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Biomedical subjects

J E Barrett

Publications and source records attributed to J E Barrett.

At least 19 recordsLinked to original sources
PubMed1992

Neurochemical effects of 5-HT1 receptor ligands in pigeons.

Pigeon cerebrospinal fluid was assayed for 5-HT (5-hydroxytryptamine) and catecholamine metabolites after systemic drug injection. The 5-HT1-like receptor agonists 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), and 1-(3-chlorphenyl)piperazine (mCPP) decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) without altering other metabolites. 5-HIAA decreases occurred at doses of 8-OH-DPAT and RU 24969 that have anti-conflict effects in pigeons, whereas TFMPP and mCPP decreased 5-HIAA only at behaviorally disruptive doses. The novel compound 1-(2-methoxyphenyl)-1-(4-(2-phthalimido)butyl)piperazine (NAN-190), a putative 5-HT1A receptor antagonist, did not affect 5-HIAA, but attenuated the decreases produced by the agonists. NAN-190 and the alpha 1-adrenoceptor antagonist prazosin increased levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol and had additive effects when co-administered. The rank order of potency in inhibiting [3H]8-OH-DPAT binding in pigeon cerebrum was 8-OH-DPAT = RU 24969 > NAN-190 >> mCPP > TFMPP. The results support suggestions that decreased 5-HT neurotransmission underlies the anxiolytic-like effects of 5-HT1A receptor agonists in pigeons.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Discriminative stimulus effects of 8-OH-DPAT in pigeons: antagonism studies with the putative 5-HT1A receptor antagonists BMY 7378 and NAN-190.

Pigeons were trained to discriminate 0.3 mg/kg of the 5-HT1A receptor agonist 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) from saline. RU 24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole), at doses of 5.6-10 mg/kg, and eltoprazine (5.6 mg/kg), both mixed 5-HT1A/B agonists, substituted completely for 8-OH-DPAT, whereas 3.0-10 mg/kg of the 5-HT1B/C agonist TFMPP (1-(m-trifluromethylphenyl)piperazine) and 0.1-3.0 of the 5-HT3 antagonist MDL 72222 (3-tropanyl-3,5-dichlorobenzoate) yielded only saline-appropriate responses. Substitution for 8-OH-DPAT by eltoprazine and RU 24969, which does not occur in rats, provides in vivo support for the suggestion that the absence of a 5-HT1B receptor in the pigeon allows more complete expression of 5-HT1A-mediated effects. BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)]8-azaspirol-[4.5]- decane-7,9-dione) attenuated the 8-OH-DPAT stimulus at doses from 1.0 to 10 mg/kg but, when administered alone, also resulted in approximately 40% 8-OH-DPAT-appropriate responding at the highest dose. NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalamido)butyl)-piperazine (0.3-3.0 mg/kg) produced a dose-dependent and complete antagonism of the 8-OH-DPAT-discriminative stimulus; administered alone NAN-190 resulted only in saline-key responding. NAN-190 also reversed the rate-decreasing effects of higher doses of 8-OH-DPAT. The beta-adrenoceptor antagonist (+/-)-pindolol (5.6-17 mg/kg) antagonized the discriminative stimulus effects of lower 8-OH-DPAT doses but was unable to block the effects of higher doses of 8-OH-DPAT. Prazosin (1.0-10 mg/kg), which like NAN-190, is an alpha 1-antagonist, neither substituted for nor blocked the discriminative stimulus effects of 8-OH-DPAT. These results suggest that NAN-190 is an effective 5-HT1A receptor antagonist in this procedure with pigeons, with no indication of agonist actions, whereas BMY 7378 and pindolol are best characterized as partial 5-HT1A receptor agonists.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Historical influences affecting the behavioral actions of abused drugs.

The studies summarized briefly in this chapter provide several examples of experiments in which a behavioral or pharmacologic history produced profound changes in the effects of an abused drug. In many instances these changes were qualitative, that is, the direction of the effects that drug usually has on behavior was modified dramatically. AMPH and cocaine--both of which may normally decrease a particular behavior--will, after a suitable history, produce large increases in the behavior under study. If the behavioral effects of a drug are related to the abuse potential of that drug, then any condition that alters the behavioral effects of that drug could be an important component underlying vulnerability to drug abuse. A noteworthy aspect of the studies that have been described is the lasting influence that prior experience can have on behavior and the behavioral effects of drugs in the absence of overt changes in behavior itself. The traces of past experience may not be apparent in ongoing behavior until a drug is administered. This feature makes drugs an important tool for studying behavioral processes and raises several related questions pertaining to the mechanisms responsible for these effects (Barrett 1986). Although at present there is little information available to answer the several questions raised by these experiments, newer techniques available in the neurosciences promise to help reveal the neurobiological correlates of these changes that should be of general importance in understanding both behavioral and pharmacologic processes.

