Correction to: One Plus One Equals Two-will that do? A trial protocol for a Swedish multicentre randomised controlled trial to evaluate a clinical practice to reduce severe perineal trauma.

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One Plus One Equals Two-will that do? A trial protocol for a Swedish multicentre randomised controlled trial to evaluate a clinical practice to reduce severe perineal trauma {1}.

BACKGROUND: Severe perineal trauma sustained during childbirth is a serious complication since it can lead to both short- and long-term consequences for women. Some of the methods used to prevent perineal injuries have been evaluated in clinical trials, but there are still gaps in the evidence. A new clinical practice has been introduced, adopted by more than half of the maternity wards in Sweden with the aim of reducing severe perineal trauma. This procedure involves two midwives assisting the woman during the second stage of labour. METHODS/DESIGN: In this multicentre randomised controlled trial, 2946 women will be randomised to be assisted by one or two midwives during the second stage of labour. Women age 18-47, who plan for their first vaginal birth, with a singleton pregnancy in cephalic presentation, will be asked to participate when admitted to the maternity ward. Five maternity wards comprising 19,500 births/year in different parts of Sweden will participate in this study. The sample size is powered to demonstrate a 50% reduction (from 4.1-2.0%) in primary outcome, which is the prevalence of severe perineal trauma (3rd and 4th degree). Secondary outcomes will include maternal and neonatal outcomes, women's experiences, midwives' experiences of the intervention, incontinence, and pelvic floor symptoms. The primary analysis is intention to treat. Questionnaires will be sent to the women at 1 month and 1 year after the birth to assess women's experiences, pain, incontinence, pelvic floor symptoms, sexual function, and mental health. DISCUSSION: It is important for care during labour and birth to be evidence based. There is a strong desire among midwives to reduce the risk of severe perineal trauma. This may lead to new strategies and practices being implemented into practice without scientific evidence. The intervention might have negative side effects or unintended consequences. On the other hand, there is a possibility of the intervention improving care for women. TRIAL REGISTRATION {2A}: ClinicalTrials.gov NCT03770962 . Registered on 10 December 2018.

Otomastoiditis caused by non-tuberculous mycobacteria: report of 16 cases, 3 with infection intracranially.

OBJECTIVE: To analyse the clinical presentation, treatment and outcome in patients diagnosed with otomastoiditis caused by non-tuberculous mycobacteria. METHODS: A retrospective case review of 16 patients diagnosed with otomastoiditis caused by non-tuberculous mycobacteria from 2000 to 2012 was conducted in a hospital and tertiary referral centre in Sweden. The main outcome measures were microbiology findings, and surgical and medical interventions and outcomes. In addition, the relevant literature was reviewed. RESULTS: In three patients with otomastoiditis, the disease had spread intracranially. The bacteriological findings revealed Mycobacterium abscessus (n = 12), Mycobacterium fortuitum (n = 2) and Mycobacterium avium complex (n = 2). Surgical treatment was undertaken in all but three patients, including exploration of the temporal lobe in one patient. Systemic antibiotic treatment was given to all but one patient. Eight patients healed completely. Eight patients developed hearing loss. Two patients had relapse of the mycobacterial infection several months after the antibiotic treatment had been discontinued. CONCLUSION: Non-tuberculous otomastoiditis is a severe ear disease with challenging considerations, and should be treated aggressively in order to avoid morbidity.

Meropenem-clavulanic acid has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis.

We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB.

Little difference between minimum inhibitory concentrations of Mycobacterium tuberculosis wild-type organisms determined with BACTEC MGIT 960 and Middlebrook 7H10.

The MIC wild-type (WT) distribution for Mycobacterium tuberculosis in BACTEC 960 MGIT is not defined, which may result in poor reproducibility for drug susceptibility testing (DST), as several DST methods with different breakpoints are in use. In a comparison between MGIT and Middlebrook 7H10 medium of seven first- and second-line drugs, including 133 MIC determinations of 15 WT isolates, we found an agreement of 91.7% within ± one MIC dilution step. The results confirm the agreement in MIC testing between 7H10 and MGIT and indicate that breakpoints could be harmonized in order to avoid misclassification.

