Cellular targets of brain reinforcement systems.
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Animals↗
Biomedical subjects
L Stein
Publications and source records attributed to L Stein.
In vitro reinforcement of hippocampal bursting by the cannabinoid receptor agonist (-)-CP-55,940.
Involvement of cannabinoid receptors in behavioral reinforcement is suggested by widespread human use of marihuana, although animal tests of cannabinoid reinforcement have produced mixed results. Cannabinoid receptors are found in high density in rat hippocampus and other brain areas. Using the hippocampal-slice preparation, we attempted to demonstrate in vitro reinforcement of CA1 bursting with local micropressure applications of the high-affinity synthetic cannabinoid receptor agonist (-)-CP-55,940. Approximately 60% of the tested neurons showed increased burst activity after a series of brief, burst-contingent applications of (-)-CP-55,940 at pipette concentrations of 5 and 10 microM. Identical microinjections of (-)-CP-55,940 administered independently of cellular activity did not increase and usually suppressed hippocampal bursting. Since general stimulation of CA1 activity by (-)-CP-55,940 can thus be ruled out, we conclude that burst-contingent applications of a cannabinoid receptor agonist can reinforce hippocampal firing in vitro.
Action Potentials↗
Chest wall configuration assessed at total lung capacity during acute asthma and after recovery.
During acute asthma reversible increase in lung compliance and total lung capacity (TLC) have been observed. The magnitude of the increase in TLC, however, was found to be relatively small when TLC was measured radiographically. We wondered if structural distortion of the respiratory bellows develops during acute asthma attacks, accounting for the limited increase in TLC. We analyzed the chest wall dimensions using chest roentgenograms obtained in 32 patients who had previously participated in the study of radiographic evaluation of TLC. We found that the dimensional changes accompanying the small increase in TLC during acute asthma were nonuniform, consisting of mainly an increase in lung height (0.45 +/- 0.15 cm) with limited coordinated expansion of other dimensions and a small but significant distortional contraction of lung width at the lowest portion of the rib cage (-0.25 +/- 0.12 cm). These findings were interpreted to mean that in response to the decrease in elastic lung recoil (internal load) occurring during acute asthma, the diaphragm makes limited but effective further caudad descent without provoking serious structural distortion and that rib cage muscles, working at mechanical disadvantage at high lung volume, act largely as fixators.
Asthma↗
A binary (Bethesda) system for classifying cervical cancer precursors: criteria, reproducibility, and viral correlates.
This study of cervical squamous precursors addressed the consistency with which pathologists could agree on diagnosis using a Bethesda system and the degree to which the classification system discriminated "high-risk" human papillomavirus (HPV) types. Four pathologists independently assessed biopsies of 75 squamous lesions; all contained HPV DNA amplified from archival fixed tissue with polymerase chain reaction (PCR) and typed by restriction digestion of the PCR product. Lesions were categorized as low or high grade using published criteria. In independently performed histologic evaluations a majority (three or more) of observers agreed on the classification of 63 of the 75 cases (84%) with good to very good interobserver (kappa values, 0.43 to 0.63), and fair to excellent intraobserver (kappa values, 0.32 to 0.83) agreement. A majority of the observers classified as high grade 15 of 17 (88%) HPV 16-positive lesions (P < .002), but only 15 of 21 (71%) lesions associated with other high-risk HPV types 18, 31, 35, and 39 (P = .089). Concurrence among observers also varied with HPV type; majority agreement between three or more observers was present for 100% and 94%, respectively, for lesions associated with HPV 6/11 and HPV 16 versus 82% and 76% for lesions associated with HPV 18/31/35/39 and other HPV types. A binary system for grading cervical precursor lesions was applied with good reproducibility among pathologists, and segregated as high-grade virtually all lesions associated with the prototype high-risk HPV (HPV 16). Conversely, other presumed high-risk HPV types, particularly type HPV 18, were not distinguished by this grading scheme and were segregated frequently with low-grade lesions. This finding suggests that variables other than HPV type alone will influence lesion grade. Resolution of these variables will determine whether lesion grade is a more potent biologic parameter than HPV type.
