Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies.

Administration of the non-competitive NMDA receptor antagonists phencyclidine (PCP) (0.6-5 mg/kg s.c.) and MK-801 (0.1-0.8 mg/kg s.c. ) dose-dependently increased locomotor activity in the rat. Pre-treatment of rats with SB 221284 (0.1-1 mg/kg, i.p.) a 5-HT(2C/2B) receptor antagonist or SB 242084 (1 mg/kg, i.p.) a selective 5-HT(2C) receptor antagonist, doses shown to block mCPP induced hypolocomotion, significantly enhanced the hyperactivity induced by PCP or MK-801. Neither compound altered locomotor activity when administered alone. Furthermore, systemic administration of PCP (5 mg/kg s.c.) increased nucleus accumbens dopamine efflux in the rat to a maximum of approximately 220% of basal, 40-60 min after administration. Pre-treatment with the 5-HT(2C/2B) receptor antagonist SB 221284 (1 mg/kg, i.p.) and the 5-HT(2C) receptor antagonist SB 242084 (1 mg/kg i.p.) failed to affect nucleus accumbens dopamine efflux per se but significantly enhanced the magnitude and duration of the increase induced by PCP. However, the time course of the neurochemical and behavioural effects were qualitatively and quantitatively different, suggesting the potential involvement of other neurotransmitter pathways. Nevertheless, the present results provide behavioural and neurochemical evidence which demonstrate that, in the absence of effects per se, blockade of 5-HT(2C) receptors enhanced the activation of mesolimbic dopamine neuronal function by the non-competitive NMDA receptor antagonists PCP and MK-801.

Sustained nuclear localization of p21/WAF-1 upon growth arrest induced by contact inhibition.

We assessed the expression and distribution of p21/Waf-1 in TLM1 melanoma cells that exhibit contact inhibition and require serum for growth. The growth stage of cells stimulated to enter the mitotic cell cycle synchronously and grow to confluence was characterized by distinct, yet consistent levels and patterns of distribution of p21/Waf-1. Significantly, sustained accumulation of p21/Waf-1 in the nuclear compartment was seen only after 4 days in culture when cell-to-cell contacts were established, leading to a diminished rate of cell growth. Overexpression of wild-type waf-1 in melanoma cells reduced growth of subconfluent cells, decreased Cdk4 activity with a concomitant increase in hypophosphorylated Rb, and promoted cell death by apoptosis. The data support the premise that cell-to-cell contacts provide signals that mediate sustained nuclear localization of p21/Waf-1 leading to cell growth arrest; furthermore, an elevation in the activity of this protein can lead to apoptosis.

Inhibition of hippocampal 5-HT synthesis by fluoxetine and paroxetine: evidence for the involvement of both 5-HT1A and 5-HT1B/D autoreceptors.

Hippocampal serotonin (5-hydroxytryptamine, 5-HT) synthesis, as determined by the accumulation of 5-hydroxytryptophan (5-HTP) following inhibition of L-aromatic amino acid decarboxylase with NSD 1015, was inhibited by systemic administration of the selective serotonin reuptake inhibitors fluoxetine (10 mg/kg i.p.) and paroxetine (3 mg/kg i.p.). Pretreatment of rats with the selective 5-HT1A receptor antagonist WAY 100635 for a period of 7 days using subcutaneously implanted osmotic minipumps (1 mg/kg/day) was sufficient to block the inhibition of 5-HT synthesis following the 5-HT 1A receptor agonist 8-OH-DPAT (0.3 mg/kg s.c.), but failed to inhibit the decrease of hippocampal 5-HT synthesis by fluoxetine (10 mg/kg i.p.) or paroxetine (3 mg/kg i.p.). Similarly, pretreatment of rats with GR 127935 (5 mg/kg i.p.), an antagonist with high affinity for 5-HT1B/D receptors, blocked the reduction of hippocampal 5-HT synthesis following the 5-HT receptor agonist TFMPP (3 mg/kg s.c.) without affecting the reduction of hippocampal 5-HT synthesis by either fluoxetine or paroxetine. In contrast, pretreatment with WAY 100635 (1 mg/kg/day, for 7 days s.c. in osmotic minipumps) in combination with GR 127935 (5 mg/kg i.p.) significantly attenuated the decrease of hippocampal 5-HT synthesis by both fluoxetine and paroxetine. These results indicate that both 5-HT1A and 5-HT1B/1D receptors, which function in the rat as inhibitory somatodendritic and nerve terminal autoreceptors, independently regulate hippocampal 5-HT synthesis and must be simultaneously blocked to prevent the inhibition of 5-HT synthesis by selective serotonin reuptake inhibitors which increase 5-HT availability at both nerve terminals in hippocampus and 5-HT cell bodies in the raphe nuclei.

