Anxiolytic activity of adenosine receptor activation in mice.

1. Purine analogues have been examined for anxiolytic- and anxiogenic-like activity in mice, by use of the elevated plus-maze. 2. The selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) had marked anxiolytic-like activity at 10 and 50 microg kg(-1), with no effect on locomotor performance at these doses. 3. The A1 selective adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (CPX) had no significant effect on anxiety-related measures or locomotor behaviour, but blocked the anxiolytic-like activity of CPA. The hydrophilic xanthine, 8-(p-sulphophenyl) theophylline did not prevent anxiolysis by CPA. 4. Caffeine had anxiogenic-like activity at 30 mg kg(-1) which was prevented by CPA at 50 micro kg(-1). 5. The A2 receptor agonist, N6-[2-(3,5-dimethoxyphenyl)-2(2-methylphenyl)-ethyl]adenosine (DPMA) had no effect on anxiety behaviour but depressed locomotor activity at the highest dose tested of 1 mg kg(-1). The A2 receptor antagonist, 1,3-dimethyl-l-propargylxanthine (DMPX) had no effect on anxiety-related measures or locomotion and did not modify the anxiolytic-like activity of CPA. 6. Administration of DPMA in combination with anxiolytic doses of CPA prevented the anxiolytic-like activity of the latter. 7. The results suggest that the selective activation of central A1 adenosine receptors induces anxiolytic-like behaviour, while the activation of A2 sites causes locomotor depression and reduces the effects of A1 receptor activation. The absence of any effect of CPX alone suggests that the receptors involved in modulating behaviour in the elevated plus-maze in mice are not activated tonically by endogenous adenosine.     

Induction of a novel form of hippocampal long-term depression by muscimol: involvement of GABAA but not glutamate receptors.

1. Unlike long-term potentiation, long-term depression (LTD) in the central nervous system remains poorly understood. The present study was undertaken to investigate the role of GABAA receptors in LTD and synaptic plasticity. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). 3. Muscimol induced a time- and concentration-dependent LTD of the amplitude of orthodromic potentials. Increasing the stimulation frequency from 0.01 Hz to 1 Hz for 10 s reversed the LTD induced by muscimol. Muscimol also induced LTD in the absence of electrical stimulation. 4. Adenosine decreased the spike size in a concentration-dependent manner, but failed to induce LTD. 5. Alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one at concentrations that did not have any effect themselves on the population spike (0.5 and 1 microM), potentiated the inhibitory effect of muscimol on the population spike size, including concentrations which were not effective by themselves. Both steroids were able to potentiate the ability of muscimol to induce LTD. 6. Bicuculline, 5 microM, reversed the LTD induced by muscimol, 10 microM. 7. The NMDA receptor antagonist (+/-)-2-amino-5-phosphonopentanoic acid (2-AP5), the NMDA/metabotropic antagonist 2-AP3 and selective metabotropic antagonist L-(+)-2-amino-3-phosphonopropionic acid (L(+)-AP3) failed to modify the LTD. Similarly, quisqualic acid and (1S, 3R)-aminocyclopentane dicarboxylic acid (ACPD) a selective agonist at metabotropic receptors did not induce LTD or short-term depression, whereas kynurenic acid prevented the reversal of the LTD obtained at 1 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: A phase I study

Background: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. Methods: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m², three patients were treated at 90 mg/m², and five patients received 120 mg/m². A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. Results: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p<0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m². Conclusions: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC. The results of this study were presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Effects of purine analogues on spontaneous alternation in mice

The Y-maze was used to examine the effects of purines acting at A₁ and A₂ adenosine receptors upon spontaneous alternation, a model of working memory, in mice. In support of previous work, scopolamine produced a loss of spontaneous alternation behaviour to the 0.5 chance level. The A₁ receptor selective agonist N6-cyclopentyladenosine (CPA) did not change spontaneous alternation behaviour alone, but it prevented the decrease of spontaneous alternation scores produced by scopolamine. The A₁ receptor selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (CPX) blocked the effect of CPA in combination with scopolamine but had no effect alone. The A₂ receptor selective agonist (N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), and the A₂ receptor selective antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) had no effect of alternation behaviour alone and did not modify the effect of scopolamine. The results indicate the ability of A₁ but not A₂ receptor activation to modify working memory deficits induced by scopolamine, but suggest that endogenous adenosine does not normally participate in working memory processes.     

Reflex sympathetic dystrophy in brain-injured patients.

One-hundred consecutive patients were prospectively evaluated on admission to our Brain Injury Unit for signs and symptoms of reflex sympathetic dystrophy (RSD) in the upper extremity. Patients averaged 4 months postinjury and had an average age of 29 years. Thirteen patients had clinical signs and symptoms of RSD and were then evaluated with standard radiographs and 3-phase radionuclide scintigraphy. Twelve of 13 patients had 3-phase bone scans (TPBS) consistent with RSD (12% overall incidence). RSD was present exclusively in the spastic upper extremity. There were 9 patients with hemiparesis and 3 with quadraparesis. There was a significantly higher (P < 0.01) incidence of associated upper extremity injury in the group with RSD (75%). All patients had a mean Rancho Cognitive Level of V and initial Glasgow Coma Scores less than 8. Patients who developed RSD had lower Glasgow Coma Scores than the non-RSD patients. Brain-injured patients often display agitation, hyperalgesia, disuse or neglect of the RSD-involved extremity. In addition, these patients are often cognitively unable to vocalize complaints of pain. Undiagnosed RSD in these patients can result in a significant delay in rehabilitation and possible loss of the use of an otherwise functional upper extremity.