Animals↗
PubMed1992

Antagonism studies with BMY-7378 and NAN-190: effects on 8-hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons.

The purported serotonin (5-HT)1A antagonists BMY-7378 and NAN-190 were examined in pigeons for their potential to block the effects of the prototypical 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on punished ("conflict") and unpunished behavior and for their binding affinity at the 5-HT1A receptor site labeled by [3H]-8-OH-DPAT. Although BMY-7378 and NAN-190 both displayed high affinity for the 5-HT1A receptor (IC50 values of 0.8 and 7.5 nM, respectively), their effects, when administered alone, as well as in combination with 8-OH-DPAT, were distinct. 8-OH-DPAT (0.3-3.0 mg/kg) produced large increases in punished responding at doses that did not affect or that decreased unpunished responding. Administration of NAN-190 (1.0-3.0 mg/kg) did not increase punished responding, whereas BMY-7378 (1.0-5.6 mg/kg) slightly increased behavior suppressed by punishment. Pretreatment with BMY-7378 attenuated the rate-increasing effects of 8-OH-DPAT on punished responding; however, these effects were accompanied by dose-dependent enhancement of the rate-decreasing effects of 8-OH-DPAT on unpunished responding. In contrast, NAN-190 blocked the rate-increasing effects of 8-OH-DPAT on punished responding and also reversed the rate-decreasing effects of 8-OH-DPAT on responding that was not punished. Pretreatment with NAN-190 failed to block increases in punished responding produced by 0.1 to 1.0 mg/kg of the benzodiazepine midazolam. These data suggest that NAN-190 may be characterized as an antagonist and BMY-7378 a partial agonist with respect to 5-HT1A-induced behavioral changes observed in the conflict procedure with pigeons.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Punishment of schedule-controlled behavior with beta-carboline injections: antagonism and comparisons with other compounds.

Squirrel monkeys were trained to press a key under a multiple schedule of food presentation. In the presence of either green or red stimulus lights, the 30th response produced a food pellet (fixed-ratio schedule). In the presence of the red stimulus lights (punishment component), the first response of each fixed-ratio produced either an i.v. injection of histamine [30.0-100.0 micrograms/kg/injection (inj)] or saline, accompanied by a 200-msec presentation of amber stimulus lights. Sessions in which histamine was injected alternated with sessions in which saline was injected. Another group of subjects was studied under identical schedule conditions except that electric shock was scheduled with the 200-msec stimulus light. During alternate sessions, electric shock at a high or low intensity with the stimulus, or the stimulus alone was scheduled. When performances stabilized, histamine or high intensity electric shock selectively suppressed responding in the punishment component; saline, low intensity electric shock or the stimulus light alone had no effects. Subsequently, different doses of histamine, I-nicotine, cocaine or beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were substituted for histamine during single sessions. Histamine (17.8-100 micrograms/kg/inj), I-nicotine (32 micrograms/kg/inj) and beta-CCE (10-56 micrograms/kg/inj), but not cocaine (10.0-100.0 micrograms/kg/inj), produced a dose-related selective suppression of responding similar to that obtained with electric shock, suggesting that the drugs were functioning as punishers. Punishment by beta-CCE was antagonized with the benzodiazepine antagonist, flumazenil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists.

The ability of selective 5-HT3 receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT3 receptor antagonists that are substituted tropines, ICS 205-930 (0.1-0.56 mg/kg) and MDL 72222 (3.0-17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT3 receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25-40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56-1.7 mg/kg), which is also a 5-HT3 receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT2 receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT3 mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT3 receptor antagonists influence their ability to block this action of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Involvement of 5-HT1A activity in the discriminative stimulus effects of imipramine.