Female↗
Pertussis toxin attenuates intracranial morphine self-administration.
Mu and delta opioid receptor subtypes are thought to mediate the reinforcing actions of opioids. Since these opioid receptors use pertussis toxin (PTX)-sensitive inhibitory G-proteins for signal transduction, we determined whether PTX would block the opioid reinforcement signals produced by intrahippocampal or intraventral tegmental area (VTA) injections of morphine in rats. Hippocampal PTX pretreatment prevented the acquisition of intrahippocampal morphine self-administration. Similarly, in rats previously trained to self-administer morphine in the VTA, PTX injections in the VTA abolished morphine self-administration behavior, while sparing behavior reinforced by food pellets. This result suggested that the toxin did not interfere generally with motor capacity but rather acted selectively to block morphine reinforcement. Inactivated PTX did not reduce VTA morphine self-administration, thus demonstrating that PTX blockade of opioid reinforcement is primarily due to enzymatic inactivation of inhibitory G-proteins. All these findings are consistent with the hypothesis that inhibitory G-proteins in the hippocampus and VTA mediate the reinforcing effects of opioid drugs.
Animals↗
Pure red cell aplasia and hepatitis A.
A patient with pure red cell aplasia associated with hepatitis A showed a dramatic and rapid recovery after initiation of oral prednisone therapy. The response to corticosteroid therapy suggests an immune etiology for this life-threatening disorder.
Female↗
A cellular analogue of operant conditioning.
Using the hippocampal-slice preparation, we attempted to model operant conditioning in vitro by reinforcing pyramidal cell bursting responses with local micropressure applications of transmitters and drugs. The same injections were administered independently of bursting to provide a "noncontingent" control for direct pharmacological stimulation or facilitation of firing. The results suggested that the bursting responses of individual CA1 pyramidal neurons may be reinforced in a dose-related manner by response-contingent (but not noncontingent) injections of dopamine and the selective dopamine D2 agonist, N-0923. N-0924, a stereoisomer of N-0923 that is largely devoid of D2-agonist activity, failed to reinforce CA1 bursting. Burst-contingent injections of the excitatory neurotransmitter glutamate also failed to reinforce CA1 bursting; indeed, the glutamate applications (whether contingent or random) reduced the likelihood of bursts while increasing the frequency of solitary spikes. Reinforcement delays exceeding 200 ms largely eliminated the reinforcing efficacy of the D2 agonist N-0437 in CA1 operant conditioning. The results are consistent with the suggestion that the behaviorally reinforcing effects of dopaminergic agents can be modeled in vitro in the hippocampal-slice preparation.
Animals↗
The D1 agonists SKF 82958 and SKF 77434 are self-administered by rats.
The reported failure of the prototypical (but partial) D1 agonist SKF 38393 to support self-administration behavior contradicts hypotheses of D1-mediated reinforcement. Here we demonstrate that rats will readily self-administer two SKF 38393 analogs, the partial D1 agonist SKF 77434 and the full D1 agonist SKF 82958; both compounds produce inverted U-shaped dose-response curves. When compared to the parent compound, both analogs display enhanced lipophilicity and somewhat decreased D1/D2 selectivity. It is suggested that these properties, rather than partial D1 agonist efficacy, explain the failure of SKF 38393 to act as a reinforcer.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Hyperamylasemia and hematologic malignancies.
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Adult↗
Receptor subtypes in opioid and stimulant reward.
Studies of the behaviourally-reinforcing actions of opioid and stimulant drugs of abuse are reviewed in an attempt to identify their reward-related brain receptors. We focus on data generated by drug self-administration, brain stimulation reinforcement, and conditioned place preference paradigms. A consistent body of evidence supports a role for mu and delta, but not kappa, receptors in opioid reward. Stimulant reward apparently involves both D1 and D2 receptors; the data favour D2 mediation of stimulant drug reinforcement with a permissive or modulatory role for D1 receptors. The reward-relevant opioid and dopamine receptors, as well as the cannabinoid (marijuana) receptor, share the ability to couple Gi proteins that mediate inhibition of adenylate cyclase and stimulation of K+ conductance. These signal transduction mechanisms thus may be generally implicated in the reinforcing properties of diverse drugs of abuse.
