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D J Critchett

Publications and source records attributed to D J Critchett.

5 recordsLinked to original sources
PubMed1986

Desensitization of muscarinic acetylcholine receptors: possible relation to receptor heterogeneity and phosphoinositides.

The increases in firing rates of hippocampal cells were examined following microiontophoretic application of several muscarinic cholinergic receptor agonists. The agonists studied had been pharmacologically characterized previously and divided into two classes: class A agonists (e.g. acetylcholine, carbamylcholine, and oxotremorine-M) which maximally stimulate PI turnover and reveal mAChR heterogeneity, and class B agonists (e.g. bethanecol and oxotremorine-1) which poorly stimulate PI turnover and do not alter mAChR conformation/orientation in the hippocampus. While comparable stimulatory effects on hippocampal pyramidal cell firing rates were seen with both classes of agonists during short (20 s) ejection periods, longer applications (greater than 25 s) produced class-dependent differential firing patterns. Prolonged ejection of class A agonists selectively desensitized cells to further, continued application in the same ejection period, and the firing rates declined. Class B agonists produced stimulatory responses in hippocampal cells during the entire ejection period, and DE was not observed. This desensitization effect (DE) was observed only for bursts and not for simple spikes.

Acetylcholine↗
PubMed1985

Conformational changes in muscarinic receptors may produce diminished cholinergic neurotransmission and memory deficits in aged rats.

Both clinical and laboratory studies suggest that age-related memory deficits may be due, at least in part, to disturbances in muscarinic acetylcholine (mAChR) receptors. In order to further evaluate this premise, the present studies examined the electrophysiological responses rates of hippocampal pyramidal cells to iontophoretically applied ACh in young, middle-age and aged animals. The relationship between age and muscarinic agonist and antagonist binding in the hippocampus was also examined. In addition, possible age-related changes in receptor-effector coupling were assessed by determining calmodulin levels and the activities of phospholipid methyl-transferase I and II. Analysis of electrophysiological data showed selective age-related decrements in the ability of ACh to alter burst rate but not simple spike rate. These age-related decreases in the efficacy of ACh to increase burst rate were not paralleled by decreases in mAChR density as assessed by 3H-QNB binding, but they were temporally paralleled by age-related changes in the ability of oxotremorine to inhibit 3H-QNB binding. In the young animals, the resultant Hill coefficients derived from these analyses approached 1, while in the middle and old aged animals, the Hill coefficients deviated significantly from 1, indicating the possible existence of 2 or more receptor states with differential affinity for oxotremorine in the 2 older age groups. When carbamylcholine was used to inhibit 3H-QNB, these complex binding patterns were seen even in the young, since carbamylcholine induces conformational/orientational changes in the mAChR while oxotremorine does not.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1981

Lateral olfactory tract lesions reveal neuronal localization of benzodiazepine recognition sites.

The effects of neuronal degeneration on benzodiazepine binding parameters were assessed following bilateral electrolytic lesions of rat brain lateral olfactory tracts. [3H]Flunitrazepam binding was measured in olfactory bulb homogenates 1, 7 and 14 days post-lesion. Specific [3H]flunitrazepam binding was significantly decreased two weeks after lesions. Diminution in binding was associated with a decreased population of sites (Bmax) rather than affinity alterations (KD). The time course for the loss of receptors is compatible with retrograde degeneration and suggests that specific benzodiazepine binding sites are in part located on mitral cell-bodies.

Animals↗
PubMed1980

Brain cholinergic dysfunction and memory in aged rats.

Age related alterations in mnemonic ability and in the functional status of muscarinic receptors were evaluated and compared to biochemical measures of pre and post-synaptic cholinergic functioning. Retention of a single trial passive avoidance task was considerably disturbed as a function of aging. The functional status of muscarinic receptors, as measured by the ability of microiontophoretically applied acetylcholine to stimulate the firing of hippocampal pyramidal cells, was similarly disturbed in aged rats. A small, but significant decrease in muscarinic receptors was detected in the dorsal hippocampi of these same aged rats, while choline acetyltransferase activity did not change. When considered with prior psychopharmacological studies, these data suggest that specific muscarinic receptor impairments may play a critical role in the memory disturbances associated with old age.

Acetylcholine↗