Biomedical subjects

L D Calder

Publications and source records attributed to L D Calder.

At least 19 recordsLinked to original sources

PubMed2000

Prevalence of hip fracture risk factors in women aged 70 years and over.

We estimated the prevalence of common risk factors for hip fracture and the numbers needed to treat (NNT) to prevent a hip fracture in various high-risk population groups, using a postal risk factor survey of women aged 70 years and above from General Practices in Grampian and Yorkshire. Recorded risk factors included prior fracture of any type; low body weight; smoking; and family history of fracture. The prevalence rates of hip fracture risk factors were 34%, 7% and 11% for previous fracture, maternal hip fracture and smoking, respectively for the Grampian practices (low body weight being defined as falling in the lowest quartile) and 34%, 7% and 7% for a single practice in the York area. Applying previously published estimates of risk, NNT analysis produced a value of about 300 for women with no risk factors, whilst for women with three risk factors it was between 32 and 71, depending on which risk factors were present and assuming intervention reduced fracture rates by 30% or 50%. Groups of women at high risk of hip fracture can easily be identified in primary care and offered treatment, with realistic prospects of hip fracture prevention.

Aged↗

PubMed1999

The diagnostic performance of a PC-based teleradiology link.

AIM: Evaluation of the diagnostic performance of a personal computer based teleradiology link. MATERIALS AND METHODS: Two experienced radiologists assessed 100 cases, all based on chest and skeletal films using teleradiology for 50. These assessments were compared with the consensus of a panel of three independent radiologists. RESULTS: Diagnostic performance of teleradiology and conventional film was similar (sensitivity 88 vs. 90%; specificity 96 vs. 90%; accuracy 91 vs. 90%; not significant). However, the quality of teleradiology images was rated poorer, and the confidence in diagnosis was lower with teleradiology. ROC curve analysis, taking into account diagnostic confidence, showed significantly poorer performance for teleradiology at all thresholds when chest X-rays only were considered. There was no significant difference for skeletal images, although the two smooth curves crossed, suggesting teleradiology might be better when the specificity is high. CONCLUSION: These findings suggest that when this type of teleradiology system is used, the value of rapid reporting must be balanced against poorer image quality, particularly for chest X-rays.

Bone and Bones↗

PubMed1998

The role of dopamine and GABA in the frontal cortex of mice in modulating a motor-stimulant effect of amphetamine and cocaine.

The results of previous studies have indicated that the activation of dopaminergic and GABAergic systems in the prefrontal cortex can decrease dopaminergic and glutamatergic activity in the striatum, ostensibly by the inhibition of corticofugal glutamatergic pathways. The present studies were designed to investigate the cortical influence of dopamine and GABA agonists and antagonists on the motor response to systemically administered amphetamine and cocaine in the mouse. The results show that both dopamine and THIP, the GABA(A) agonist, injected intracortically (i.c.) depress amphetamine- or cocaine-induced stereotypy. That these responses are functionally significant is illustrated by the i.c. effects of sulpiride and bicuculline; they enhance the motor activity of the stimulants, suggesting that both dopaminergic and GABAergic systems in the cortex are activated by systemically administered amphetamine or cocaine. Additional experiments demonstrated that bicuculline i.c. can antagonize the depressant effect of dopamine i.c.; therefore, the dopaminergic inhibition in the cortex appears to be mediated by the activation of a cortical GABA system. These results show that systemically administered amphetamine or cocaine causes dopaminergic effects not only in the striatum but also in the cortex, and that the dopaminergic effect in the cortex may activate a cortical GABAergic system, which in turn, may account for the noted cortical inhibition of the dopaminergic motor-stimulatory action in the striatum.

Amphetamine↗

PubMed1998

The role of dopamine in the mouse frontal cortex: a new hypothesis of behavioral sensitization to amphetamine and cocaine.

