Biomedical subjects

J E Barrett

Publications and source records attributed to J E Barrett.

At least 37 records · Page 2Linked to original sources

PubMed1997

Blockade of behavioral effects of bretazenil by flumazenil and ZK 93,426 in pigeons.

Benzodiazepine receptor partial agonists manifest full efficacy in preclinical tests of anxiolytic drug action but do not fully reproduce the discriminative stimulus effects of benzodiazepine receptor full agonists in pigeons. The partial agonist, bretazenil, binds to both diazepam-sensitive and diazepam-insensitive GABAA receptors. Previous studies have suggested a role for each of these receptor populations in some behavioral effects of bretazenil in pigeons. A possible role for these receptor subtypes in the behavioral effects of bretazenil was further investigated through drug interaction studies with the benzodiazepine receptor antagonists, flumazenil and ZK 93,426. Whereas flumazenil binds with high affinity to both receptor isoforms, ZK 93,426 binds preferentially to diazepam-sensitive binding sites. Bretazenil markedly increased punished responding of pigeons without significantly affecting nonpunished responding. In pigeons discriminating the full benzodiazepine receptor agonist, midazolam, from saline, bretazenil produced only 60-75% maximal effect. Flumazenil and ZK 93,426 neither increased punished responding nor substituted for midazolam, but dose-dependently blocked the effects of bretazenil on punished responding. Flumazenil also dose-dependently blocked the effects of bretazenil in midazolam-discriminating pigeons, whereas ZK 93,426 only attenuated this effect. These results indicate that bretazenil's actions as a partial agonist at diazepam-sensitive benzodiazepine receptors mediate increases in punished responding and substitution for the discriminative stimulus effects of midazolam in pigeons. The differences in the effects of flumazenil and ZK 93,426 on the discriminative stimulus effects of bretazenil suggest a potential contribution of diazepam-insensitive sites to this behavioral effect.

Animals↗

PubMed1997

Attenuation of the locomotor activating effects of D-amphetamine, cocaine, and scopolamine by potassium channel modulators.

1. Locomotor activating effects of D-amphetamine, cocaine, and scopolamine were determined alone and after pretreatment with K-channel modulators in mice. 2. When administered alone, D-amphetamine (1.0- 30 mg/kg) and cocaine (3.0- 56 mg/kg) produced inverted U-shaped dose-effect curves characteristic of psychomotor stimulant drugs. 3. When administered alone, scopolamine (3.0-56 mg/kg) also produced dose-dependent increases in locomotor activity but these effects plateaued with similar increases in locomotor activity induced by 10-56 mg/kg of scopolamine. 4. Pretreatment with the K-channel blockers 4-aminopyridine (0.3-1.7 mg/kg), quinine (30-100 mg/kg) or apamin (0.3-1.0 mg/kg) attenuated the locomotor increases induced by d-amphetamine, cocaine, and scopolamine. 5. Like the K-channel blockers, pretreatment with the K-channel openers cromakalim (1.0-3.0 mg/kg) and pinacidil (3.0-10 mg/kg) also attenuated the locomotor increases induced by D-amphetamine and scopolamine but did not modify the locomotor activating effects of cocaine. 6. These results demonstrate that K-channel modulation modifies the effects of D-amphetamine, cocaine, and scopolamine. 7. The results also demonstrate that K-channel openers can differentially alter the behavioral effects of cocaine and D-amphetamine.

4-Aminopyridine↗

PubMed1997

Punishment alters the discriminative stimulus effects of midazolam.

Experiment 1 examined the effects of punishment on the discriminative stimulus (DS) effects of midazolam (M) and pentobarbital (P) in 3 pigeons. Sessions began with a fixed-interval (FI) 3-min schedule of food reinforcement. After 40 min, either saline (S) or 0.56 mg/kg of M was injected. A drug-discrimination (DD) component began 10 min later. Pecking the left key produced grain after S injections, whereas pecking the right key produced grain after M. Dose-response curves for M and P were obtained under these conditions and also when every 30th peck during the FI was punished by shock. The introduction of punishment increased sensitivity to the DS effects of M and P. Experiment 2 examined whether a punishment history increases sensitivity to the DS effects of M. After DD training and testing, pecking was punished for 10 sessions. This history shifted the M dose-response curve to the left for 3 of 4 pigeons. These results emphasize the contribution of behavioral variables to the DS effects of drugs. Environmental variables appear to play a prominent role in guiding sensitivity to the subjective effects of drugs.

