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Biomedical subjects

A D Crocker

Publications and source records attributed to A D Crocker.

At least 19 recordsLinked to original sources
PubMed1992

Localisation of striatal muscarinic receptors involved in dopamine receptor-mediated behavioural responses.

Stereotyped sniffing responses to the direct dopamine agonist, apomorphine, were assessed following intrastriatal injection of the alkylating derivative of oxotremorine, BR 401. Subsequently, the localisation and extent of muscarinic receptor alkylation after injection into various striatal sites were assessed by quantitative autoradiography. The results of these experiments provide evidence that a regional subset of striatal muscarinic receptors is involved in apomorphine-induced stereotyped sniffing. In addition, these receptors are localised in a similar area to that previously shown to contain the dopamine D2 receptors responsible for mediating apomorphine-induced sniffing. Thus, striatal muscarinic receptors involved in dopamine-agonist induced behaviours share a close anatomical association with the dopamine receptors at which the agonist acts.

Animals↗
PubMed1992

Selective breeding for increased cholinergic function: biometrical genetic analysis of muscarinic responses.

Biometric genetic analyses of behavioral and physiologic responses known to be related to muscarinic cholinergic receptors (hypothermia, hypoactivity, inhibited avoidance, and reduced responding for water) were studied in genetic crosses and backcrosses of the Flinders sensitive line (FSL) and Flinders resistant line (FRL) of rats. The FSL rats were more sensitive to the direct muscarinic agonists, arecoline and oxotremorine, and to the indirect agonist, physostigmine, than any other group. The next most sensitive group was the F1 x FSL backcross, followed by the F2, F1, F1 x FRL backcross, and the FRL, in that order. These differences between the genetic groups could be accounted for completely by either solely additive or additive plus dominance genetic factors. When dominance genetic factors contributed to the differences among groups (6 out of 15), the F1 responded like the FRL rats. The variance of the responses measured made it impossible to obtain reliable estimates of the number of genes involved in many instances; when such estimates were possible, several genes (greater than or equal to 3) appeared to be involved. We conclude that muscarinic sensitivity in rats is under genetic control, with the greatest contribution coming from additive genetic factors. Because the FSL rat appears to be a genetic animal model of depression, the finding of several genes influencing muscarinic responses may help account for the difficulties investigators have had in locating a single major gene or biological marker for human depressive disorders.

Analysis of Variance↗
PubMed1991

Dopamine sensitivity in rats selectively bred for increases in cholinergic function.

Because of the extensive literature demonstrating an interaction between cholinergic and dopaminergic systems, the Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats, selectively bred for differences in cholinergic function, were tested for differences in dopamine sensitivity. Large differences in sensitivity to dopamine agonists were detected, but the direction depended upon the function: The FSL rats were supersensitive to the hypothermic effects of dopamine agonists, but were subsensitive to the stereotypy-inducing effects. Measurement of dopamine receptors by either standard binding techniques or autoradiography failed to demonstrate any receptor differences in the FSL and FRL rats. Behavioural studies with dopamine antagonists were less clear-cut, but suggested that the FSL rats might be more sensitive to their catalepsy-inducing effects. These findings indicate that the changes in dopamine sensitivity which accompany cholinergic supersensitivity are function-dependent, but are not associated with parallel changes in dopamine receptor concentration.

Animals↗
PubMed1990

Effects of inactivation of D1 dopamine receptors on stereotypic and thermic responses to quinpirole (LY 171555).

The purpose of the present study was to investigate reports that the expression of dopamine agonist-induced behaviours is dependent upon the ratio of D1 to D2 receptor activation. Selective inactivation of the D1 dopamine receptor was achieved using the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while D2 receptors were maintained at control levels by the use of a D2 antagonist, raclopride. Stereotypic and hypothermic responses to quinpirole (LY 171555) were assessed and related to striatal D1 and D2 receptor concentrations. Results showed that the incidence of stereotyped sniffing behaviour induced by LY 171555 was reduced in parallel with D1 receptor loss and sniffing behaviour was abolished at low D1 receptor (less than 40% of control) concentrations. Hypothermic responses to LY 171555 were unaffected by D1 receptor loss. These findings suggest that activation of D1 receptors is a critical component of stereotypic, but not hypothermic, responses to LY 171555, the magnitude of the sniffing response being positively associated with D1 receptor concentration.