Meropenem-clavulanate has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis.

AIMS AND OBJECTIVES: With the relentless increase in multidrug- and extensively-drug resistant tuberculosis (MDR/XDR-TB), new treatment strategies are necessary. Favorable results have been reported by combining a ß-lactam antibiotic and a ß-lactamase inhibitor. The ß-lactamase encoded by the blaC gene of Mycobacterium tuberculosis (MTB) is the major mechanism of resistance to ß-lactam antibiotics (e.g., penicillin). Meropenem, a ß-lactam antibiotic of the carbapenem group, is a relatively weak substrate for the ß-lactamase of MTB. The ß-lactamase inhibitor clavulanate irreversibly inactivates the ß-lactamase encoded by the blaC gene, thus making the combination of meropenem and clavulanate an interesting treatment alternative for MTB. However, very few isolates of MTB have been tested for this drug combination and few clinical reports exist. Thus, the present study investigates the in vitro activity of meropenem-clavulanate for drug-resistant MTB isolates, including MDR/XDR-TB. METHODS: The minimum inhibitory concentration (MIC) distribution of meropenem-clavulanate was determined using Middlebrook 7H10, including MDR and XDR strains of MTB (n=68). Meropenem was prepared in a stock solution with a final concentration range of 0.002-512mg/L. Clavulanate was added at a fixed concentration of 64mg/L, to avoid a decline of the ß-lactamase to insufficient levels during the experiment. All isolates were evaluated after three weeks of growth. The pan-susceptible strain H37Rv was used as a control. RESULTS: There was a Gaussian MIC-distribution between 0.125 and 2mg/L of meropenem-clavulanate (expressed as the concentration of meropenem), but four isolates had very high MIC levels (16 and 32mg/L), which is likely to be out of reach in clinical doses (Fig. 1). The susceptibility of the isolates to meropenem-clavulanate was not correlated to the level of resistance to first- or second-line anti-tuberculous drugs. The MIC of the pan-susceptible control strain H37Rv was 1mg/L of meropenem, when combined with clavulanate. CONCLUSIONS: The present study shows that meropenem-clavulanate has low MICs against MTB in vitro, including MDR and XDR-TB isolates. Meropenem has good tissue penetration and low protein-binding, but requires an intravenous access and is relatively expensive. Meropenem-clavulanate may be a treatment option in selected cases of MDR/XDR-TB, although further clinical studies are warranted.

Intra- and extracellular activities of trimethoprim-sulfamethoxazole against susceptible and multidrug-resistant Mycobacterium tuberculosis.

We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC0-24/MIC) using ≥ 25 as a potential target, the cumulative fraction response was ≥ 90% at doses of ≥ 2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

Proficiency of drug susceptibility testing of Mycobacterium tuberculosis against pyrazinamide: the Swedish experience.

BACKGROUND: Pyrazinamide (PZA) is a key drug in the treatment of tuberculosis (TB), including multidrug-resistant TB. Drug susceptibility testing (DST) of Mycobacterium tuberculosis against PZA is not included in the World Health Organization's yearly proficiency testing. There is an increasing need to establish quality control of PZA DST. OBJECTIVE: To evaluate the performance of PZA DST and to introduce a quality assurance system for the test in Sweden. METHOD: Panels with PZA-susceptible and -resistant isolates were used in three rounds of proficiency testing in all five Swedish clinical TB laboratories and our reference laboratory. All laboratories used the MGIT 960 system. Minimum inhibitory concentrations (MICs) were determined and the pncA gene was sequenced to further characterise the 52 panel strains. RESULTS: Good agreement was seen between the phenotypic PZA DST and pncA sequence data, and MIC determination confirmed high levels of resistance. However, in contrast to other drugs, for which correct proficiency test results were observed, specificity problems occurred for PZA DST in some laboratories. CONCLUSIONS: In Sweden, using panel testing, differences were seen in the proficiency of TB laboratories in correctly identifying PZA susceptibility. Improved results were noted in the third round; PZA has therefore been included in yearly proficiency testing.