L-701,324, a glycine/NMDA receptor antagonist, blocks the increase of cortical dopamine metabolism by stress and DMCM.

Dopamine metabolism, as reflected by the concentration of dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex was significantly increased following 30 min immobilisation stress or systemic administration of the benzodiazepine/GABA(A) receptor inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). The response to stress was attenuated by pretreatment of rats with the benzodiazepine/GABA(A) receptor agonists diazepam and zolpidem. Furthermore, pretreatment with R-(+)-3-amino-1-hydroxypyrrolid-2-one (R-(+)-HA-966), a low efficacy partial agonist, and 7-chloro-4-hydroxy-3(3-phenoxy) phenylquinolin-2-(H)-one (L-701,324) a novel, high affinity, full antagonist at the glycine/NMDA receptor attenuated the response to both stress and DMCM. These results demonstrate that antagonists at the glycine/NMDA receptor complex are comparable with benzodiazepine/GABA(A) receptor agonists in their ability to prevent activation of the mesocortical dopamine system by stress and GABA(A) receptor inverse agonists. Results are discussed in relation to the interaction between glycine/NMDA receptor antagonists, the mesocorticolimbic dopamine system and stress related disorders.

Factors affecting treatment decisions and satisfaction of owners of cats with cancer.

Cancer in cats is being diagnosed with increasing frequency. Euthanasia or an active intervention such as chemotherapy, radiation therapy, or surgery are treatment choices for the owner at diagnosis of the cat's disease. In this study, 2 interviews with cat owners, one soon after diagnosis of cancer in the cat and one 6 months later, were used to identify owner characteristics associated with a decision of euthanasia or intervention, to identify factors associated with an owner's satisfaction with euthanasia or intervention, and to evaluate inappropriate expectations of the owners who selected an intervention. The study included 89 owners from 3 referral hospitals. In logistic regression analysis, significant factors were not found that affected the owner's decision to euthanatize the cat versus intervene. Satisfaction with the decision to euthanatize the cat was associated with the ability of the cat to groom itself, eat, and play at the first interview. Among owners who selected an intervention, 4 combinations of factors were associated with being satisfied. The first combination was clinic of origin (CLIN), having a live cat at the 6-month follow-up interview (LIVE), and understanding the number of return visits required for the intervention. The second was CLIN, LIVE, and type and frequency of adverse effects from the intervention at the 6-month interview. The third was CLIN, LIVE, and feeling guilty at the 6-month interview. The fourth was CLIN, LIVE, and whether the cat had a good or excellent quality of life at the first interview. Thirty percent (21/69) of the owners tended to overestimate their cats' life expectancy. Owners also felt they had reasonably accurate estimations of adverse effects of treatment and number of return visits, but underestimated the costs required for an intervention. For owners who elect an intervention, a reminder from the veterinarian that emotional upheavals may develop even after the decision has been made is important. To provide optimal patient care and client education, veterinarians must find a middle ground between being knowledgeable, practical, and informed, and being compassionate and approachable.

The role of laser assisted uvulopalatoplasty in snoring and sleep apnea.