Animals↗

PubMed1996

Behavioral and biochemical characterization of benzodiazepine receptor partial agonists in pigeons.

The ability of benzodiazepine receptor partial agonists to exhibit full efficacy in preclinical anxiolytic tests, in conjunction with initial clinical results, has suggested the possibility of a reduced clinical side-effect profile compared to benzodiazepine receptor full agonists like diazepam. Because punished behavior of pigeons has been useful in detecting effects of novel anxiolytic drugs, effects of imidazobenzodiazepine and beta-carboline benzodiazepine receptor partial agonists and some related compounds were evaluated in this species. The abilities of these compounds to substitute for the discriminative stimulus effects of the full agonists midazolam also was determined. Intrinsic efficacy was assessed by the degree to which gamma-aminobutyric acid increased ligand potency to displace [(3)H]Ro15-1788 (flumazinil) from membranes of pigeon cerebrum, and ranged from full agonist-like efficacy (Ro 19-5470; 7-(3-cyclopropyl-1,2,4-oxodiazol-5-yl)-5,6-dihydro-5-methyl-4H- imidazo[1,5a]-thieno[3,2-f]diazin-4-one) to minimal gamma-aminobutyric acid potentiations close to that of the antagonist flumazenil (abecarnil and Ro 41-7812; 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a] -[1,4 ]benzodiazepine-6-one). Punished responding was increased markedly by midazolam and by all partial agonists, except Ro 41-7812 and Ro 42-8773 (7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4,5-dihyro-5 -methyl-6H-imidaz o[1,5-a][1,4]benzodiazepine-6-one), at doses that did not affect nonpunished responding. In contrast to the full substitution generally observed in mammals, all of the partial agonists produced incomplete substitution (40-70%) in the midazolam drug discrimination procedure in pigeons. A positive relationship was observed between the degree of substitution and intrinsic efficacy. The benzodiazepine antagonists, flumazenil and ZK 93,426 (ethyl-5-isopropoxy-4-methoxymethyl-beta-carboline-3-carboxylate), neither increased punished responding nor substituted for midazolam. The results of the present study suggest that benzodiazepine receptor partial agonists and related compounds may provide full anxiolytic activity at doses that do not fully reproduce the subjective effect profile of full agonists.

Animals↗

PubMed1995

Prevalence of mental disorders in primary care. Implications for screening.

OBJECTIVES: To determine the prevalence of five mental disorders in primary care and to identify patient groups that have a relatively high prevalence of these disorders. DESIGN: Two-stage case identification design that involves administration of a 16-item screening instrument followed by an independent diagnostic assessment. SETTING: Three family practice offices in Rhode Island. SUBJECTS: A total of 937 primary care patients completed the brief screen, 388 of whom completed the independent diagnostic assessment. PREVALENCE ESTIMATION: A Bayesian procedure was used to estimate prevalence of mental disorder from screening and assessment results. Independent assessments were based on the Structured Clinical Interview for DSM-III-R administered by a mental health professional. RESULTS: The prevalence estimates were alcohol abuse or dependence, 3.2%; generalized anxiety disorder, 2.8%; major depressive disorder, 14.1%; obsessive-compulsive disorder, 2.2%; panic disorder, 6.2%; and any of the five disorders, 22.0%. The prevalence of any of the five disorders was higher in patients returning for follow-up visits (27.9%) than in those either presenting with a new illness (21.7%) or seeking a routine physical examination (11.8%). The combined prevalence was also higher in patients with a chronic medical problem (25.8%) than in those without (16.7%). CONCLUSIONS: Patients returning for follow-up care and, to a lesser extent, those with chronic medical problems appear to be at increased risk of having a mental disorder. The practice of selectively screening new patients for mental health problems is questioned. Screening efforts in primary care should include established patients and those with chronic medical illnesses as well as new patients.

Adult↗

PubMed1995

Development and validation of the SDDS-PC screen for multiple mental disorders in primary care.