Rifampicin-resistant and rifabutin-susceptible Mycobacterium tuberculosis strains: a breakpoint artefact?

OBJECTIVES: It has long been assumed that some rifampicin-resistant Mycobacterium tuberculosis strains are susceptible to, and thus treatable with, rifabutin. However, clinical breakpoints for susceptibility testing of rifabutin as well as the evidence for a clinical effect of rifabutin in rifampicin-resistant strains remains poorly defined. The objective of this study was to re-evaluate the breakpoint for rifabutin in relation to its MIC wild-type distribution and the presence of mutations in rpoB. METHODS: The MIC in 7H10 Middlebrook medium was determined for clinical isolates of M. tuberculosis (n = 95), where a majority were multidrug resistant. Additionally, all strains were screened for rpoB mutations by sequencing and the GenoType MTBDRplus assay. RESULTS: Rifampicin resistance was confirmed by genotypical and/or phenotypical tests in 73 isolates (76.8%). Nineteen isolates, defined as rifampicin resistant and rifabutin susceptible according to the present breakpoint, exhibited significantly higher MICs of rifabutin (0.064-0.5 mg/L) than rifabutin-susceptible isolates without any detectable mutations in rpoB (P < 0.001). These 19 isolates were clearly resistant to rifampicin (MIC 2-256 mg/L) and all but one had mutations in rpoB, with 9 (47.4%) specifically in Asp516Val. CONCLUSIONS: Our results indicate that rifampicin-resistant but rifabutin-susceptible isolates according to the present breakpoints harbour rpoB mutations and have a rifabutin MIC significantly higher than strains without any detectable mutations in rpoB. So far there are no clinical, pharmacological or microbiological data to confirm that such isolates can be treated with rifabutin and we suggest a revision of the current breakpoints.

Reevaluation of the critical concentration for drug susceptibility testing of Mycobacterium tuberculosis against pyrazinamide using wild-type MIC distributions and pncA gene sequencing.

Pyrazinamide (PZA) is a potent first-line agent for the treatment of tuberculosis (TB) with activity also against a significant part of drug-resistant Mycobacterium tuberculosis strains. Since PZA is active only at acid pH, testing for susceptibility to PZA is difficult and insufficiently reproducible. The recommended critical concentration for PZA susceptibility (MIC, 100 mg/liter) used in the Bactec systems (460 and MGIT 960) has not been critically evaluated against wild-type MIC distributions in clinical isolates of Mycobacterium tuberculosis. Using the Bactec MGIT 960 system, we determined the PZA MICs for 46 clinical M. tuberculosis isolates and compared the results to pncA sequencing and previously obtained Bactec 460 data. For consecutive clinical isolates (n = 15), the epidemiological wild-type cutoff (ECOFF) for PZA was 64 mg/liter (MIC distribution range, ≤ 8 to 64 mg/liter), and no pncA gene mutations were detected. In strains resistant in both Bactec systems (n = 18), the PZA MICs ranged from 256 to ≥ 1,024 mg/liter. The discordances between pncA sequencing, susceptibility results in Bactec 460, and MIC determinations in Bactec MGIT 960 were mainly observed in strains with MICs close to or at the ECOFF. We conclude that in general, wild-type and resistant strains were clearly separated and correlated to pncA mutations, although some isolates with MICs close to the ECOFF cause reproducibility problems within and between methods. To solve this issue, we suggest that isolates with MICs of ≤ 64 mg/liter be classified susceptible, that an intermediary category be introduced at 128 mg/liter, and that strains with MICs of >128 mg/liter be classified resistant.

Wild-type distributions of seven oral second-line drugs against Mycobacterium tuberculosis.