1. A careful history and favorable physical exam is mandatory for consideration of LAUP. 2. Concurrent diseases must be addressed for optimal results. 3. A sleep study should be recommended with any evidence suggestive of sleep apnea. 4. LAUP cures snoring. 5. Primary treatment of severe sleep apnea is nasal continuous positive airway pressure (NCPAP). 6. Mild sleep apnea with appropriate physical exam can be expected to have acceptable results when treated by LAUP. 7. LAUP should be considered for moderate to severe sleep apnea only if NCPAF intolerance is intractible.

Isolation and structural characterisation of herring gull (Larus argentatus) pancreatic polypeptide.

Pancreatic polypeptide (PP) has been isolated from pancreatic extracts of the herring gull (Larus argentatus) using a radioimmunoassay employing an antiserum (PP 221), generated to the conserved C-terminal hexapeptide amide of mammalian PP. Gel permeation and reverse-phase HPLC fractionation of crude pancreatic extracts resolved a single molecular form of gull PP in each case. Purification of gull PP to homogeneity indicated that the mammalian PP antiserum employed was only 4% cross-reactive with this peptide. When radioimmunoassay data were corrected for this, the herring gull pancreas was found to contain 5 nmol PP/g wet wt. The molecular mass of gull PP was determined as 4237 +/- 2 Da by 252Cf plasma desorption mass spectroscopy (PDMS). Gas-phase sequencing established unequivocally the entire primary structure of a 36-amino-acid residue peptide as Gly-Pro-Val-Gln-Pro-Thr-Tyr-Pro-Gly-Asp-Asp-Ala-Pro-Val-Glu-Asp-Leu-Val- Arg-Phe - Try-Asn-Asp-Leu-Gln-Gln-Tyr-Leu-Asn-Val-Val-Thr-Arg-His-Arg-Tyr. The computed molecular mass of this peptide (4235.6 Da) was in close agreement with that derived by PDMS. The primary structure of herring gull PP differs from that of the chicken in four residues at positions 3 (Val/Ser), 18 (Val/IIe), 22 (Asn/Asp), and 23 (Asp/Asn). Avian PP thus appears to be a highly conserved regulatory peptide.

An immunocytochemical study of putative neurotransmitters in the metacercariae of two strigeoid trematodes from rainbow trout (Oncorhynchus mykiss).

Whole mounts of the metacercariae of Diplostomum sp. and Cotylurus erraticus from rainbow trout have been treated cytochemically for the demonstration of cholinergic, serotoninergic (5-hydroxytryptamine) and peptidergic elements in the nervous system. Antisera directed against four vertebrate (pancreatic polypeptide, peptide YY, substance P and peptide histidine isoleucine) and two invertebrate peptides (neuropeptide F and FMRFamide) were used in an indirect immunofluorescence procedure in conjunction with confocal scanning laser microscopy (CSLM). Of the seven antisera tested, all except peptide histidine isoleucine showed significant immunoreactivity. Cholinergic and serotoninergic staining was found primarily in the central nervous system (CNS) and in cell bodies associated with the ventral and dorsal nerve cords in both trematodes. Peptidergic immunoreactivity was localised in the CNS and PNS of both genera, revealing an extensive innervation within the holdfast organ and in and around the oral and ventral suckers.

Rainbow trout (Oncorhynchus mykiss) neuropeptide Y.

Neuropeptide Y (NPY) has been isolated from brain extracts of the rainbow trout (Oncorhynchus mykiss) and subjected to structural analyses. Plasma desorption mass spectroscopy estimated the molecular mass of the purified peptide as 4303.9 Da. Automated Edman degradation unequivocally established the sequence of a 36 amino acid residue peptide as: Tyr-Pro-Pro-Lys-Pro-Glu-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Pro-Glu-Glu-Leu-Ala- Lys- Tyr-Tyr-Thr-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr. The molecular mass calculated from this sequence (4304 Da) is consistent with that obtained by mass spectroscopy. The presence of a C-terminal amide was established by radioimmunoassay. Rainbow trout NPY is identical in primary structure to coho salmon (Oncorhynchus kisutch) pancreatic polypeptide (PP). These data may indicate that, in this group of salmonid fishes, a single member of the NPY/PP peptide family is expressed in both neurons and peripheral endocrine cells.