In previous studies we demonstrated that dopamine, specifically a D2-receptor system, in the frontal cortex of the mouse functions to inhibit the motor response elicited by systemically administered amphetamine or cocaine; the inhibition appears to be the result of the dopaminergic activation of a GABAergic system. In the present study the inhibitory role of dopamine and GABA in the cortex was investigated in animals that were behaviorally sensitized to stimulant-induced stereotypy. For these studies various dopaminergic and GABAergic drugs were injected intracortically (i.c.) and their effects on stimulant-induced stereotypy were compared in nonsensitized and sensitized mice. The results indicate that the dopaminergic system in the cortex of sensitized animals, in contrast to nonsensitized controls, no longer functions to inhibit the motor response to the stimulants. The change in dopaminergic function in sensitized animals appears to be the result of a qualitative change in the D2 dopamine receptor system and not the result of a change in the associated GABA system. The loss of the inhibitory activity of dopamine in the cortex correlated with the persistence of sensitization. These results suggest a new mechanism to account for behavioral sensitization; that is, the phenomenon is the result of a loss of stimulant-induced dopaminergic inhibition of motor activity normally mediated by the frontal cortex.

Amphetamine↗

PubMed1997

The role of the frontal cortex in the mouse in behavioral sensitization to amphetamine.

Pharmacological studies have shown that a variety of neuroeffectors are involved in behavioral sensitization to amphetamine-induced stereotypy. In the present work, the effect of some of these drugs on sensitization was studied after intracortical administration in order to determine the role of the cortex in mediating their systemic effects. The dopamine antagonists sulpiride and spiperone were both ineffective against the acute response to amphetamine; nevertheless, both blocked the induction of sensitization, suggesting that the mesocortical dopamine pathway is not involved in the acute response but is necessary for the induction of sensitization. Both CPP, an NMDA receptor antagonist, and THIP, a GABA(A) agonist, blocked the acute response and the induction of sensitization to amphetamine. On the other hand, mecamylamine, the nicotinic cholinergic antagonist, failed to affect either the acute response or the induction of sensitization, which suggests that the cortex is not a locus of its activity. Anisomycin, an inhibitor of protein synthesis, and diltiazem, a calcium-channel blocker, were both ineffective against the acute response, but both blocked induction. All of the drugs, except CPP and THIP, were ineffective against the expression of sensitization; therefore, the ability of the other drugs to block expression must reside within another locus. Bicuculline injected intracortically in non-convulsant doses produced a stereotypy indistinguishable from that induced by amphetamine; and the effect was readily antagonized by CPP administered either systemically or intracortically. In contrast, sulpiride by either route of administration failed to block the bicuculline-induced stereotypy; we conclude, therefore, that the stereotypic effect of bicuculline is not mediated by dopamine. These results imply that amphetamine-induced stereotypy is mediated in the cortex by the removal of the inhibitory control of the excitatory system. The data also suggest that cortical dopamine, as well as the NMDA and GABA(A) systems, is important in sensitization to amphetamine. In general the data demonstrate that different neuroeffectors involved in sensitization exert their effects at different brain loci.

Amphetamine↗

PubMed1997

The role of the striatum in the mouse in behavioral sensitization to amphetamine.

Previous results of pharmacological studies of the mechanisms of amphetamine- and cocaine-induced stereotypy in the mouse suggest the involvement of dopaminergic, glutamatergic and GABAergic systems in the striatum. The present experiments were designed to evaluate pharmacologically the role of these neuroeffector systems in behavioral sensitization. Whether administered systemically or in the striatum, pretreatment with the neurotransmitter antagonists, sulpiride, bicuculline and CPP, blocked both the induction and the expression of behavioral sensitization. Efforts to induce sensitization or evoke expression with intrastriatal microinjections of amphetamine, NMDLA or THIP were not successful. The data indicate that these three neuroeffector systems interact at the level of the striatum to mediate the induction and expression of behavioral sensitization to amphetamine. The results are discussed in light of our previous reports and lead to the conclusion that two groups of drugs that affect sensitization can be defined: (1) antagonists of the dopaminergic, GABAergic and glutamatergic systems which block the acute effects of amphetamine as well as the induction and expression of sensitization and (2) another group of drugs which antagonize only sensitization-associated phenomena. The mouse data suggest that both the induction and the expression of sensitization involve not only multiple loci but also novel neuroeffector systems.

