is not seen or is thicker than 5 mm then endometrial biopsy is indicated.

Aged↗
PubMed1998

Milnacipran, a new specific serotonin and noradrenaline reuptake inhibitor.

Milnacipran is a new antidepressant which inhibits equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo with no effect on dopamine reuptake. Microdialysis studies have shown increased extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor. In particular, and unlike tricyclic antidepressants (TCAs), it has no activity at noradrenergic, muscarinic or histaminergic receptors. Contrary to TCAs, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. Milnacipran has a high bioavailability, low plasma protein binding, and is largely eliminated in the urine as the parent drug or as a glucuronide. These features suggest that interactions with other drugs given concurrently are unlikely. Studies in patients with liver dysfunction and in the elderly suggest that dose adjustment is not necessary. In patients with renal impairment, decreased elimination of milnacipran is correlated to the degree of renal impairment allowing an easy dosage adjustment. An intermediate half-life of approximately 8 h is compatible with twice-daily administration. Clinical studies comparing milnacipran, placebo and other antidepressants provide evidence of its efficacy in moderate to severe depression in both hospitalized and outpatient settings. Meta-analyses of the original data of controlled trials comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs) show that milnacipran provides antidepressant efficacy similar to that of TCAs and significantly superior to that of SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of TCAs with notably less cholinergic side effects. The tolerance of milnacipran was comparable to that of SSRIs with a higher incidence of dysuria with milnacipran but a higher frequency of nausea and anxiety with the SSRIs. Milnacipran represents an interesting new therapeutic option in depression, being as well tolerated as the SSRIs but offering clinical efficacy similar to the TCAs.

Journal Article↗
PubMed1998

Pasteur Euroconference on future therapies for an anxious world.

The aim of this meeting was to explore the molecular targets for tomorrow's drugs with a group of European and North American speakers from the pharmaceutical industry and academia presenting both data and ideas. Several speakers considered 5-hydroxytryptamine(1B/D) (5-HT(1B/D)) receptor antagonists to be a promising target for the treatment of obsessive compulsive disorders (OCD). 5-HT moduline, a peptide modulator of the 5-HT(1B/D) receptor, presents a potentially subtle way of intervention. No clinical data are as yet available on 5-HT(1B/D) receptor antagonists. The paradox of agonists, partial agonists and antagonists at the 5-HT(1A) receptor (all having anxiolytic activity in animal models) was discussed. Although the 5-HT(1A) agonists tested in clinical trials to date have been disappointing, the clinical potential of 5-HT(1A) antagonists still has to be evaluated. Similarly, both agonists and antagonists at the 5-HT(2C) receptor have been shown to be active in animal models of anxiety. It seems, however, that 5-HT(2C) agonists may have a therapeutic potential in panic disorders and OCD, while the antagonists may be more appropriate in generalised anxiety. Cholecystokinin (CCK) has been shown to be implicated in panic attacks which can be induced by agonists at the CCK-B subtype. CCK-B antagonists are thus potential antipanic agents although this has not yet been confirmed by clinical trials. Finally, inhibition of glutamatergic neurotransmission produces anxiolytic effects in a wide-range of animal models and the new antagonists at the metabotropic glutamate receptors may have potential as anti-anxiety agents. This report focuses on the presentations that addressed novel drug candidates or potential new drug targets.

Journal Article↗
PubMed1997

Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis.

Serotonin (5-hydroxytryptamine, 5-HT) synthesis was determined in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) in rat frontal cortex after inhibition of aromatic amino acid decarboxylase by administrative of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). The selective 5-HT reuptake inhibitor, citalopram, the 5-HT1A agonists, (+/-) 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), ipsapirone, gepirone and the 5-HT1A/B agonist, 7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo[1,2-a]-quinox ali ne (CGS 12066B), the 5-HT1A/B ligands and beta-adrenoceptor antagonists, (+/-) pindolol and (+/-) alprenolol, and the non-selective 5-HT ligands, m-chlorophenylpiperazine (mCPP) and metergoline, all inhibited the synthesis of 5-HT. The 5-HT1A/5-HT2 antagonist, spiperone, alone, had no effect on basal 5-HT synthesis, however it attenuated the effect of 8-OH-DPAT by 56% and CGS 12066B by 39% but only barely that of citalopram by 17%. The selective 5-HT1A antagonist, WAY 100635, which did not modify by itself 5-HT synthesis, had no effect on citalopram-induced reduction of 5-HT synthesis. Neither the 5-HT2 agonist, (+/-)1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI) nor the 5-HT2 antagonist, ritanserin, had any effect on the synthesis of 5-HT. In addition, ritanserin did not modify the inhibitory effect of citalopram. Methiothepin was the only compound to increase 5-HT synthesis. These results suggest that the effect of citalopram on the synthesis of 5-HT is not mediated by 5-HT1A or 5-HT2 receptors and that other receptors may be involved.

Animals↗
PubMed1997

Effects of milnacipran and pindolol on extracellular noradrenaline and serotonin levels in guinea pig hypothalamus.