OBJECTIVE: To develop, validate, and cross-validate a patient-completed screen for multiple mental disorders in primary care. DESIGN: Comparison of a patient self-report screen with an independent diagnostic assessment by mental health professionals using the Structured Clinical Interview for DSM-III-R diagnoses as criterion standard. SETTING: Three Rhode Island family practices and a South Carolina family medicine residency. SUBJECTS: In the initial validation study, 937 patients in Rhode Island were screened; 388 were interviewed. In the cross-validation study, 775 patients were screened in Rhode Island and South Carolina, and 257 were interviewed. SCREEN ITEMS: Sixty-two questions pertaining to nine mental disorders and suicidal ideation. RESULTS: A 16-item screen remained after analysis of item and scale performance. Sensitivity, specificity, and positive predictive value, respectively, were calculated for the following scales: alcohol abuse or dependence (62%, 98%, and 54%), generalized anxiety disorder (90%, 54%, and 5%), major depression (90%, 77%, and 40%), obsessive-compulsive disorder (65%, 73%, and 5%), panic disorder (78%, 80%, and 21%), and suicidal ideation (43%, 91%, and 51%). Replication in a new sample showed attenuated but acceptable operating characteristics for cross-validation. CONCLUSIONS: The Symptom-Driven Diagnostic System for Primary Care screen assesses multiple mental disorders that are common to primary care. It serves as a sensitive, valid, and patient-friendly first step in a new approach to recognizing and managing mental disorders in primary care. Finally, it aids the primary care clinician in selecting an appropriate diagnostic interview module for the disease for which the patient screened positive.

Adult↗

PubMed1995

Brief diagnostic interviews (SDDS-PC) for multiple mental disorders in primary care. A pilot study.

OBJECTIVE: To pilot test the feasibility and validity of new, brief, structured, physician-administered diagnostic interviews for six mental disorders in primary care patients identified from a patient-completed screen. DESIGN: Comparison of the new diagnostic interviews with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, version P (SCID-P), administered independently by a mental health professional. SETTING: Three Rhode Island family practices and a South Carolina family medicine residency. SUBJECTS: Consecutive patients of either sex, aged 18 to 70 years, who were able to read and write English were eligible for screening; 775 patients completed the screen. Of these, 246 screened positive for at least one disorder and received at least one module. Of these, 158 received a SCID-P interview. RESULTS: The diagnostic interviews were found useful by all 16 participating physicians. Eighty-seven percent reported that they diagnosed a new mental problem, and 93% said that the modules clarified suspected symptoms. However, 26% thought the procedure was too time consuming, and 80% believed that reimbursement would be necessary for routine use. Detection of cases using the diagnostic modules was associated with physician intervention and with independent assessment of patient impairment. Over three quarters of the patients (76.4%) who were classified as positive by the physician interview for any of the diagnoses also tested positive on the SCID-P. Two thirds of the patients (62.7%) with at least one of the disorders (according to SCID-P) were classified by the physician interview as having a mental disorder. However, the operating characteristics varied across specific disorders and indicated a need for revisions and testing in larger samples. CONCLUSIONS: These brief physician-administered diagnostic interview modules are part of a screening and diagnostic system (Symptom-Driven Diagnostic System for Primary Care [SDDS-PC], The UpJohn Co, Kalamazoo, Mich) to detect mental disorders in primary care patients. The pilot results help establish their feasibility and validity.

Adult↗

PubMed1995

The discriminative stimulus effects of methamphetamine in pigeons.

This experiment was designed to elucidate the neurotransmitter systems that mediate the discriminative stimulus effects of methamphetamine. Four pigeons were trained to peck one key following saline injections and a second key following methamphetamine injections (1.0 or 1.7 mg/kg, IM). Substitution tests revealed drug-appropriate responding following administration of the psychomotor stimulants methamphetamine, amphetamine and cocaine, the dopamine (DA) reuptake inhibitor bupropion, norepinephrine (NE) reuptake inhibitors imipramine and tomoxetine, and the serotonin (5-HT) releaser fenfluramine. Saline-key responding occurred following administration of the D1 agonist SKF-38393, the D1 antagonist SCH-23390, the alpha 2 receptor agonist clonidine, the alpha 1 antagonist prazosin, a nonselective beta-antagonist propranolol and the selective 5-HT reuptake inhibitor fluoxetine. The D2/D3 agonist quinpirole produced drug-appropriate responding in two pigeons and partial substitution in the remaining two pigeons. The 5HT1A agonist 8-OH-DPAT produced drug-appropriate responding at higher doses (0.3-1.0 mg/kg), whereas much lower doses (0.003-1.0 mg/kg) antagonized the methamphetamine stimulus. The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT3 antagonist, MDL 72222, failed reliably to attenuate drug key responding. These results suggest that NE and DA reuptake inhibition and 5-HT release mediate the discriminative stimulus effects of methamphetamine as do the 5-HT1A and DA D1 and D2 receptors.