Animals↗
PubMed1990

Pretreatment with an irreversible muscarinic agonist affects responses to apomorphine.

The main aim of the present study was to investigate if responses to the direct dopamine agonist, apomorphine, could be modified by changes in the activity of cholinergic neurones. A novel approach was adopted in which these responses were assessed following reduction of muscarinic receptor concentration (mAChR) in the brain (assessed from [3H] QNB binding) by the alkylating derivative of oxotremorine, N-[4-(2-chloroethylmethylamino)]-2-pyrrolidone (BM 123). Stereotyped responses elicited by apomorphine were significantly reduced when QNB binding was 12% and 50% of control values. No changes in [3H] spiperone binding were found. There was significant hypothermia in the group with 12% QNB binding sites which was significantly increased by apomorphine. Body temperature returned to normal when QNB binding was 50% of control values. There was a significant decrease in activity when QNB sites were reduced to 12% of normal and vertical activity was still significantly reduced at 50% QNB binding, though horizontal activity was not then different from controls. These data are consistent with the hypothesis that changes in the function of mAChR modify responses elicited by dopamine receptor stimulation in both the striatum and other brain regions.

Animals↗
PubMed1990

The hypothyroid rat as a model of increased sensitivity to dopamine receptor agonists.

Control and hypothyroid rats were challenged with a range of doses (0.5-4 mumol/kg) of either the nonselective dopamine agonist, apomorphine, or the selective D2 receptor agonist. LY 171555, and their stereotyped head-down sniffing (SHDS) responses measured. The dose-response curves for both agonists were shifted to the left in the hypothyroid rats compared to water-treated controls. Increasing doses of the selective D2 antagonist, raclopride, caused a parallel shift to the right in the LY 171555-induced SHDS dose-response curve. Schild analysis revealed a decreased sensitivity to raclopride in the hypothyroid animals. The selective D1 antagonist SCH 23390 was observed to decrease the maximal response elicited by LY 171555 in a dose-dependent manner and the hypothyroid rats were more sensitive to this effect. It was concluded that hypothyroid rats showed an apparent increased sensitivity to D2 receptor agonists and a decreased sensitivity to D2 antagonists. In addition, the facilitation effect of the D1 receptor on the D2 receptor appeared less tightly coupled in the hypothyroid rats.

Animals↗
PubMed1989

Effects of adrenalectomy on responses mediated by dopamine D-1 and D-2 receptors.

The effects of surgical adrenalectomy were investigated on behavioural responses produced by the selective D-1 agonist, SK&F 38393, alone, and in combination with the D-2 agonist, quinpirole (LY171555). Further, stereotyped responses to apomorphine and LY171555 were assessed following treatment with either the D-1 or the D-2 antagonists, SCH 23390 and raclopride, respectively. There was no difference between sham-adrenalectomized (sham) and adrenalectomized (ADX) groups in responses to SK&F 38393. Although concomitant stimulation of both receptor subtypes increased the incidence of stereotyped sniffing behaviour, there was no difference in the magnitude of this effect between the sham and ADX groups. Raclopride reduced LY171555-induced sniffing and hypothermia less in ADX rats than in sham controls, which was consistent with the hypothesis that adrenocortical hormones affect D-2 receptor responsiveness. SCH 23390 had a greater inhibitory effect on LY171555 responses, but a smaller effect on apomorphine responses in the ADX group compared with their sham controls. It is concluded that the amplified D-2-stimulated response observed in ADX rats may be more dependent on tonic D-1 receptor activation than the control D-2 response of shams.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Localization of striatal dopamine receptor function by central injection of an irreversible receptor antagonist.