OBJECTIVES: To determine wild-type minimum inhibitory concentration (MIC) distributions for Mycobacterium tuberculosis, as the background data for defining susceptibility breakpoints are limited. METHODS: We determined wild-type MIC distributions of M. tuberculosis using a 96-stick replicator in Middlebrook 7H10 (7H10) medium for ethionamide (ETH), prothionamide, thiacetazone, cycloserine, rifabutin (RFB), clofazimine and linezolid in consecutive susceptible clinical isolates (n = 78). RESULTS: Tentative epidemiological wild-type cut-offs (ECOFF) were determined for all investigated drugs where World Health Organization recommended critical concentrations for 7H10 are lacking, except for ETH. As the ECOFF was closely related to the non-wild-type strains for ETH and thiacetazone, the use of an intermediary (I) category in drug susceptibility testing could increase reproducibility. The cross-resistance between ETH and isoniazid was 21%. Applying 0.5 mg/l as a breakpoint for RFB classified two non-wild type and rpoB mutated isolates as susceptible for RFB and resistant against rifampicin. CONCLUSIONS: We propose that wild-type MIC distributions should be used as a tool to define clinical breakpoints against second-line drugs. This is increasingly important considering the rapid emergence of drug resistance.

Wild-type MIC distributions for aminoglycoside and cyclic polypeptide antibiotics used for treatment of Mycobacterium tuberculosis infections.

The aminoglycosides and cyclic polypeptides are essential drugs in the treatment of multidrug-resistant tuberculosis, underscoring the need for accurate and reproducible drug susceptibility testing (DST). The epidemiological cutoff value (ECOFF) separating wild-type susceptible strains from non-wild-type strains is an important but rarely used tool for indicating susceptibility breakpoints against Mycobacterium tuberculosis. In this study, we established wild-type MIC distributions on Middlebrook 7H10 medium for amikacin, kanamycin, streptomycin, capreomycin, and viomycin using 90 consecutive clinical isolates and 21 resistant strains. Overall, the MIC variation between and within runs did not exceed +/-1 MIC dilution step, and validation of MIC values in Bactec 960 MGIT demonstrated good agreement. Tentative ECOFFs defining the wild type were established for all investigated drugs, including amikacin and viomycin, which currently lack susceptibility breakpoints for 7H10. Five out of seven amikacin- and kanamycin-resistant isolates were classified as susceptible to capreomycin according to the current critical concentration (10 mg/liter) but were non-wild type according to the ECOFF (4 mg/liter), suggesting that the critical concentration may be too high. All amikacin- and kanamycin-resistant isolates were clearly below the ECOFF for viomycin, and two of them were below the ECOFF for streptomycin, indicating that these two drugs may be considered for treatment of amikacin-resistant strains. Pharmacodynamic indices (peak serum concentration [Cmax]/MIC) were more favorable for amikacin and viomycin compared to kanamycin and capreomycin. In conclusion, our data emphasize the importance of establishing wild-type MIC distributions for improving the quality of drug susceptibility testing against Mycobacterium tuberculosis.

Wild-type MIC distributions of four fluoroquinolones active against Mycobacterium tuberculosis in relation to current critical concentrations and available pharmacokinetic and pharmacodynamic data.

OBJECTIVES: To describe wild-type distributions of the MIC of fluoroquinolones for Mycobacterium tuberculosis in relation to current critical concentrations used for drug susceptibility testing and pharmacokinetic/pharmacodynamic (PK/PD) data. METHODS: A 96-stick replicator on Middlebrook 7H10 medium was used to define the MICs of ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin for 90 consecutive clinical strains and 24 drug-resistant strains. The MICs were compared with routine BACTEC 460 susceptibility results and with MIC determinations in the BACTEC MGIT 960 system in a subset of strains using ofloxacin as a class representative. PK/PD data for each drug were reviewed in relation to the wild-type MIC distribution. RESULTS: The wild-type MICs of ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin were distributed from 0.125 to 1, 0.25 to 1, 0.032 to 0.5 and 0.125 to 0.5 mg/L, respectively. The MIC data correlated well with the BACTEC 960 MGIT and BACTEC 460 results. PD indices were the most favourable for levofloxacin, followed by moxifloxacin, ofloxacin and ciprofloxacin. CONCLUSIONS: We propose S (susceptible)

Drug susceptibility testing of Mycobacterium tuberculosis by a nitrate reductase assay applied directly on microscopy-positive sputum samples.