Animals↗

PubMed1995

K-channel blockers attenuate the presynaptic effects of the D2/D3 agonist quinpirole in monkeys.

The present study investigated whether potassium channel blockade could modify the behavioral effects of the dopamine D2/D3 receptor agonist quinpirole in squirrel monkeys. The duration of immobility and/or unusual postures indicative of catalepsy-associated behavior or the duration of scratching, known to be related to the effects of low and high doses, respectively, of quinpirole, were scored during 5-min observation periods in three squirrel monkeys. Saline or incremental doses of quinpirole were administered 10 min before each observation period. Administration of saline did not increase the durations of catalepsy-associated behavior (8% of the observational period) or scratching (< 1% of the observational period). Low doses of quinpirole (0.003-0.03 mg/kg) dose dependently increased the duration of catalepsy-associated behavior to approximately 54% of the observational periods. Higher doses of quinpirole (0.1-0.3 mg/kg) did not increase the duration of catalepsy; rather, these doses increased the duration of scratching to approximately 57% of the observational periods. The differential induction of catalepsy-associated behavior or scratching is believed to be related to, respectively, pre- and postsynaptic activity of quinpirole on dopamine D2/D3 receptors. Pretreatment with the potassium channel blockers apamin, 4-aminopyridine, and amodiaquin attenuated the effects of quinpirole (0.03 mg/kg) on catalepsy-associated behavior, with cataleptic postures maintained for 27, 21, and 24% of the observational periods, respectively. In contrast, pretreatment with potassium channel blockers did not consistently affect the scratching induced by quinpirole. In addition, apamin did not attenuate the catalepsy-associated behavior induced by the postsynaptic D2 receptor antagonist haloperidol (0.01-0.1 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗

PubMed1995

5-HT3 receptor-independent inhibition of the depolarization-induced 86Rb efflux from human neuroblastoma cells, TE671, by ondansetron.

The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells. This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 microM), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205-930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron. A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(1H)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.

Anti-Anxiety Agents↗

PubMed1995

The SDDS-PC: a diagnostic aid for multiple mental disorders in primary care.

The Symptom Driven Diagnostic System for Primary Care (SDDS-PC) is a new computerized clinical procedure to assist primary care physicians in diagnosing mental disorders during the course of routine practice. It has three components: (1) a 5-minute patient-administered 16-item screening questionnaire, (2) six 5-minute physician-administered diagnostic interview modules based on DSM-III-R criteria, and (3) a longitudinal tracking form. The SDDS-PC covers five disorders (major depression, panic disorder, alcohol abuse or dependence, generalized anxiety disorder, and obsessive compulsive disorder) as well as suicidal ideation. Patients who screen positive for a disorder receive the corresponding diagnostic interview module. Patients who meet mental disorder criteria on the diagnostic interview module are then followed with the longitudinal tracking form. Minor or subsyndromal conditions are also addressed at the physician's discretion. This article describes the development of SDDS-PC and summarizes results from two studies which involved comparisons between the SDDS-PC and independently administered full-length structured diagnostic interviews.

Depression↗

PubMed1995

Psychological management by family physicians.

BACKGROUND: It is frequently assumed that primary care physicians seldom provide psychological interventions to their patients with mental health problems. This study examines self-reports of psychological interventions by family physicians. METHODS: Primary care patients (N = 937) completed a mental health screening form immediately prior to their medical visit. Results were withheld from their seven respective physicians. Following the visit, the physicians were asked to classify the range of psychological interventions they used to manage their patients' emotional problems during the visit. A structured psychiatric diagnostic interview was subsequently administered to a subgroup of the patients (n = 388). RESULTS: At least one psychological intervention was provided to nearly one fourth (24.1%) of the patients. The interventions included listening to the patient's emotional problems (22.4%), providing advice (19.0%), discussing the patient's mental disorder diagnosis (11.4%), and providing individual counseling (8.4%) or family counseling (0.6%). Two thirds (66.7%) of the patients who reported that their emotional health was poor received at least one of these psychological interventions. In a multivariate model, the likelihood of receiving a psychological intervention was higher for patients who were separated or divorced; those between 45 and 59 years of age; those with less than a college education; those who received disability payments; those who reported poor emotional health; and those who had a positive screening result for panic disorder, major depressive disorder, or obsessive-compulsive disorder. CONCLUSIONS: Primary care physicians may be far more extensively involved in providing psychological interventions than is commonly assumed.