The stereotypic head-down sniffing response to systemically administered apomorphine (0.65 mumol/kg) was assessed in rats 48 h after the bilateral injection of 0.2-0.5 microliters of the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (60 micrograms/microliters) into the caudate-putamen and nucleus accumbens. This response was significantly attenuated in animals that had received injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline into the anterior/ventral part of the caudate-putamen but not in those that received injections into regions more dorsal/posterior. Animals were killed after apomorphine challenge and the region of dopamine D1 or D2 receptor reduction due to N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline mapped and quantified. This analysis revealed that the dopamine receptors involved in the apomorphine-induced stereotyped head-down sniffing response were located in a discrete region of the ventrolateral caudate-putamen and the dorsolateral nucleus accumbens. Animals that were pretreated with the selective dopamine D2 receptor antagonist raclopride (0 20 mumol/kg, i.p.) 20 min prior to central injection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline into this area showed a dose-dependent protection of the stereotyped sniffing response to systemic apomorphine 48 h later. This combination of techniques constitutes a novel way to investigate striatal function and the results obtained support the concept of a functional subdivision of both the caudate-putamen and the nucleus accumbens.

Animals↗
PubMed1989

Receptor alkylating agents: novel tools for the study of receptor function in the central nervous system of the rat.

1. The use of alkylating agents to investigate receptor function in the central nervous system is discussed. 2. Examples of strategies which can be used are illustrated by studies with the irreversible dopamine receptor blocker, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). 3. Recent work, in which EEDQ was injected into selected sites of the striatum and receptor loss assessed by quantitative autoradiography, is described to show how this approach can be used to elucidate dopamine receptor function in the striatum.

Alkylating Agents↗
PubMed1988

Adrenocortical hormone status affects responses to dopamine receptor agonists.

The effects of altered adrenocortical hormone status were investigated on hypothermic and behavioural responses elicited following systemically administered apomorphine or LY171555. Hormonal status was modified by surgical adrenalectomy, followed by subsequent replacement therapy with corticosterone, and by chronic corticosterone treatment of intact rats, followed by its withdrawal. The incidence of stereotyped sniffing produced by both apomorphine and LY171555 was increased in the adrenalectomized group and decreased following replacement therapy and in intact rats treated with chronic corticosterone, compared with sham-operated animals and saline-treated controls, respectively. Withdrawal of chronic corticosterone treatment in intact rats reversed the effects of the chronic treatment on dopamine-mediated responses. Similar changes were observed in hypothermic responses to the two dopamine agonists. Striatal D-1 and D-2 dopamine receptor concentration and affinity were unaffected by adrenal hormone modification suggesting that corticosterone may act at a site distal to the dopamine receptor to bring about the observed changes in dopamine-mediated behavioural responsiveness.

Adrenal Cortex Hormones↗
PubMed1988

Alkylation of striatal dopamine receptors abolishes stereotyped behavior but has no effect on dopamine stimulated adenylate cyclase activity.

The role of dopamine stimulated adenylate cyclase (AC) activity in behaviours elicited by apomorphine stimulation of striatal dopamine receptors was investigated. Rats were treated with the irreversible dopamine receptor alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) alone or after pretreatment with either a D1 or D2 receptor antagonist and subsequently challenged with apomorphine. Animals that received no antagonist pretreatment showed significantly decreased striatal concentrations of D1 and D2 receptors and an abolition of apomorphine induced sniffing behaviour despite showing no change in striatal AC activity. In the groups which received antagonist pretreatment the reduction in the sniffing response paralleled the reduction in D2 receptor concentration whereas the incidence of vacuous oral movements was inversely related. In no case were the behavioural responses associated with changes in AC activity. We conclude that these behavioural effects observed in response to dopamine stimulation by apomorphine may be mediated through another second messenger system.

Adenylyl Cyclases↗
PubMed1988

Genetic and pharmacological models of cholinergic supersensitivity and affective disorders.