Animals↗
Absence of sensorineural hearing loss in treated infants and children with congenital toxoplasmosis.
Educationally significant hearing loss has been reported in 10% to 15% of children with congenital toxoplasmosis. As part of a pilot study to assess feasibility and safety of prolonged therapy for congenital toxoplasmosis, 30 congenitally infected infants and children were evaluated for auditory function. Serial testing, beginning within 2 months of birth, was performed. Availability of auditory brainstem response (ABR) testing made evaluation at an earlier age than previously possible. Six (20%) of the 30 infants had mild to moderate conductive type hearing loss associated with otitis media. No infant or child had sensorineural hearing loss. The better outcome we observed compared to previous reports of a 15% to 26% incidence of sensorineural hearing loss and 10% to 15% incidence of educationally significant, bilateral hearing impairment may be related to early initiation and/or prolonged institution of antimicrobial therapy. Continued followup to exclude progressive hearing impairment and study of larger numbers of children are needed to verify these preliminary findings.
Audiometry, Evoked Response↗
Hippocampal mu-receptors mediate opioid reinforcement in the CA3 region.
Dependence on reinforcing chemicals is manifested when drug-seeking and drug-taking behaviors come to dominate the response repertoire. Clinical observations suggest that the craving and compulsive drug-seeking that characterize drug dependence are aroused by memories of the reinforcing drug experience. If so, a brain structure intimately associated with memory--the hippocampus--would be a plausible substrate for drug reinforcement effects. We report here that drug-naive rats rapidly learn to self-administer the opioid peptide dynorphin A in the CA3 region of hippocampus, and that this behavior is blocked by co-administration of the non-selective opiate antagonist naloxone. Subsequent studies demonstrated that coadministration of mu-, but not kappa- or delta-opioid antagonists also blocked self-administration behavior. We conclude that mu-receptors in the CA3 region of hippocampus may be important target sites for opioid dependence.
Animals↗
Review of human and animal cases of coccidioidomycosis diagnosed in Canada.
The first Canadian case of coccidioidomycosis in a human was reported in 1952 and 11 more cases since then. This study provides details of other cases of coccidioidomycosis that have been diagnosed in Canada. Based on clinical details, isolation of Coccidioides immitis, detection of a specific antibody (F band) for coccidioidomycosis by macro- or microimmunodiffusion tests, concurrently used with the complement fixation procedure, and histopathological findings, 116 more cases of this disease were verified. The great majority (94%) of these cases were diagnosed in the western Canadian provinces of British Columbia, Alberta, Saskatchewan and Manitoba, and the others in Quebec, Ontario and Nova Scotia (5, 1, and 1 cases, respectively). Available information indicates that the C. immitis infections were contracted during visits to endemic areas in the United States (Arizona, California and New Mexico), Mexico, and Bolivia. Pulmonary infections were the most common type of coccidioidomycosis (93%) followed by the disseminated or meningeal types C. immitis infections occurred in individuals with or without predisposing factor(s) and were more common in males than in females. The exoantigen procedure was very useful and reliable in the accurate and rapid identification of suspected C. immitis isolates. Two cases of coccidioidomycosis were reported in animals in Ontario, Canada.
Aged↗
Naloxone blockade of amphetamine place preference conditioning.