Amphetamine↗

PubMed1996

A novel nicotinic-cholinergic role in behavioral sensitization to amphetamine-induced stereotypy in mice.

Cholinergic antagonists were used to investigate the role of the cholinergic system in amphetamine- and cocaine-induced behavioral sensitization to stereotypy in mice. Systemically, mecamylamine (1 mg/kg) and dihydro-beta-erythroidine (2 mg/kg) - nicotinic antagonists - and atropine (2 mg/kg) - a muscarinic antagonist - were ineffective against psychostimulant-induced stereotypy in naive animals. The nicotinic antagonists, however, blocked both the induction and expression of sensitization to amphetamine; in contrast, atropine was ineffective. All three drugs were ineffective against either the induction or expression of cocaine sensitization. Intrastriatally, the nicotinic antagonists blocked induction but not expression of amphetamine-induced sensitization. The results suggest that the nicotinic system participates in sensitization induced by amphetamine but not cocaine; that the nicotinic component of the amphetamine response in sensitized animals is novel as compared to the response in naive animals; and that the striatum is a locus for the nicotinic involvement in induction but not expression. The data add support to the inference that behavioral sensitization represents not only a quantitative but a qualitative change in response to amphetamine.

Acetylcholine↗

PubMed1996

Comparative behavioral sensitization to stereotypy by direct and indirect dopamine agonists in CF-1 mice.

The present experiments were designed to compare the properties of behavioral sensitization induced by the indirect agonists, amphetamine and cocaine, to that induced by the direct dopamine agonists, apomorphine and PPHT. Both classes of agonist produced sensitization when administered either in relatively low daily doses or in a single high dose. Mice sensitized to the indirect agonists were cross-sensitized to the direct agonists and vice versa. A pharmacological evaluation of the sensitization induced by the two types of agonist demonstrated both similarities and dissimilarities. Induction to the indirect agonists is blocked by CPP, DNQX and diltiazem, whereas only CPP and diltiazem blocked induction to the direct agonists. Furthermore, although none of these antagonists block the expression of sensitization by the direct agonists, all three were previously shown to block the amphetamine expression of sensitization. Striking differences were also observed in the persistence of the sensitization induced by the two types of agonists. While the indirect agonist-induced sensitization is long lasting, the direct agonist-induced sensitization is relatively short-lived. Furthermore, cross-sensitization of PPHT in amphetamine-sensitized animals was also short-lived, as was amphetamine cross-sensitization in PPHT-sensitized animals. The data suggest that the induction of sensitization consists of two separable mechanisms, one for induction per se, the other for persistence.

Amphetamine↗

PubMed1995

The dopaminergic, glutamatergic, GABAergic bases for the action of amphetamine and cocaine.

The present experiments were designed to evaluate pharmacologically the role of three neuroanatomically related systems--dopamine, glutamate and GABA--in the motor-stimulant response to amphetamine and cocaine. The data indicate that stimulant-induced stereotypy is blocked by antagonists of all three systems and that agonists of all three systems administered into the striatum induce stereotypy. Furthermore, the interaction among them occurs in the striatum; and the reaction sequence, as determined by the effect of the relatively selective antagonists on agonist-induced stereotypy, appears to be a dopaminergic activation of a glutamatergic system which in turn activates a GABAergic system. Because the GABAergic system represents the major efferents from the striatum, the evidence suggests that the motor-stimulatory effects of amphetamine and cocaine result from a disinhibition of inhibitory systems in the thalamus, resulting in facilitation of excitation in the cortex.

Amphetamine↗

PubMed1994

A dopaminergic-glutamatergic basis for the action of amphetamine and cocaine.

