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Biomedical subjects

J W McKearney

Publications and source records attributed to J W McKearney.

At least 19 recordsLinked to original sources
PubMed1990

Effects of serotonin agonists on operant behavior in the squirrel monkey: quipazine, MK-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine.

The behavior of squirrel monkeys was studied under fixed-interval (FI) schedules with responding maintained either by food presentation or by termination of stimuli correlated with impending electric shock delivery (stimulus-shock termination). The 5-HT agonists m-trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP), and 6-chloro-2(l-piperazinyl)pyrazine (MK-212) decreased responding under both the food and shock schedules (0.3-5.6 mg/kg). These decreases in responding were blocked by the nonselective 5-HT antagonists methysergide and mianserin (0.3, 1.0 mg/kg), but not by the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) or pirenperone (0.001-0.1 mg/kg). Quipazine (0.3-5.6 mg/kg) decreased responding under the food schedule, and this effect was blocked by both the nonselective and selective 5-HT2 antagonists. This pattern of antagonism suggests that the decreases in responding produced by quipazine involve significant actions at 5-HT2 sites, whereas those produced by TFMPP, mCPP, and MK-212 do not. In contrast to the decreases in responding seen with the food schedules, quipazine produced moderate increases in responding under the shock schedules. Moreover, these increases in responding were not blocked by methysergide or mianserin, but instead were enhanced. The results with antagonists suggest that certain behavioral effects of quipazine are probably due to actions at 5-HT2 sites, whereas similar effects of TFMPP, mCPP, and MK-212 are more related to actions at other 5-HT receptor subtypes.

Animals↗
PubMed1989

Serotonin-antagonist effects of 1-(1-naphthyl)piperazine on operant behavior of squirrel monkeys.

1-(1-Naphthyl)piperazine (1-NP) has been reported to have serotonin antagonist properties at the 5-HT2 subtype of receptor, and it has been suggested that it may have agonist actions at the 5-HT1 site. In the present experiments, the effects of 1-NP alone and in combination with a variety of 5-HT agonists, were studied in squirrel monkeys performing under a number of reinforcement schedules. The phenalkylamine hallucinogen 4-bromo-2,5-dimethoxyamphetamine (DOB, 0.01-0.3 mg/kg), which is thought to have predominant actions at 5-HT2 sites, reduced responding under fixed-interval (FI) schedules of presentation of food, and these decreases were blocked by 1-NP (0.3-1.0 mg/kg) or by the selective 5-HT2 antagonist, ketanserin (0.3 mg/kg). 1-(1-Naphthyl)piperazine also antagonized the decreases in responding produced by quipazine (0.1-5.6 mg/kg), another agonist with predominant 5-HT2 actions. 1-(m-Chlorophenyl)piperazine (mCPP, 0.1-3.0 mg/kg) and 1-(m-trifluoromethylphenyl)piperazine (TFMPP, 0.1-3.0 mg/kg), both thought to act primarily at 5-HT1 sites, also decreased responding and this effect was blocked by methysergide and by 1-NP, but not by ketanserin. The effects of 1-NP (0.3-5.6 mg/kg) given alone were not like those of mCPP or TFMPP. 1-(1-Naphthyl)piperazine produced moderate increases in responding under shock-avoidance schedules, whereas only decreases in responding were seen after mCPP and TFMPP.(ABSTRACT TRUNCATED AT 250 WORDS)

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1989

Apparent antinociceptive properties of piperazine-type serotonin agonists: trifluoromethylphenylpiperazine, chlorophenylpiperazine, and MK-212.

Squirrel monkeys were studied under a titration procedure in which responding adjusted the intensity of an electrical stimulus delivered to the tail (0.1-3.3 mA range in 15 steps). The 5-HT agonists trifluoromethylphenylpiperazine (TFMPP), chlorophenylpiperazine (mCPP), and 6-chloro-2(1-piperazinyl)pyrazine (MK-212) increased the intensity at which shock was maintained. The order of potency was: MK-212 greater than mCPP greater than TFMPP. Reductions in absolute rates of responding were small, and not related systematically to increases in shock intensity. Pretreatment with the nonselective 5-HT antagonist methysergide (0.1-1.0 mg/kg) resulted in a 3- to 10-fold shift to the right of the dose-effect curves for the 5-HT agonists. In contrast, the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) and pirenperone (0.001-0.1 mg/kg) did not alter the effects of these agonists. This suggests that the apparent antinociceptive actions of these 5-HT agonists are probably mediated by effects at the 5-HT1 receptor subtype.

Animals↗
PubMed1988

Variability in the effects of 4-bromo-2,5-dimethoxyamphetamine (DOB) on operant behavior of squirrel monkeys.

