Signal transduction and hormone-dependent internalization of the thyrotropin-releasing hormone receptor in cells lacking Gq and G11. (1/143)

The thyrotropin-releasing hormone (TRH) receptor was expressed in embryonic fibroblasts from mice lacking the alpha subunits of Gq and G11 (Fq/11 cells) to determine whether G protein coupling is necessary for agonist-dependent receptor internalization. Neither TRH nor agonists acting on endogenous receptors increased intracellular calcium unless the cells were co-transfected with the alpha subunit of Gq. In contrast, temperature-dependent internalization of [3H]MeTRH in Fq/11 cells was the same whether Gqalpha was expressed or not. A rhodamine-labeled TRH analog and fluorescein-labeled transferrin co-localized in endocytic vesicles in Fq/11 cells, indicating that endocytosis took place via the normal clathrin pathway. Cotransfection with beta-arrestin or V53D beta-arrestin increased TRH-dependent receptor sequestration. Fq/11 cells were co-transfected with the TRH receptor and a green fluorescent protein (GFP)-beta-arrestin conjugate. GFP-beta-arrestin was uniformly distributed in the cytoplasm of untreated cells and quickly translocated to the periphery of the cells when TRH was added. A truncated TRH receptor that lacks potential phosphorylation sites in the cytoplasmic carboxyl terminus signaled but did not internalize or cause membrane localization of GFP-beta-arrestin. These results prove that calcium signaling by the TRH receptor requires coupling to a G protein in the Gq family, but TRH-dependent binding of beta-arrestin and sequestration do not.  (+info)

Role of the dorsomedial hypothalamus in mediating the response to benzodiazepines on trial 2 in the elevated plus-maze test of anxiety. (2/143)

Trial 2 in the elevated plus-maze provides an animal model of specific phobia (fear of heights). On this trial, rats no longer respond to benzodiazepines. The present experiment examined the role of the dorsomedial hypothalamus in mediating insensitivity to chlordiazepoxide on trial 2. Rats received a 5 min exposure to the maze, undrugged. Forty-eight hours later, rats injected with control infusions into the dorsomedial hypothalamus showed the usual lack of response to chlordiazepoxide (5 mg/kg, i.p.). However, those receiving lidocaine injections (40 micrograms/microliter in a volume of 0.2 microliter) in the dorsomedial hypothalamus (producing functional inactivation), immediately before trial 2, responded with an anxiolytic response to chlordiazepoxide, characterised by an increased percentage of time on the open arms and by an increased number of entries into, and time spent on, the distal portions of the open arms. Since the lidocaine injections were without anxiolytic effects, our results suggest that this region of the hypothalamus regulates the functional state of benzodiazepine receptors in other brain regions.  (+info)

Drug discrimination under a concurrent fixed-ratio fixed-ratio schedule. (3/143)

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-ratio 10 fixed-ratio 40 schedule of food presentation, in which the fixed-ratio component with the lower response requirement was programmed to reinforce responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized, pigeons averaged 98% of their responses on the pentobarbital-biased key during training sessions preceded by pentobarbital, and they averaged 90% of their responses on the saline-biased key during training sessions preceded by saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, or ethanol, pigeons switched from responding on the saline-biased key at low doses to responding on the pentobarbital-biased key at higher doses (the dose-response curve was quantal). High doses of phencyclidine produced responding on both keys, whereas pigeons responded almost exclusively on the saline-biased key after all doses of methamphetamine. These and previous experiments using concurrent reinforcement schedules to study drug discrimination illustrate that the schedule of reinforcement is an important determinant of the shape of dose-effect curves in drug-discrimination experiments.  (+info)

Outpatient detoxification of the addicted or alcoholic patient. (4/143)

Outpatient detoxification of patients with alcohol or other drug addiction is being increasingly undertaken. This type of management is appropriate for patients in stage I or stage II of withdrawal who have no significant comorbid conditions and have a support person willing to monitor their progress. Adequate dosages of appropriate substitute medications are important for successful detoxification. In addition, comorbid psychiatric, personality and medical disorders must be managed, and social and environmental concerns need to be addressed. By providing supportive, nonjudgmental, yet assertive care, the family physician can facilitate the best possible chance for a patient's successful recovery.  (+info)

The effect of dexamethasone pretreatment on chlordiazepoxide and oxazepam levels in rat plasma. (5/143)

The effect of dexamethasone pretreatment on the level of chlordiazepoxide and oxazepam was examined in the plasma of rats administered with 80 mg/kg of chlorodiazepoxide per os. The concentration of free chlordiazepoxide and unconjugated oxazepam was determined by HPLC method after solid-phase extraction. Pretreatment with dexamethasone significantly increased chlordiazepoxide plasma level 3, 6 and 12 hrs after ingestion, however increase of oxazepam concentration was not statistically significant. AUC 1-24 h after dexamethasone was elevated, for chlordiazepoxide and for oxazepam.  (+info)

Marijuana smoking and reduced pressure in human eyes: drug action or epiphenomenon? (6/143)

Normal pressure within the human eye was reduced after smoking a socially relevant dose of marijuana (12 mg. delta9-9-tetrahydrocannabinol), but only for light to moderate users who experienced a substantial "high" and a state of peaceful relaxation from the experimental dose. Analysis suggests an indirect effect of the drug associated with relaxation-a psychophysiologic state that can be produced by drug and nondrug means.  (+info)

Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity. (7/143)

The present study examines the effect of pregabalin (previously S-Isobutylgaba and CI-1008) in two distinct rat models of anxiety. Pregabalin binds with high affinity and selectivity to the alpha(2)delta subunit of voltage dependent calcium channels (VDCC). Its corresponding R-enantiomer (R-isobutylgaba) is approximately 10 fold weaker. Pregabalin dose-dependently induced anxiolytic-like effects in both the rat conflict test and elevated X-maze with respective minimum effective doses (MED) of 3 and 10 mg kg(-1). In contrast, R-isobutylgaba only showed activity at the highest dose of 100 mg kg(-1) in the conflict test. These data indicate that pregabalin may possess clinical utility as a novel anxiolytic agent and demonstrates the importance of the alpha(2)delta subunit of VDCC in the mediation of anxiety related behaviours.  (+info)

Repeated acquisition of response sequences: stimulus control and drugs. (8/143)

Pigeons obtained food by making four responses on three keys in a specified sequence, e.g., left, right, center, right. Under the "tandem-learning" condition, all three keys were the same color throughout the response sequence, and the sequence was changed from session to session. After total errors per session (overall accuracy) and within-session error reduction (learning) had stabilized, the effects of varying doses phenobarbital and chlordiazepoxide were assessed. For comparison, the drug tests were also conducted under a "tandem-performance" condition, in which the response sequence was the same from session to session, and under corresponding "chain-learning" and "chain-performance" conditions, where different colored keylights were associated with the response sequence. Under all four baseline conditions, the largest dose of each drug impaired overall accuracy. Under the two learning conditions, the error rate decreased across trials within each session, but the degree of negative acceleration was less in the drug sessions than in the control sessions. In contrast, under the two performance conditions, the error rate was relatively constant across trials, but was higher in the drug sessions than in the control sessions. Of the four baselines, the chain-learning condition was the most sensitive to the drug effects.  (+info)