Adolescent↗

PubMed1995

Modification of the behavioral effects of (+/-)BAY k 8644, cocaine and d-amphetamine by L-type calcium channel blockers in squirrel monkeys.

Behavioral effects of the 1,4-dihydropyridine L-type calcium channel activator (+/-)BAY k 8644 [(+/-)methyl-1,4-dihydro-2,6-dimethyl-3- nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate] the monoamine reuptake inhibitor cocaine and the monoamine releaser d-amphetamine were determined alone and after pretreatment with the structurally distinct L-type calcium channel blockers nimodipine (1,4-dihydropyridine), verapamil (phenylakylamine), diltiazem (benzothiazepine) and flunarizine (diphenylalkylamine) in squirrel monkeys responding under a 10-response fixed-ratio schedule of stimulus-shock termination. When administered alone, (+/-)BAY k 8644 (0.1-0.56 mg/kg) produced dose-dependent decreases in rates of responding. Pretreatment with nimodipine (3.0-10 mg/kg) or verapamil (1.0-3.0 mg/kg) produced dose-dependent rightward shifts of the (+/-)BAY k 8644 dose-response curve. In contrast, pretreatment with flunarizine (3.0 mg/kg) produced a leftward and downward shift of the (+/-)BAY k 8644 dose-response curve. Pretreatment with diltiazem (10-17.8 mg/kg) did not modify the (+/-)BAY k 8644 dose-effect curve. In addition, stereoselectivity was evident in the behavioral effects of (+/-)BAY k 8644 with the S(-)-enantiomer being approximately 3-fold more potent than the racemate. When administered alone, cocaine (0.1-5.6 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) produced dose-dependent decreases in rates of responding. Pretreatment with flunarizine (3.0 mg/kg) produced rightward shifts of the cocaine and d-amphetamine dose-response curves. Pretreatment with nimodipine (10 mg/kg), verapamil (3 mg/kg) or diltiazem (17.8 mg/kg) did not modify the effects of cocaine or d-amphetamine. The results of the present study suggest that the behavioral effects of (+/-)BAY k 8644 are differentially modified by L-type calcium channel blockers interacting with different sites on the channel and also suggest that the calcium channel blockers can be distinguished based on their differing interactions with (+/-)BAY k 8644, cocaine and d-amphetamine.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1994

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (-)S 20500.

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock ("conflict" procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01-3.0 mg/kg) and (-) S 20500 (0.3-5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03-5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (-)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (-)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (-)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [3H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in displacing [3H]8-OH-DPAT (IC50 = 2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Evaluation of the discriminative stimulus effects of the novel sedative-hypnotic CL 284,846.

CL 284,846, N-[3-(3-cyanopyrazolo[1, 5-a]pyrimidin-7-yl)phenyl)]-N- ethylacetamide, is a novel non-benzodiazepine sedative-hypnotic with benzodiazepine-like sedative effects, but with less apparent liability for accompanying undesired side effects. In an effort to further characterize its pharmacological activity, CL 284,846 (3.0 mg/kg, IP, 30 min pretreatment) was established as a discriminative stimulus (DS) in rats (n = 7). CL 284,846 (0.3-10.0 mg/kg) showed a dose-related increase in drug-appropriate responding up to the training dose and a dose-related decrease in response rate. The benzodiazepine agonist triazolam (0.1-1.0 mg/kg), the benzodiazepine partial agonist Ro 17-1812 (0.3-3.0 mg/kg) and the triazolopyridazine CL 218,872 (1.0-3.0 mg/kg) substituted for CL 284,846 in all rats, whereas the imidazopyridines zolpidem (3.0-10.0 mg/kg) and alpidem (10.0-30.0 mg/kg), the benzodiazepine partial agonist bretazenil (0.03-10.0 mg/kg) and the novel putative anxiolytic CL 273,547 (10.0-56.0 mg/kg) substituted in most, but not all, rats. Ro 17-1812, bretazenil, and CL 218,872 had no effect on response rate while the other drugs showed a concomitant decrease in rate. The 5-HT1A agonist buspirone (1.0-10.0 mg/kg) and the barbiturate pentobarbital (3.0-17.0 mg/kg) failed to substitute for CL 284,846 up to rate-decreasing doses. The benzodiazepine antagonist flumazenil (3.0-10.0 mg/kg) blocked the DS effects of CL 284,846 in most rats with no effect on response rate. Taken together, these results suggest that the DS effects of CL 284,846 are mediated via benzodiazepine receptors; however, the DS profile of CL 284,846 remains distinct from both benzodiazepine and non-benzodiazepine sedative-hypnotic drugs.