The behavioral effects of amphetamine and cocaine are generally considered to be the result of their indirect dopaminergic activity. Recent reports, however, suggest that the activity of the psychomotor stimulants involves not only the dopaminergic but also the glutamatergic system. In the present study the role of the glutamate system in the action of the stimulants was investigated in mice with the use of glutamatergic agonists and antagonists administered either intraperitoneally or intracranially into the striatum. CPP, an NMDA-type glutamate antagonist, given systemically or intrastriatally, blocked stereotypy induced by either amphetamine or cocaine. These results represent pharmacological evidence that the glutamate system is an essential component in the expression of the stereotypic effect of the psychomotor stimulants, and that a locus of this action of glutamate is in the striatum. These conclusions were supported further by the observation that NMDLA administered focally into the striatum caused stereotypy which was indistinguishable from that produced by either amphetamine or dopamine. Stereotypy induced by amphetamine injected into the striatum was blocked by CPP or sulpiride administered either systemically or directly into the striatum; in contrast, stereotypy induced by NMDLA given into the striatum was blocked by CPP but not by sulpiride, regardless of whether the antagonists were presented systemically or into the striatum. The data suggest that stereotypy induced by amphetamine or cocaine is mediated by a dopaminergic activation of a glutamatergic system within the striatum.

Amphetamine↗

PubMed1994

Cocaine behavioral sensitization and the excitatory amino acids.

Studies were conducted to identify neuroeffector systems involved in behavioral sensitization to cocaine-induced stereotypy in mice, and to compare the results with those from our previous amphetamine studies. The effects of eight relatively selective neuroeffector agonists and antagonists were measured in mice in order to identify specific functional changes associated with the sensitization. In contrast to amphetamine, the only neuroeffector response altered by cocaine sensitization was a decrease in convulsive threshold to kainate. The persistence of the change in convulsive threshold correlated with the persistence of behavioral sensitization. The induction of sensitization was blocked by pretreatment with four different classes of drugs, represented by haloperidol, dizocilpine, diltiazem and DNQX. These results suggest that the mechanism of induction to cocaine is similar to that of amphetamine; both the glutamate and dopaminergic systems appear to be involved in induction. The expression of the sensitized cocaine response was blocked by haloperidol, CPP and diltiazem. These results differed from those obtained previously insofar as CPP did not affect the expression of sensitization to amphetamine. Furthermore, DNQX, in contrast to its antagonism of the expression of amphetamine sensitization, did not affect the expression of cocaine sensitization. The pharmacological data suggest that the mechanism of induction differs from that of expression, and that the mechanism of expression for cocaine sensitization differs from that for amphetamine.

Amphetamine↗

PubMed1993

Blockade of behavioral sensitization to cocaine and amphetamine by inhibitors of protein synthesis.

Anisomycin and cycloheximide were used to investigate the role of protein synthesis in the mechanism of behavioral sensitization to the stereotypic effects of cocaine and amphetamine in mice. The drugs completely antagonize induction and partially block expression of the sensitization. Because these drugs were found to be neither antidopaminergic nor antiglutamatergic, it seems that they disrupt sensitization at a novel locus. The antagonism of expression is limited to that quantitative fraction of the response derived from the sensitization reaction; the acute response is unaffected by the inhibitors of protein synthesis. The results differ from those obtained with haloperidol which can completely block either the acute or sensitized response to the stimulants. These results suggest that the sensitized response is functionally different from that of the acute response. The blockage of sensitization induction by the protein synthesis inhibitors may be related to other reports that the stimulants induce the transcription of immediate early genes; however, the relationship between the activation of immediate early genes and behavioral sensitization remains to be determined.

Amphetamine↗

PubMed1992

Excitatory amino acids and the actions of cocaine.

Antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

Animals↗

PubMed1991

DNQX blockade of amphetamine behavioral sensitization.

The role of the N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino acid (EAA) receptors in the mechanism of behavioral sensitization to amphetamine-induced sterotypy was investigated in mice. The results confirm previous observations that NMDA antagonists can block the induction of the phenomenon but not the expression; in contrast, DNQX, a non-NMDA receptor antagonist, can block both the induction and the expression of the sensitization. The differential effects of the two classes of antagonists suggest that the induction and the expression are the result of different mechanisms, both of which involve the EAA system. The DNQX results differ from those of haloperidol, which can also block both the induction and expression, because haloperidol can completely block the amphetamine-induced responses in naive and in sensitized animals; whereas DNQX is without effect on the amphetamine activity in naive animals and, in the sensitized animal, can block only that portion of the response that is derived from the sensitization phenomenon. The effects of the EAA antagonists support the hypothesis that the enhanced responsiveness in the sensitized animals is derived from the activation of EAA receptors, which, in turn, increases the release of dopamine in the striatum. Finally, the involvement of the non-NMDA receptors in the expression of the behavioral sensitization further substantiates the postulate that the amphetamine-induced sensitization is a behavioral manifestation of long-term potentiation (LTP).