Current methods for drug susceptibility testing of Mycobacterium tuberculosis are either costly or slow. As the prevalence of multidrug-resistant strains increases, the need for fast, reliable, and inexpensive methods that can also be applied in settings with scarce resources is obvious. We evaluated a rapid colorimetric nitrate reductase assay (NRA) for direct drug susceptibility testing of M. tuberculosis directly from clinical sputum samples with positive microscopy results for acid-fast bacilli with more than 10 acid-fast bacilli per high-power field. We have saved valuable time by omitting the preisolation step. The sensitivity (ability to detect true drug resistance) and specificity (ability to detect true drug susceptibility) of the direct NRA, using the direct proportion method as the reference, were 100 and 100%, 93 and 100%, 76 and 100%, and 55 and 99% for rifampin, isoniazid, streptomycin, and ethambutol, respectively, when tested on M. tuberculosis strains present in 121 samples. The results were in most cases available in 14 days. The direct NRA could be used as a rapid, inexpensive, and accurate method to determine rifampin and isoniazid susceptibility directly from sputum. The technique might become a valid alternative to traditional methods, especially in low-income countries.

Should the 'bleach microscopy method' be recommended for improved case detection of tuberculosis? Literature review and key person analysis.

SETTING: It has been proposed that the sensitivity of direct sputum smear microscopy can be improved if sputum is liquefied with sodium hypochlorite (NaOCl or household bleach), and concentrated by centrifugation before acid-fast staining. OBJECTIVE: To summarise the results of the studies of the bleach method for improved sensitivity of sputum microscopy and to describe the opinions and knowledge of key persons in National Tuberculosis Control Programmes (NTPs) about this method. DESIGN: We searched Medline, EMBASE and Web of Science for studies comparing the bleach method to direct sputum smear microscopy in low- or middle-income countries. Each study was assessed regarding methodology and field applicability. We also sent out questionnaires concerning the bleach method to key persons in NTPs in 85 countries. RESULTS: In 15 of the 19 studies identified there was a statistically significant improvement in the proportion of positive tests or sensitivity ranging from 7-253%. The majority (73%) of the key persons had heard of the bleach method. Forty-four per cent thought it could improve case detection in their countries, while 49% did not know; 93% of them would promote the bleach method; the most common reasons for doing so would be recommendations from the WHO or the IUATLD, or favourable studies performed in their own country. The bleach method was used routinely in only three countries. CONCLUSION: There is enough evidence to recommend the evaluation and introduction of the bleach method in most settings where mycobacterial culture is not performed routinely.

Evaluation of the BacT/ALERT 3D system for recovery and drug susceptibility testing of Mycobacterium tuberculosis.

We evaluated the BacT/ALERT 3D system for recovery and drug susceptibility testing (DST) of Mycobacterium tuberculosis (MTB). Of 2659 clinical specimens, MTB was detected in 92 using BacT/ALERT, compared to 94 using Löwenstein-Jensen culture. Detection time was 25% shorter with BacT/ALERT. Sensitivities were 92%, 96%, 78% and 100% for resistance to rifampicin, isoniazid, streptomycin and ethambutol, respectively, while specificity was 100% for all antibiotics, when BacT/ALERT was compared with the BACTEC 460 method on 50 MTB isolates. The BacT/ALERT system is fully automated and creates no radioactive waste. It seems to be a valid alternative for primary isolation, but further evaluation is needed regarding DST.

Rapid and inexpensive drug susceptibility testing of Mycobacterium tuberculosis with a nitrate reductase assay.