Effects of the hallucinogenic drug (+/-)-4-bromo-2,5-dimethoxyamphetamine HCl (DOB, 0.003-0.3 mg/kg) were studied in squirrel monkeys. Only decreases in responding were seen in monkeys studied under 5-min fixed-interval schedules of food presentation. These decreases were blocked by pretreatment with the 5-HT2 antagonist ketanserin (0.1-1.0 mg/kg) and by the non-selective 5-HT antagonists methysergide (0.3 mg/kg) or mianserin (0.1-1.0 mg/kg). Similar decreases in responding and antagonism by 5-HT antagonists were seen at slightly higher doses of DOM HCl (methyl rather than bromo at the 4 position). In contrast to effects under the food schedule, DOB initially produced marked increases in responding of three monkeys studied under schedules of shock avoidance. However, a complex pattern of changes in the effects of DOB emerged when the same doses were given on subsequent occasions. In one monkey, there were graded increases in responding to a peak of just over 200% of control at 0.17 mg/kg when DOB was given in a roughly ascending dose series. However, no increases in responding were observed at any dose when DOB was given on many subsequent occasions (some very widely spaced). A second monkey showed similar increases initially, but responding was suppressed by a formerly rate-increasing dose of DOB (0.1 mg/kg) on two subsequent test days. Later, this dose again produced increases in responding of about the same magnitude as seen initially, but these increases eventually diminished and were no longer observed. In the third monkey, increases in responding after the initial ascending dose series diminished in an irregular manner over the course of successive redeterminations.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1985

Comparison of regional CNS ligand binding in two inbred rat strains: effects of chronic morphine.

Male rats of the F-344 and BUF inbred strains were given free access to a 10% sucrose solution containing 0.5 mg/ml morphine sulfate (controls received sucrose only) as their sole source of fluids. The daily intake of morphine averaged 101 +/- 13 mg/kg. After 18 days on this regimen, animals were sacrificed and assayed for 3H-clonidine (alpha-2 adrenergic), 3H-dihydroalprenolol (DHA, beta 1 and 2 adrenergic) and 3H-spiperone (SPD, 5-HT2 and D2) binding in several brain regions. In the absence of morphine treatment, BUF rats displayed higher levels of SPD binding in brainstem, as compared with the F-344 strain. In contrast, untreated F-344 rats exhibited higher levels of DHA binding in hypothalamus and SPD binding in striatum than BUF rats. Chronic morphine resulted in an increase in clonidine and DHA binding in the brainstem and hippocampus respectively of BUF, but not F-344 rats, suggesting a greater sensitivity of adrenergic function to opiate treatment in the BUF strain. The two strains differed qualitatively in the effect of morphine on striatal SPD binding, with BUF rats exhibiting a decrease, and F-344 rats an increase. The one consistent change observed in both strains was a quantitatively similar increase in hippocampal SPD binding after chronic morphine. The results demonstrate that despite strain-dependent differences in binding characteristics, chronic morphine elicits a strain-independent alteration in hippocampal 5-HT2 binding. On the basis of these preliminary findings, it may be speculated that this particular neurochemical consequence contributes to morphine-induced behaviors which are observed independent of rat strain.

Animals↗
PubMed1985

Tolerance to behavioral effects of clonidine after chronic administration of morphine.

Male rats (Buffalo strain) were studied under a procedure in which each 30th lick of a drinking tube resulted in the delivery of 0.01 ml water. The effects of clonidine HC1 (0.003-0.3 mg/kg, IP) were determined before, during and after exposure to conditions in which a morphine sulfate solution (0.5 mg/ml in 0.4% saccharin) was the only source of fluid. After either 10 or 80 days exposure to the chronic morphine regimen, rats were maintained under a repetitive cycle in which the morphine was available for 3 days and then removed for 4 days. The subjects consumed an average of 100 mg/kg/day morphine during the times it was available. The effects of clonidine were redetermined once weekly, on the 4th day after removal of the morphine solution. The effects of clonidine were also determined after morphine was removed for more prolonged periods (18-67 days). Chronic exposure to the morphine solution resulted in a 4- to 5-fold shift to the right in the dose-effect curve for clonidine (decreased responding). ED50 values returned to pre-morphine levels when rats were tested at longer post-morphine times (e.g., 18 days). Under the conditions of this experiment, chronic exposure to morphine produced marked cross-tolerance to the behavioral effects of clonidine.

Animals↗
PubMed1983

Effects of clonidine on operant behavior and electric shock titration in the squirrel monkey: effects of alpha 2-adrenoreceptor antagonism.