Pigeons were trained to discriminate the tricyclic antidepressant imipramine (3.0 or 5.6 mg/kg) from saline. The selective 5-HT1A agonist 8-OH-DPAT (0.03-1.0 mg/kg) resulted in dose-dependent increases in responding on the key correlated with imipramine administration. Doses of 8-OH-DPAT from 0.3 to 1.0 mg/kg substituted completely for imipramine. NAN-190 (0.3-3.0 mg/kg), a putative 5-HT1A antagonist with affinity for both 5-HT1A and alpha 1 receptors, blocked the discriminative stimulus effects of imipramine and resulted in saline-key responding. The discriminative stimulus effects of imipramine were also blocked by administration of the alpha 1-adrenoceptor antagonist prazosin, suggesting a dual mediation of imipramine through both 5-HT1A and alpha 1-adrenoreceptor systems. Although antidepressants have not been used frequently as stimuli in drug discrimination studies, it may be possible to arrive at a more complete understanding of their neurochemical and behavioral effects using this procedure.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Evaluation of the effects of PD 134308 (CI-988), a CCK-B antagonist, on the punished responding of squirrel monkeys.

Lever pressing of squirrel monkeys was maintained by a fixed-interval 3-min schedule of food presentation during which every 30th response also produced a brief electric shock. Lever pressing was suppressed during this stimulus (conflict or punishment) compared to that occurring prior to the introduction of shock or, with some monkeys, during an alternate stimulus in which punishment did not occur. PD 134308 (CI-988), administered i.m. (0.03-3.0 mg/kg), increased punished responding but had no effect on non-punished responding. Peak increases of 150% of control occurred at 3.0 mg/kg. There was no indication of sedation at the highest dose of PD 134308 (10.0 mg/kg). By comparison, chlordiazepoxide (1.0-10 mg/kg, i.m.) produced similar effects, except the magnitude of increases in punished responding reached approximately 200% of control performance levels and the higher doses reduced non-punished response rates. PD 134308 produces anxiolytic-like effects in this animal model of anxiety that would suggest potential clinical efficacy in humans of a novel class of compounds with actions at or modulated by cholecystokinin receptors.

Animals↗
PubMed1991

Neurochemical changes correlated with behavior maintained under fixed-interval and fixed-ratio schedules of reinforcement.

Key pecking of 4 pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixed-ratio schedule of food presentation. Only one schedule was in effect during an experimental session, and each was correlated with a different keylight stimulus and location (left vs. right). The different schedule components alternated across days or weeks. Cerebrospinal fluid was collected from chronically implanted intracerebroventricular cannulae following sessions with the different schedules, as well as following sessions in which reinforcement was withheld (extinction), when response-independent food was delivered, and when the experimental chamber was dark and there were no scheduled events. Metabolites of the neurotransmitters serotonin, norepinephrine, and dopamine were assayed in cerebrospinal fluid using high-performance liquid chromatography with electrochemical detection. Compared to the fixed-ratio condition, responding maintained under the fixed-interval schedule resulted in consistently higher levels of the serotonin metabolite 5-hydroxyindoleacetic acid and of the dopamine metabolite homovanillic acid in all pigeons. Levels of 3-methoxy-4-hydroxyphenylethylene glycol, a metabolite of norepinephrine, and dihydroxyphenylacetic acid, another dopamine metabolite, were also higher in 3 of the 4 pigeons following exposure to the fixed-interval schedules when compared to levels of these metabolites after exposure to the fixed-ratio schedule. Extinction of fixed-ratio responding resulted in large increases in 5-hydroxyindoleacetic acid compared to levels of this metabolite under the fixed-ratio schedule, whereas this serotonin metabolite decreased during extinction of responding under the fixed-interval schedule. Control procedures suggested that the neurochemical changes were not related to the rate of responding but were a function of the specific experimental conditions. Distinctive neurochemical changes that accompany schedule-controlled responding show the sensitivity of the neurochemical environment to behavioral contingencies and demonstrate further the profound impact that such contingencies have on biobehavioral processes.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Imipramine as a discriminative stimulus.

The tricyclic antidepressant imipramine was established as a discriminative stimulus in pigeons at two doses (3.0 or 5.6 mg/kg). Because imipramine has multiple effects on different neurotransmitter systems, a range of compounds from several pharmacological classes were tested for substitution. The tricyclic antidepressants desipramine, amitriptyline and doxepin, all of which block serotonin (5-HT) and norepinephrine (NE) reuptake, resulted in imipramine-key responding. The psychomotor stimulants cocaine and d-amphetamine also occasioned responding on the imipramine key, as did the NE reuptake inhibitor tomoxetine; nomifensine, which blocks the reuptake of both NE and dopamine (DA), also resulted in responding on the key correlated with imipramine injections. Bupropion, a DA reuptake inhibitor, resulted in drug key responding but substitution did not occur with another DA uptake inhibitor GBR 12909. The alpha-2 agonist clonidine, the 5-HT2 antagonist ritanserin or the 5-HT reuptake inhibitor fluoxetine also did not occasion drug-key responding. Drug-appropriate responding occurred in pigeons trained at the lower dose of imipramine with the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide and gepirone; partial substitution occurred in pigeons trained with the higher dose of imipramine. Substitution for the imipramine stimulus by gepirone, an antidepressant with actions mediated by the 5-HT1A receptor, as well as with 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, suggests that imipramine may have effects at this receptor site and confirms reports that compounds active at this receptor may have antidepressant activity. This appears to be the first report of the successful, long-term establishment of imipramine as a discriminative stimulus without the development of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMed1991

Strategic planning: a biomedical communications model.