Multidrug-resistant tuberculosis is an increasing public health concern in many parts of the world, especially in low-income countries, where most cases occur. Traditional drug susceptibility testing is either time-consuming, such as the proportion method on solid media, or expensive, such as the BACTEC 460 system. We have evaluated a new nitrate reductase assay (NRA) that depends on the ability of Mycobacterium tuberculosis to reduce nitrate to nitrite. The reduction can be detected using specific reagents, which produce a color change. We tested a panel of 57 M. tuberculosis strains with various resistance patterns. The bacteria were inoculated on Löwenstein-Jensen medium, either without drugs or with rifampin, isoniazid, streptomycin, or ethambutol and with potassium nitrate (KNO(3)) incorporated. After incubation for 7, 10, or 14 days, the reagents were added and nitrate reduction, indicating growth, could be detected by a color change. Sensitivities to and specificities for drugs as determined by the NRA method compared to those determined by the BACTEC 460 method were 100 and 100% for rifampin, 97 and 96% for isoniazid, 95 and 83% for streptomycin, and 75 and 98% for ethambutol, respectively. The results were in the majority of the cases available in 7 days. The evaluated method is rapid and inexpensive and could correctly identify most resistant and sensitive M. tuberculosis strains. It has the potential to become an interesting alternative to existing methods, such as the proportion and BACTEC methods, particularly in resource-poor settings.

Improved sputum microscopy for a more sensitive diagnosis of pulmonary tuberculosis.

Diagnosis of tuberculosis in low-income countries is hindered by the low sensitivity of direct sputum smear microscopy. We compared an improved method based on liquefaction of sputum with NaOCl followed by centrifugation with standard direct smear in a central hospital and at peripheral health centres in Honduras. Specificity was high and sensitivity significantly better with the NaOCl method. Moreover, this technique is safe, inexpensive and easy to perform. We recommend its implementation to enable rapid, sensitive laboratory diagnosis of pulmonary tuberculosis, especially in resource-poor settings where culture is not possible.

The ergolene derivative MPME induces in the rat a behavioural syndrome associated with activation of dopamine D-1 receptors belonging to the dotted type of forebrain dopamine nerve terminals.

The ergolene derivative MPME (PTR 17402; (5R,8R)-8-(4-p-methoxyphenyl)-1-piperazynylmethyl-6- methylergolene], a dopamine (DA) receptor agonist acting mainly at DA D-1 receptors linked to dotted types of forebrain DA nerve terminals, induces a characteristic behavioural syndrome consisting of increased locomotion, head-bobbing and sniffing activity without oral stereotypies or increased rearing. Haloperidol and cis-flupenthixol, nonselective DA receptor antagonists, but not selective D-2 receptor antagonists such as remoxipride and sulpiride, could significantly counteract the locomotion and head-bobbing behaviour induced by MPME. In contrast, the sniffing behaviour induced by MPME was only marginally affected by haloperidol and cis-flupenthixol pretreatment. These results suggest that activation of D-1 receptors in the forebrain mainly linked to the dotted types of DA nerve terminals in the striatum, and in the limbic forebrain, can result in behavioural effects which differ from those caused by stimulation of D-2 receptors located mainly within the diffuse types of DA nerve terminal systems.

Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain.

The novel substituted benzamide, remoxipride, preferentially blocked apomorphine-induced hyperactivity with weak effects on stereotypies. The potency of remoxipride was about 50 times higher than that of sulpiride. Remoxipride caused a weak, atypical form of catalepsy and showed a high separation between the ED50 for blockade of apomorphine-induced hyperactivity and the ED50 for induction of catalepsy (ratio 24). Remoxipride was shown to be a selective dopamine D2 receptor antagonist since it displaced [3H]spiperone (IC50 = 1570 nM) but not [3H]flupentixol (IC50 greater than 100 000 nM) in rat striatum, and did not inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100 000 nM). Remoxipride is a potent antagonist of D2 receptors showing a dose-dependent blockade of [3H]spiperone and [3H]n-propylnorapomorphine in vivo binding with a potency equal to that of chlorpromazine. In contrast to haloperidol, remoxipride caused a preferential blockade of in vivo [3H]spierone binding in the mesolimbic DA rich areas and the substantia nigra with much less effect in the striatum. In addition, remoxipride produced a preferential increase of DA utilization following synthesis inhibition in the olfactory tubercle. Only minor changes in NA and 5-HT metabolism were observed while HVA and DOPAC levels were markedly elevated. Taken together, these results indicate that remoxipride is a potent, selective D2 receptor blocking agent with a preferential action in mesolimbic and extrastriatal dopamine-containing neurons.