Effects of single-dose L-asparaginase on coagulation values in healthy dogs and dogs with lymphoma.

Ten healthy dogs and 10 dogs with multicentric lymphoma were given a single dose of L-asparaginase at a rate of 10,000 IU/m2 of body surface. Assessment of concentrations of contributors to the coagulation process and of the ability to coagulate including antithrombin III, one-stage prothrombin time, prothrombin-proconvertin time, activated partial thromboplastin time, plasminogen, fibrinogen, and platelet number were performed prior to drug administration (day 0). These tests were repeated 24 hours (day 1), 48 hours (day 2), and 7 days after treatment with L-asparaginase. Antithrombin-III concentrations were significantly lower in the dogs with lymphoma than in healthy dogs on days 0, 1, 2, and 7; however, with the exception of day 1, mean values remained within normal limits. There was also a difference between the 2 groups in prothrombin/proconvertin values on day 7 and in platelet number on day 2, with the lymphoma group having significantly shorter prothrombin/proconvertin time than healthy dogs, and the difference in platelet numbers being associated with increased counts in the healthy dogs. Data obtained from the healthy dogs and dogs with lymphoma for each coagulation test were pooled for each treatment day (0, 1, 2, and 7), and day-0 values for each coagulation test were compared with data obtained on days 1, 2, and 7. Antithrombin-III concentration on day 7 was significantly lower than on day 0, prothrombin/proconvertin time on day 1 was significantly longer than on day 0, and fibrinogen concentrations on days 1 and 2 were significantly lower than on day 0.(ABSTRACT TRUNCATED AT 250 WORDS)

Comments on functional endoscopic sinus surgery.

A brief comment on functional endoscopic sinus surgery with the result of 208 cases were presented. It was stressed that all sinus patients must have very intensive conservative management, much longer than previously thought, before functional endoscopic sinus surgery should be employed. Functional endoscopic sinus surgery is a vastly superior method of surgically treating the paranasal sinuses. It is based on the principles of reestablishing normal physiology of the sinus mucosa. It affords an excellent basis for removal of disease, establishing natural drainage, aeration and restoration of normal physiology.

Hepatozoon canis in a dog with oral pyogranulomas and neurologic disease.

A ten-month-old Cocker Spaniel presented for fever, difficulty walking, and oral lesions. Muscle pain, bloody diarrhea, respiratory disease and central nervous system inflammation were found while the animal was hospitalized. Merozoites of Hepatozoon canis were discovered in association with pyogranulomas in a muscle biopsy. No other etiologic agent for the clinical signs was identified.

Dermal leishmaniasis in a Texas cat.

Leishmaniasis was diagnosed by demonstrating amastigotes of Leishmania from dermal lesions on the ear of a male long-haired domestic cat from Uvalde, Texas. Leishmania from the cat were propagated in Syrian hamsters, bovine macrophages, and in NNN medium. The organism, in the L. mexicana complex, is apparently the same as that reported from recent human cases in the same area.

A modified technique for semen collection by electroejaculation in the domestic cat.

A method was developed for collecting feline semen by electroejaculation combined with the use of a urethral catheter. The catheter facilitated handling the small volumes of semen for laboratory analysis. In 14 cats, semen volumes ranged from 0.019 to 0.284 ml (mean 0.076) and spermatozoa counts of ejaculates collected in the catheter ranged from 0.32 to 49.60 x 10(6) (mean 11.64 x 10(6)). Nine individuals were evaluated for retrograde ejaculation by quantitation of spermatozoa in pre-ejaculation and post-ejaculation urine samples. No spermatozoa were detected in pre-ejaculation samples but post-ejaculation urine samples contained from 0 to 11.88 x 10(6) (mean 4.55 x 10(6)) spermatozoa. The antegrade portion of the ejaculate contained from 6.3 to 100% (mean 59.1%) of the total number of spermatozoa ejaculated.