Squirrel monkeys were studied under fixed-interval schedules in which responding was maintained either by food presentation or by termination of stimuli correlated with electric shock delivery, or under a schedule in which responses decreased the intensity of electric shock, which periodically increased in intensity (shock titration). Clonidine-HCl (0.01-1.7 mg/kg) decreased responding under the fixed-interval schedules and increased the intensity at which shock was maintained under the titration schedule. Pretreatment with the alpha 2-adrenoreceptor antagonist yohimbine-HCl (0.1-1.0 mg/kg) resulted in a 3-10-fold shift to the right in the clonidine dose-response curve. Similar antagonism was seen after pretreatment with small doses of the less selective alpha-adrenoreceptor antagonist, tolazoline-HCl (3.0, 5.6 mg/kg), but not with the alpha 1 antagonist prazosin (0.1, 0.3 mg/kg). The effects of clonidine on behavior under these conditions were apparently due to actions at alpha 2-adrenoreceptor sites.

Adrenergic alpha-Antagonists↗
PubMed1982

Stimulant actions of histamine H1 antagonists on operant behavior in the squirrel monkey.

Squirrel monkeys were studied under fixed-interval schedules of reinforcement in which the first response (lever press) after a fixed period time resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. Benztropine mesylate (0.03-1.7 mg/kg), promethazine HCl (0.3-10 mg/kg), and diphenhydramine HCl (0.3-17 mg/kg) all produced marked increases in responding at intermediate doses. The increases in responding were at least as great as those observed with psychomotor stimulants, such as amphetamine, in this species under similar behavioral conditions. Benztropine was most potent and diphenhydramine was least potent in most monkeys and, in some, promethazine and diphenhydramine were about equipotent. The order of potency and the magnitude of potency differences among the drugs suggest that the behavioral effects were due to antagonist actions at histamine H1 receptors, rather than to effects on dopamine uptake or on muscarinic receptors.

Animals↗
PubMed1982

Effects of dopamine uptake inhibitors on schedule-controlled behavior in the squirrel monkey.

Squirrel monkeys responded under a multiple fixed-interval (FI) fixed-ratio (FR) schedule of stimulus-shock termination. Benztropine mesylate (0.03-1.7 mg/kg), bupropion HCl (0.3-5.6 mg/kg), mazindol (0.01-0.3 mg/kg), and nomifensine maleate (0.1-1.0 mg/kg) markedly increased responding under the FI schedule, but not under the FR schedule. Mazindol was about three-times more potent than nomifensine and ten-times more potent than bupropion. Benztropine and mazindol were about equal in potency. The order and relative magnitude of potency differences for mazindol, nomifensine, and bupropion are similar to those reported by others for in vitro inhibition of dopamine uptake in rat striatum, but the relative potency of benztropine was greater in these behavioral experiments than expected from its potency in inhibiting dopamine uptake.

Animals↗
PubMed1982

Effects of tricyclic antidepressant and anticholinergic drugs on fixed-interval responding in the squirrel monkey.

Squirrel monkeys responded under fixed-interval schedules in which the first response after a fixed time period resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. tricyclic antidepressant drugs markedly increased responding in 3 of 10 monkeys studied; less marked but reliable increases in responding were seen with 3 others, whereas the remaining 4 monkeys showed no increases in responding. Increases in responding were observed with amitriptyline HCl (0.1-17 mg/kg), imipramine HCl (0.3-17 mg/kg), chlorimipramine HCl (0.3-17 mg/kg), nortriptyline HCl (1-17 mg/kg) and desmethylimipramine HCl (1-17 mg/kg). Amitriptyline was most potent and desmethylimipramine least potent. The pattern of individual differences in the effects of the antidepressants was matched by a similar pattern of differences in the effects of atropine sulfate (0.03-1.7 mg/kg) and scopolamine HBr (0.003-0.3 mg/kg). That is, atropine and scopolamine increased responding only in those monkey showing increases in responding with the antidepressant drugs. In contrast, all monkeys showed increases in responding with the histamine H1 antagonist diphenhydramine HCl (0.3-17 mg/kg). The order of potency of the antidepressant drugs for producing response rate increases (i.e., amitriptyline greater than imipramine greater than desmethylimipramine) is the same as that reported by others for the affinity of these drugs for muscarinic binding sites in rat brain. This correspondence in relative potencies in addition to the similar pattern of individual differences produced by the antimuscarinic and antidepressant drugs suggests that the increases in responding observed were mediated by antimuscarinic properties of the antidepressant drugs.

Animals↗
PubMed1980

Fixed ratio schedules of food presentation and stimulus shock termination: effects of d-amphetamine, morphine, and clozapine.