Acetamides↗

PubMed1994

Shock postponement reverses the effects of cocaine on the punished pecking of pigeons.

The effects of cocaine on punished and unpunished key peck responding of pigeons was examined before and after a history of treadle pressing maintained by shock postponement. In one schedule component, the first peck after 3 min produced grain. The alternate component was similar, but every 30 responses was also punished by a mild shock. Punished responding occurred at approximately 25% of the rate of unpunished responding. Cocaine (0.1-10.0 mg/kg IM) did not affect or decrease punished responding; unpunished responding was not systemically affected. Next, a foot treadle was installed and treadle presses postponed shocks for 25 s; shocks occurred every 5 s in the absence of pressing. The treadle was removed when shocks were reliably postponed. Next, the multiple schedule of key pecking was reinstated. At least one dose of cocaine now increased punished pecking; unpunished responding was not systematically altered. These results complement related findings with monkeys and show that pigeons are suitable subjects for studying the reversal of the effects of cocaine on punished responding by a history of postponing shock.

Animals↗

PubMed1994

Anxiolytic and antidepressant mechanisms of 5-HT1A drugs in the pigeon: contributions from behavioral studies.

The discovery that compounds acting through 5-hydroxytryptamine (5-HT) receptor subtypes can produce anxiolytic and/or antidepressant therapeutic effects in humans has resulted in considerable interest in the role of the 5-HT receptor system in both anxiety and depressive disorders. Because many of the clinically efficacious 5-HT1A anxiolytic drugs are either ineffective or produce inconsistent results in traditional or standard types of preclinical punishment or conflict procedures with rodents and other nonhuman mammals, there is considerable need for alternative behavioral assays sensitive to and selective for these compounds. In contrast to data with nonhuman mammals, 5-HT1A drugs are quite effective in pigeons studied under a punishment procedure. This paper reviews the use of the pigeon conflict procedure as a method for the detection and analysis of potential anxiolytic drugs acting through 5-HT1A receptors. Additionally, recent studies, also with the pigeon, have indicated that, in contrast to the rat, it is possible to establish an antidepressant such as imipramine as a discriminative stimulus, and then to use this procedure to evaluate the neuropharmacological bases for the behavioral and, presumably, therapeutic actions of these drugs. Using the drug discrimination procedure, it has been possible to examine a number of selective compounds that substitute for imipramine, thereby clarifying specific substrates for the antidepressant activity of this and related drugs. The pigeon promises to be a useful species in the pharmacological analyses of novel anxiolytic drugs and provides new approaches to the analysis and understanding of traditional as well as the more recently introduced antidepressant drugs.

Animals↗

PubMed1994

Use of cultured human neuroblastoma cells in rapid discovery of the voltage-gated potassium-channel blockers.

Depolarization of human neuroblastoma cells by high concentrations of extracellular potassium ions, leads to the activation of the voltage-gated potassium channels. The activity of such potassium channels can be effectively and rapidly monitored by tracking the efflux of 86Rb from pre-loaded target cells in response to the depolarizing stimulus. The inclusion of compounds with unknown activity in the assay medium, can result in the identification of novel blockers of the voltage-gated potassium channels. Since this functional assay is performed in 96-well microtitre plates, it represents a rapid and high-volume primary screening method for the detection and identification of the voltage-gated potassium-channel blockers, which may have therapeutic utility in several indications including memory degeneration and cardiac arrhythmias.

4-Aminopyridine↗