This article describes a biomedical communications approach to strategic planning. This model produces a short-term plan that allows a department to take the competitive advantage, react to technological change, and make timely decisions on new courses of action. The model calls for self-study, involving staff in brainstorming sessions where options are identified and ideas are prioritized into possible strategies for success. The article recommends that an evaluation and monitoring schedule be implemented after decisions have been made.

Communication↗
PubMed1990

Interactions of corticotropin-releasing factor with antidepressant and anxiolytic drugs: behavioral studies with pigeons.

A number of studies have shown significant interactions between neuronal systems involved with corticotropin-releasing factor (CRF) and either the clinical manifestations of depression and anxiety or the effects of antidepressant or anxiolytic drugs. In the present study, effects of CRF were studied alone and in combination with imipramine and with the sedative-hypnotic/anxiolytic drugs pentobarbital and chlordiazepoxide. Interactions of CRF with the novel, atypical anxiolytic buspirone were also examined. Interactions were evaluated through the use of schedule-controlled responding, responding suppressed by punishment, and drug discrimination procedures using the conditioned key-pecking response of pigeons. Effects of CRF were significantly enhanced when given in combination with imipramine with low noneffective imipramine doses potentiating the rate-reducing effects of CRF. Similarly, in pigeons trained to discriminate imipramine from saline, noneffective doses of CRF shifted the imipramine dose-response curve more than twofold to the left. Low doses of imipramine that produced saline key responding, produced imipramine-key responding when coadministered with CRF. The CRF antagonist alpha-helical CRF9-41 did not alter the rate-decreasing effects of imipramine. Effects of CRF on schedule-controlled responding were, however, antagonized by the administration of chlordiazepoxide and pentobarbital but not by buspirone, suggesting that CRF interacts with the GABA/benzodiazepine receptor mechanism complex but not with those systems involved in mediating the effects of buspirone. These results suggest that CRF interacts in significant ways with specific neurotransmitter systems subserving depression and anxiety.

Animals↗
PubMed1990

5-HT1A agonist effects on punished responding of squirrel monkeys.

Buspirone and other drugs that act as 5-HT1A agonists appear to be clinically effective anxiolytics in humans, yet their anticonflict effects, though robust in pigeons, are equivocal in rodents. In the present study we examined the effects of the benzodiazepine midazolam and a series of 5-HT1A agonists on punished responding of squirrel monkeys. Lever presses were reinforced according to a fixed-interval 3-min schedule; in addition, each thirtieth lever press was punished. Midazolam produced large increases in response rates, whereas none of the 5-HT1A compounds produced any increases in responding. Most of these drugs decreased response rates at the higher doses examined. Although the reasons for the discrepancy between species in the anticonflict effects of serotonergic anxiolytics cannot be specified, the different anatomical distribution of 5-HT1A binding sites across species may suggest a different functional role for this receptor.

Animals↗
PubMed1979

Effects of chlordiazepoxide on comparable rates of punished and unpunished responding.

Identical overall rates and patterns of key pecking by pigeons were maintained under a multiple fixed-interval schedule of food presentation. In one component, every thirtieth response produced an electric shock (punishment) whereas during the other component the response that produced food had to be preceded by a pause of a minimum (10 or 11 s) duration. Although chlordiazepoxide (1.0--17.0 mg/kg) increased both punished and unpunished responding, greater increases were uniformly obtained with punished responding.

Animals↗
PubMed1979

Two Bass Scale factors and response to placebo and anxiolytic drugs.

Two principal oblique factors are identified in the Bass Social Acquiescence Scale, a measure previously shown to correlate positively with placebo response and negatively with anxiolytic drug response. The two factors appeared very similar in separate analyses of data from samples of 941 psychiatric outpatients and 1,837 college students. Also, results are presented which indicate that one factor, tentatively labeled "traditionalism", accounted for the empirically observed relationships to placebo and drug response in two clinical trials.

Anti-Anxiety Agents↗