Squirrel monkeys responded under a multiple schedule in which 30 responses during a specified time limit resulted in either food presentation or termination of visual stimuli associated with impending shoch delivery. Schedule components were associated with different colored lights and were separated by 60-s time-out periods in which all lights were extinguished. If the response requirement was not met within the time limit, either the time-out period alone (food components) was presented or a single shock was delivered coincident with onset of time-out. In experiments with d-amphetamine, different control rates of responding were engendered by varying the time limit. When the time limit was 60s, all monkeys responded at higher overall rates during food presentation components. When the time limit was reduced to 15 s, rates of responding in both components increased and became more similar than under the 60-s limit. When control rates in the two components differed under the 60-s time limit, d-amphetamine sulfate (0.01-1.0mg/kg) increased the normally lower rates under the shock schedule at intermediate doses, but generally only decreased the higher rates under the food schedule. With more comparable control rates under the 15-s time limit, the effects of amphetamine were also more comparable. In most cases low and moderate doses either had little effect or slightly increased responding in both schedule components and higher doses decreased responding. Morphine sulfate (0.03-1.7mg/kg) and clozapine (0.1-3.0mg/kg) decreased responding comparably under both food and shoch schedules with the 15-s time limit.

Animals↗
PubMed1980

Tolerance to suppressive effects of chlordiazepoxide on operant behavior: lack of cross tolerance to pentobarbital.

Pigeons responded under schedules in which either the 60th response (fixed-ratio schedule) or the first response after 3 minutes (fixed-interval schedule) resulted in food delivery. The effects of chlordiazepoxide HCl (1-30 mg/kg) and pentobarbital sodium (1-17 mg/kg) were determined before and during chronic daily exposure to either 10 or 17 mg/kg chlordiazepoxide--doses that markedly suppressed responding when given acutely. After about three weeks of daily injections of chlordiazepoxide, there was at least a three-fold shift to the right of the dose-effect curve for chlordiazepoxide, but not consistent change in the effects of pentobarbital.

Animals↗
PubMed1978

Pentobarbital, promazine, d-amphetamine, and scopolamine effects on behavior under multiple and primed schedules of reinforcement.

Pigeons responded under compound fixed-interval (FI) fixed-ratio (FR) schedules of food presentation. Distinctive discrimininative stimuli were either continuously present during each component schedule (multiple FI FR) or were present only for a brief period at the beginning of each component (primed FI FR). Similar rates and patterns of responding were maintained under the multiple and primed schedules. Pentobarbital, scopolamine, and d-amphetamine decreased FR responding, but promazine had little effect at the doses studied. d-Amphetamine and promazine increased FI responding at certain doses, pentobarbital had little effect, and scopolamine decreased responding. There were no systematic differences in the effects of drugs under the multiple and primed schedules, in spite of the differences in discriminative stimuli under the conditions.

Animals↗
PubMed1978

Changes in the effects of d-amphetamine on escape responding by its prior effects on punished responding.

Responses of squirrel monkeys adjusted the intensity of a continuous electric shock under two different schedules. In one schedule, responses decreased a shock intensity which otherwise was increased at a fixed rate (escape). In the other schedule, responses produced food pellets but also increased a shock intensity which otherwise decreased at a fixed rate (punishment). When animals were first studied under the escape schedule, d-amphetamine increased responding. Similarly, when animals had an intervening experience under the punishment schedule with no drugs administered, or when the drug was given but shock increments were tempoerarily eliminated during those drug sessions, d-amphetamine still increased subsequent escape responding. However, when animals under the punishment schedule were given d-amphetamine and shock increments occurred as usual during the drug session, the drug no longer increased either punished or subsequent escape responding. The effects of d-amphetamine on escape responding were completely different depending on the individual's prior drug experience.

Animals↗
PubMed1977

Changes in the rate-increasing effects of d-amphetamine and pentobarbital by response consequences.

Keypecking in one group of pigeons was maintained under schedules in which food was presented only when a specified number of responses was followed by a 30-s pause without a response. d-Amphetamine and pentobarbital increased low rates of responding (and, thus, decreased food presentation) only after initial injections or when, during drug sessions, responses during the 30-s period did not reset the period. When responses during the pause-interval postponed food delivery, the rate-increasing effects of both drugs diminished over succeeding administrations. Thus, immediate effects of response consequences were as influential as the actual presence of a drug in determining the reproducibility of the behavioral effects of that drug. In a second experiment, keypecking in another group of pigeons was maintained under a 10-min fixed-interval schedule of food presentation but suppressed by a 100-response fixed-ratio schedule of shock delivery (punishment). d-Amphetamine and pentobarbital increased low rates of punished responding when shock delivery was eliminated during drug sessions. Pentobarbital, but not d-amphetamine, also increased punished responding when shock delivery was present. Rate-increasing effects of these drugs were determined by not only predrug patterns of responding but also effects of reinforcers and punishers that occurred during exposure to the drug.

Animals↗