Amphetamine and naloxone were examined in place conditioning, in order to study possible interactions between endogenous opioids and catecholamines in reinforcement. After initial preferences were determined, animals were conditioned with amphetamine alone (1.0 mg/kg SC), naloxone alone (0.02, 0.2 or 2.0 mg/kg SC) or combinations of amphetamine plus naloxone. A reliable, long-lasting preference for the compartment associated with amphetamine was observed, reflecting the reinforcing properties of this drug. No preference or aversion was observed in animals that received saline in both compartments. Naloxone (0.02, 0.2 and 2.0 mg/kg) produced a dose-dependent place aversion; while the lowest dose had effects similar to saline, the higher doses produced significant place aversions. Naloxone, at all three doses examined, prevented the ability of amphetamine to produce a place preference. Thus, the lowest dose of naloxone, having no effects alone in place conditioning was still able to block the reinforcing effects of amphetamine. These results suggest that the reinforcing effects of amphetamine are dependent on activation of opiate receptors, and provide further evidence that interactions between endogenous opioids and catecholamines may be important in reinforcement.
Amphetamine↗
Digital subtraction cavernosography: method to detect venous leakage.
Cavernosography has become an important diagnostic test for detecting venous leakage as a cause of vasculogenic impotence. Digital subtraction cavernosography (DSC) was carried out on 21 patients with a history of venous leakage resulting in impotence. The DSC technique was compared to conventional cineradiography. Major venous leaks were easily identified in 16 patients. DSC was able to detect minor leaks missed by cineradiography in 2 patients. DSC seems to be a reliable technique that is easy to perform. It should be done in conjunction with pharmacologically induced erection.
Angiography, Digital Subtraction↗
Kaposi's sarcoma presenting as linitis plastica.
A 31-yr-old woman presenting with abdominal complaints and fever was found to have linitis plastica on upper gastrointestinal series. Endoscopic studies confirmed these findings; however, pathology revealed the diagnosis to be Kaposi's sarcoma. We believe this to be the first case report of linitis plastica presenting as Kaposi's sarcoma.
Adult↗
Opiate antagonists and self-stimulation: extinction-like response patterns suggest selective reward deficit.
The present study investigated the response decrement patterns produced by opiate antagonists on intracranial self-stimulation behavior, in order to determine if these drugs affect the reinforcement value of the stimulation or interfere with the ability of the animal to respond. Male rats lever-pressed in 60-min sessions on a continuous reinforcement schedule for self-stimulation of the nucleus accumbens. Naloxone (2.0 and 20 mg/kg) and naltrexone (2.0 and 20 mg/kg) suppressed self-stimulation only after a significant delay, in an extinction-like response decrement pattern, mimicking the effects of reductions in current intensity (75% and 50% of baseline). The increasing behavioral effects characteristic of the extinction pattern were observed despite the fact that testing began after the time point at which maximal suppression of self-stimulation occurs with these drugs, and when brain concentrations of these drugs were declining. Since normal responding was observed for several minutes after the beginning of the session, the results may explain why long sessions are necessary to observe suppression of self-stimulation by opiate antagonists. The extinction-like pattern produced by these drugs suggests that opiate antagonists suppress self-stimulation by reducing the reinforcement value of the stimulation, rather than by interfering with the ability of the animal to respond. These findings are consistent with a role for endogenous opioid peptides in brain stimulation reward.
Animals↗
Effects of opiate antagonists and their quaternary analogues on nucleus accumbens self-stimulation.
Naloxone and naltrexone were compared with their quaternary analogues naloxone methobromide and naltrexone methobromide for efficacy in suppressing intracranial self-stimulation behavior. These quaternary analogues effectively block opiate receptors in the periphery, but since they do not readily cross the blood-brain barrier they have little effect on central receptors. Rats with electrodes in the nucleus accumbens were trained to self-stimulate in daily 60-min sessions. Naloxone (0.2, 2.0 and 20 mg/kg) and naltrexone (20 mg/kg) potently suppressed self-stimulation behavior. In contrast, neither naloxone methobromide (0.2 and 20 mg/kg) nor naltrexone methobromide (20mg/kg) had any significant effects on this behavior. These results suggest that blockade of peripheral opiate receptors alone is insufficient to suppress self-stimulation, and therefore support the idea that opiate antagonists suppress self-stimulation by blockade of central receptors that mediate reinforcement.
Animals↗