Amphetamine↗

PubMed1991

Calcium channel blockers and excitatory amino acids.

The calcium channel blockers (CCB), diltiazem, verapamil and nifedipine, antagonize in mice both N-methyl-DL-aspartate- (NMDLA) and kainate-induced convulsions, which were not affected by carbamazepine and ethosuximide. The CCB, on the other hand, were ineffective against convulsions induced by bicuculline, pentylenetetrazol and electroshock. The results suggest that the CCB may be efficacious in the treatment of those neurodegenerative diseases putatively caused by the excitatory amino acids.

Amino Acids↗

PubMed1991

Calcium channel blockers and behavioral sensitization.

Behavioral sensitization to amphetamine-induced stereotypy was previously shown to consist of two separable phenomena, induction and expression, both of which involve the excitatory amino acids (EAA). In the present experiments, the calcium channel blockers (CCB), nifedipine, diltiazem and verapamil, were shown to block both phenomena; these results are similar to those reported earlier for DNQX, an antagonist of the non-N-methyl-D-aspartate receptors for the EAA. The CCB, like DNQX, affect only that percentage of the stereotypic response which results from the sensitization reaction, without affecting the quantitative portion of the response attributable to the acute effect of amphetamine. The results support previous conclusions that the sensitization response consists of two quantitative components, only one of which involves the EAA. The antagonism exhibited by the CCB suggests that behavioral sensitization involves Ca++ and L-type calcium channels.

Amphetamine↗

PubMed1990

Amphetamine behavioral sensitization and the excitatory amino acids.

The effects of 8 selective neuroeffector agonists and antagonists were measured in mice in order to identify specific functional changes associated with behavioral sensitization to amphetamine-induced stereotypy. The changes observed included a decreased convulsive threshold to N-methyl-DL-aspartic acid, an increased convulsive threshold to bicuculline, and an increased head-twitch response to 5-hydroxytryptophan. Of these effects, only the persistence of the two convulsive threshold changes correlated with the persistence of the behavioral sensitization. The induction of behavioral sensitization was blocked by haloperidol, dizocilpine or ketamine, but not affected by cyproheptadine or diazepam: therefore, the mechanism of the enhanced responsiveness involves not only a functional dopamine system, but also a functional N-methyl-D-aspartic acid component of the excitatory amino acid system. The block of behavioral sensitization also prevented the amphetamine-induced changes in the convulsive thresholds. Finally, neither ketamine nor dizocilpine affected the expression of the enhanced response in the behaviorally sensitized animals. The data indicate that the characteristics of amphetamine behavioral sensitization to stereotypy are similar to those of long-term potentiation.

Amino Acids↗

PubMed1990

Reverse tolerance to amphetamine evokes reverse tolerance to 5-hydroxytryptophan.

Repeated intermittent administration of amphetamine in mice caused reverse tolerance to 5-hydroxy-L-tryptophan (5-HTP)-induced head twitch, as well as to amphetamine-induced stereotypy. The repeated administration of 5-HTP alone also resulted in reverse tolerance in the head-twitch test. Daily pretreatment with haloperidol prior to amphetamine administration blocked the development of both reverse tolerance to amphetamine and to 5-HTP, whereas daily pretreatment with cyproheptadine prior to amphetamine blocked only the reverse tolerance to 5-HTP. On the other hand, 5-HTP-induced reverse tolerance was blocked by daily pretreatment with cyproheptadine, but not with haloperidol. There appears to be no difference in the persistence of the reverse tolerance to 5-HTP, whether induced by amphetamine or by 5-HTP; in both instances, the persistence does not correlate with the persistence of reverse tolerance to amphetamine. The data suggest that the reverse tolerance to amphetamine and the associated reverse tolerance to 5-HTP are independent events, both of which are mediated by dopaminergic mechanisms.

5-Hydroxytryptophan↗