Milnacipran, a dual noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitor, increased extracellular levels of NA and 5-HT in hypothalamus of freely moving guinea pigs as measured by microdialysis. The basal levels of both monoamines, which were tetrodotoxin sensitive, were increased in a dose-dependent manner and to a similar extent after the intraperitoneal administration of milnacipran (10 and 40 mg/ kg i.p.). Levels of the NA metabolite 4-hydroxy-3-methoxyphenylglycol (MHPG) were decreased by milnacipran at 10 and 40 mg/kg i.p., whereas those of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) showed no effect. Subcutaneous injection of 5-HT1A and beta-adrenergic receptor antagonist (-)-pindolol alone, at 10 mg/kg, had no effect on the extracellular levels of NA or 5-HT. The concomitant administration of (-)-pindolol (10 mg/kg s.c.) with milnacipran (10 mg/kg i.p.) increased severalfold the effect of milnacipran on the extracellular levels of NA and 5-HT. These results indicate that milnacipran, by blocking the uptake of NA and 5-HT, increases virtually equipotently the extracellular levels of NA and 5-HT, confirming previous in vitro studies. In addition, the antagonism of 5-HT1A autoreceptors by (-)-pindolol potentiates the action of milnacipran on both NA and 5-HT systems, without modifying the ratio of these activities.

Adrenergic beta-Antagonists↗
PubMed1997

Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability.

Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.

Adrenergic Uptake Inhibitors↗
PubMed1996

Effects of acute and repeated administration of citalopram on extracellular levels of serotonin in rat brain.

The effects of acute (2 days) and repeated (21 days) administration (50 mg/kg in the diet) of the selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitor, citalopram, on extracellular levels of 5-HT and their modulation by terminal autoreceptors in the hypothalamus of freely moving rats were compared in vivo by microdialysis. When studied without washout, extracellular levels of 5-HT were increased by both acute and repeated citalopram administration. In rats treated repeatedly, extracellular 5-HT levels were 43% (but not significantly) greater than in those treated acutely. Extracellular levels of 5-HT in control and citalopram-treated rats were similar when measured after 24 h washout. The enhancing effect of non-selective serotonergic autoreceptor antagonists, methiothepin (100 microM) or 1-(1-naphthyl)piperazine (NP) (10 microM), administered through the microdialysis probe, after 24 h washout, was similar in both control and chronically treated groups. These results suggest that repeated administration of citalopram followed by a washout of 24 h does not lead to desensitization of the terminal autoreceptor as measured in vivo in contrast to the effects we have shown previously in vitro. In rats treated chronically with citalopram without washout, methiothepin had a greater maximal effect on 5-HT outflow in comparison to rats receiving acute citalopram treatment. This finding suggests that a 5-HT autoreceptor antagonist or a combination of such a drug with a 5-HT uptake inhibitor would produce a greater increase of extracellular levels of 5-HT in hyposerotonergic states such as depression.

Animals↗
PubMed1996

Lack of effect of repeated administration of milnacipran, a double noradrenaline and serotonin reuptake inhibitor, on the beta-adrenoceptor-linked adenylate cyclase system in the rat cerebral cortex.

The effects of subacute administration of the double noradrenaline and serotonin uptake inhibitor antidepressant, milnacipran, and the tricyclic antidepressant, imipramine, on radioligand binding to beta-adrenergic receptors and on beta-adrenergic agonist-stimulated adenylate cyclase activity, in the rat cerebral cortex, have been determined. Rats were injected intraperitoneally for 21 days with milnacipran (3, 10 or 30 mg/kg/day) or imipramine (10 mg/kg/day). The treatment with milnacipran up to 30 mg/kg/day did not modify either the maximum number of [3H]CGP-12177 binding sites (Bmax) or the equilibrium dissociation constant (Kd). On the other hand, treatment of the rats with 10 mg/kg/day imipramine induced a decrease (27%) in Bmax [3H]CGP-12177 binding sites without affecting the Kd value. Furthermore, milnacipran did not affect the stimulation of cAMP production induced by either 30 microM isoprenaline, 10 microM GTP gamma S or 10 microM forskolin. Under similar conditions, treatment with imipramine reduced by 70% the isoprenaline-induced stimulation of cAMP production without affecting that induced by either GTP gamma S or forskolin. These results demonstrate that, unlike imipramine, subacute administration of milnacipran does not produce any change in beta-adrenoceptor sensitivity in the rat brain cortex.

Adenylyl Cyclases↗
PubMed1996

Preclinical pharmacology of milnacipran.

Milnacipran (Ixel) is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake and its lack of affinity for neurotransmitter receptors. It inhibits virtually equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo, as demonstrated by the antagonism of centrally acting monoamine displacers. It has no effect on dopamine reuptake. In addition, milnacipran has been shown by intracerebral microdialysis to increase the extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor or ion channel. In particular, and unlike tricyclic antidepressants, it does not act at noradrenergic, muscarinic or histaminergic receptors. Contrary to tricyclic antidepressants, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. This pharmacological profile, associated with an excellent bioavailability in man, was predicted to be that required for a powerful and well-tolerated antidepressant. Subsequent clinical development has shown this prediction to be well founded.

