Muscarinic receptors
To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed M1 receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the M1 and M2 receptors occur in the brain. Recent studies have shown that M1 and M3 are located postsynaptically in the brain whereas the M2 and M4 receptors occur presynaptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the M1, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron. The cholinergic system has the capacity to adapt to changes in the physiological environment of the brain. Thus the density of the cholinergic receptors is increased by antagonists and decreased by agonists. The reduction in the density of the receptors is a result of their rapid internalization into the neuronal membrane (receptor sequestration) followed by their subsequent destruction. This phenomenon may have a bearing on the long-term efficacy of cholinomimetic drugs and anticholinesterases which are currently used in the symptomatic treatment ofAlzheimer’s disease. While it is widely believed that the relapse in the response to treatment is due to the continuing neurodegenerative changes in the brain which are unaffected by cholinomimetic drugs, it is also possible that such treatments could impair cholinergic function by causing an increased sequestration and destruction of muscarinic receptors. The possible detrimental effect of cholinergic agonists on memory is supported by the observation that the chronic administration of physostigmine or oxotremorine to rats decreases the number of muscarinic receptors and leads to an impairment of memory when the drugs are withdrawn. Conversely chronic treatment with a cholinergic antagonist such as atropine increases the number of cholinergic receptors and leads to a memory improvement when the drug is withdrawn. Whether these effects in experimental animals are relevant to the clinical situation in which cholinomimetic agents are administered for several months is unknown. Although other transmitters such as noradrenaline, serotonin and glutamate are involved, there is now substantial evidence to suggest that muscarinic receptors play a key role in learning and memory. It is well established that muscarinic antagonists such as atropine and scopolamine impair memory and learning in man and that their effects can be reversed by anticholinesterases. Conversely, muscarinic agonists such as arecholine improve some aspects of learning and memory. However, cholinomimetic drugs such as carbachol which stimulate the inhibitory autoreceptors impair memory by blocking the release of acetylcholine in the hippocampus and cortex; the selective autoreceptor antagonist secoverine has the opposite effect.
To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed M1 receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the M1 and M2 receptors occur in the brain. Recent studies have shown that M1 and M3 are located postsynaptically in the brain whereas the M2 and M4 receptors occur presynaptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the M1, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron. The cholinergic system has the capacity to adapt to changes in the physiological environment of the brain. Thus the density of the cholinergic receptors is increased by antagonists and decreased by agonists. The reduction in the density of the receptors is a result of their rapid internalization into the neuronal membrane (receptor sequestration) followed by their subsequent destruction. This phenomenon may have a bearing on the long-term efficacy of cholinomimetic drugs and anticholinesterases which are currently used in the symptomatic treatment ofAlzheimer’s disease. While it is widely believed that the relapse in the response to treatment is due to the continuing neurodegenerative changes in the brain which are unaffected by cholinomimetic drugs, it is also possible that such treatments could impair cholinergic function by causing an increased sequestration and destruction of muscarinic receptors. The possible detrimental effect of cholinergic agonists on memory is supported by the observation that the chronic administration of physostigmine or oxotremorine to rats decreases the number of muscarinic receptors and leads to an impairment of memory when the drugs are withdrawn. Conversely chronic treatment with a cholinergic antagonist such as atropine increases the number of cholinergic receptors and leads to a memory improvement when the drug is withdrawn. Whether these effects in experimental animals are relevant to the clinical situation in which cholinomimetic agents are administered for several months is unknown. Although other transmitters such as noradrenaline, serotonin and glutamate are involved, there is now substantial evidence to suggest that muscarinic receptors play a key role in learning and memory. It is well established that muscarinic antagonists such as atropine and scopolamine impair memory and learning in man and that their effects can be reversed by anticholinesterases. Conversely, muscarinic agonists such as arecholine improve some aspects of learning and memory. However, cholinomimetic drugs such as carbachol which stimulate the inhibitory autoreceptors impair memory by blocking the release of acetylcholine in the hippocampus and cortex; the selective autoreceptor antagonist secoverine has the opposite effect.
No comments:
Post a Comment