Increased muscarinic sensitivity has been associated with altered hormonal states (hypothyroidism and hyperadrenocorticism), chronic administration of muscarinic antagonists or antidepressants with muscarinic actions, selective breeding for anticholinesterase sensitivity, and certain inbred strains of rats and mice. Thus, both genetic and environmental factors may influence muscarinic receptor sensitivity. The reasonably detailed studies on the selectively-bred rats have revealed that the Flinders Sensitive Line (FSL) rats weigh less, are less active, are more sensitive to muscarinic agonists and to stressors, and have higher concentrations of hippocampal and striatal muscarinic receptors than 'normal', or the selectively-bred, Flinders Resistant Line (FRL) rats. Thus, there are a number of parallels between FSL rats and depressed humans. The FSL rats may be the first animal model of depression to mimic the actual trait of depression, and not just the state.

Acetylcholine↗
PubMed1988

Stimulation of D-1 dopamine receptors facilitates D-2 dopamine receptor recovery after irreversible receptor blockade.

The hypothesis that stimulation of the D-1 dopamine receptor subtype affects the recovery of the D-2 subtype after alkylation by EEDQ was investigated. Animals were pretreated with either SCH23390, to protect D-1 receptors, or saline, before administration of EEDQ. After EEDQ one group of saline pretreated animals received 12 hourly injections of the D-1 agonist SKF38393. Animals were sacrificed at 6, 24 and 48 hours after EEDQ and Kd and Bmax of striatal D-1 and D-2 receptors measured. The concentration of D-2 receptors in the groups in which D-1 receptors had been protected by SCH23390 or stimulated by SKF38393 were significantly greater than that of the EEDQ alone group.

Adrenergic alpha-Antagonists↗
PubMed1988

Enhanced benzodiazepine responsiveness in rats with increased cholinergic function.

The effects of diazepam and muscimol on locomotor activity were examined in Flinders Sensitive Line (FSL) rats, derived by selective breeding methods from randomly bred Sprague-Dawley (RB) rats for increased behavioural and physiological sensitivity to the anticholinesterase, diisopropylfluorophosphate (DFP). Previous reports of increased behavioural sensitivity to oxotremorine, associated with increased striatal and hippocampal muscarinic receptor concentrations, were confirmed in FSL rats compared to RB rats. The FSL rats were more sensitive to the locomotor suppressant effects of diazepam and muscimol compared to RB. Binding experiments with [3H]-diazepam showed that FSL rats had an increased benzodiazepine receptor concentration in the striatum and hippocampus compared to Flinders Resistant Line rats (FRL). FRL did not differ significantly from RB in diazepam-induced changes in locomotor activity or the concentration of benzodiazepine receptors. No significant differences in the affinity of benzodiazepine receptors was detected between the three rat lines in the brain regions investigated. Thus FSL rats showed an increased behavioural sensitivity to both diazepam and muscimol which was associated with a greater concentration of benzodiazepine receptors in the striatum and hippocampus compared to RB and FRL rats.

Animals↗
PubMed1988

Selective breeding for increased cholinergic function: increased serotonergic sensitivity.

The effects of the serotonergic antagonist cyproheptadine and the agonist 1(m-chlorophenyl) piperazine (mCPP) on core body temperature, locomotor activity and operant responding for a water reward were determined in two lines of Sprague-Dawley rats selectively bred for differences in sensitivity to the anticholinesterase, diisopropyl fluorophosphate (DFP). Both cyproheptadine and mCPP induced a dose-dependent hypothermia that was significantly greater in the line of rat more sensitive to DFP (the Flinders Sensitive Line--FSL). On the other hand, the mild stimulant effects of cyproheptadine on operant responding and locomotor activity were similar in the two lines, whereas the marked inhibitory effects of mCPP on these two measures were significantly greater in the FSL rats. This study also confirmed that the FSL rats were significantly more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist, and showed that pretreatment with cyproheptadine reduced the hypothermic effects of oxotremorine to a similar extent in the two lines. These findings indicate that rats selectively bred for increased cholinergic function (FSL) also differ in their sensitivity to serotonergic agonists and antagonists, thereby extending the evidence for cholinergic-serotonergic interactions in the rat.

Animals↗