Adrenergic Uptake Inhibitors↗
PubMed1996

Efficacy and tolerability of milnacipran: an overview.

The relative benefits and risks of milnacipran, a novel antidepressant which selectively inhibits the reuptake of serotonin and noradrenaline, have been evaluated in comparative trials against tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). A total of 2462 patients with major depressive disorders have been investigated. At the optimal dose (50 mg twice a day), the efficacy of milnacipran was equivalent to that of the TCAs, with response rates of approximately 65% in both cases. Milnacipran was consistently effective against all of the principal elements of depression (anxiety, cognitive function, sleep and psychomotor retardation), and did not produce sedation or the emergence of suicidal thoughts. The Clinical Global Impression (CGI-3) score, a measure of the overall therapeutic impact of a treatment, was significantly higher with milnacipran than with TCAs (1.98 versus 1.84, p < 0.05). TCAs were associated with a higher frequency of adverse events than milnacipran, particularly with respect to anticholinergic-like effects; dysuria was the only adverse event occurring twice as frequently with milnacipran than with TCAs. Compared with TCAs, milnacipran was also associated with a lower incidence of cardiovascular adverse events. No haematological abnormalities occurred during treatment with milnacipran, and the incidence of abnormal liver function tests tended to be lower with milnacipran than with TCAs. In comparisons with SSRIs, milnacipran produced significantly higher response rates. The CGI-3 scores were significantly higher in milnacipran-treated patients (2.64 versus 2.32, p < 0.05). The adverse event profiles of the two treatments were similar, as was the incidence of abnormal liver function tests. These studies suggest that milnacipran offers clinical advantages over TCAs in terms of tolerability, and over SSRIs in terms of efficacy. In particular, the lack of cardiovascular adverse events appears to offer advantages in cases of deliberate overdose. To date, 15 such overdoses have occurred; none was fatal and each had a favourable outcome. The reproducible pharmacokinetic characteristics of milnacipran present further advantages over both groups of agents, due to lack of drug accumulation and a low risk of drug interactions.

Adrenergic Uptake Inhibitors↗
PubMed1995

Flexible 1-[(2-aminoethoxy)alkyl]-3-ar(o)yl(thio)ureas as novel acetylcholinesterase inhibitors. Synthesis and biochemical evaluation.

A series of flexible 1-(2-aminoethoxy)-3-ar(o)yl(thio)ureas was synthesized and assessed for antiacetylcholinesterase activity. This series was designed in order to optimize the spacer length linking the two pharmacophoric moieties, i.e., the basic nitrogen and the ar(o)yl(thio)-urea unit, and to test compounds with greater conformational flexibility. Thus, the replacement of the previously described spacer, 4-piperidinylethyl, by a linear ethoxyethyl chain gave compounds of slightly comparable potency, providing that they were correctly substituted. The results show that this new flexible spacer is compatible with high inhibitory activities. The optimal chain length corresponds to five methylene groups, allowing an efficient interaction between the two pharmacophoric units and the two reported hypothetical enzyme hydrophobic binding sites. Moreover, the initially optimized benzyl group, attached to the basic nitrogen, was found to be advantageously replaced by a cyclohexyl group, showing that an aromatic residue does not represent a prerequisite for activity.

Animals↗
PubMed1995

In vitro and in vivo activity of 1-(1-naphthyl)piperazine at terminal 5-HT autoreceptors in guinea-pig brain.

The effect of 1-(1-naphthyl)piperazine (NP) on the 5-HT terminal autoreceptor modulating 5-HT release was investigated in vitro and in vivo. In vitro 5-HT release was measured in slices of guinea-pig substantia nigra and hypothalamus prelabelled with 3H-5-HT, superfused with Krebs solution and depolarized electrically. NP, at 0.1 and 1 mumol/l, did not modify the calcium-dependent release of 3H-5-HT elicited by electrical stimulation using a frequency of 5 Hz, however at 0.1 mumol/l NP shifted to the right the inhibition curve of the non-selective autoreceptor agonist, 5-carboxamidotryptamine, in both regions. In hypothalamus when using lower frequencies (1 Hz or 0.2 Hz) or under pseudo-one-pulse stimulation, NP decreased the release of 3H-5-HT at 1 mumol/l. In vivo microdialysis was used to measure extracellular levels of endogenous 5-HT in the substantia nigra of freely moving guinea-pigs. The endogenous release of 5-HT was tetrodotoxin (TTX)-sensitive, indicating a neuronal origin of this efflux. NP, administered through the microdialysis probe (1-100 mumol/l), increased the levels of extracellular 5-HT in concentration-dependent and TTX-sensitive manner. These results suggest that in vitro NP acts as a 5-HT autoreceptor partial (ant)agonist in the substantia nigra and hypothalamus of guinea-pigs, and as a full antagonist in vivo. However, NP administered systemically at 10 mg/kg i.p., did not modify the levels of extracellular 5-HT in the substantia nigra. This lack of systemic effect of NP probably results from its interaction at other receptors that modify 5-HT neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