Dopamine receptors
Two types of dopamine receptors have been characterized in the mammalian brain, termed D1 and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. Detailed studies of the binding of 3H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the D1 receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the D1 receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor; conversely, the D1 receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appea rs to have a high affinity for most therapeutically active neuroleptics.There is still some controversy over the precise anatomical location of the dopamine receptor subtypes, but there is now evidence that the D2 receptors are located presynaptically on the corticostriatal neurons and postsynaptically in the striatum and substantia nigra. Conversely, the D1 receptors are found presynaptically on nigrostriatal neurons, and postsynaptically in the cortex. It is possible to differentiate these receptor types on the basis of their agonist and antagonist affinities. In addition to these two subtypes, there is also evidence that the release of dopamine is partially regulated by feedback inhibition operating via the dopamine autoreceptor. With the development of D1 and D2 agonists, however, emphasis has become centred on the pharmacological characteristics of the specific drug in order to determine whether an observed effect is mediated by D1 or D2 receptors. It is now apparent that dopamine receptors with the same pharmacological characteristics do not necessarily produce the same functional responses at the same receptor. For example, D2 receptors are present in both the striatum and the nucleus accumbens, but cause an inhibition of adenylate cyclase only in the striatum. Furthermore, recent studies indicate that dopamine receptors can influence cellular activities through mechanisms other than adenylate cyclase. These may include direct effects on potassium and calcium channels, as well as modulation of the phosphatidyl inositol cycle. D1 and D2 receptors have opposite effects on some behaviours (e.g. chewing in rats) but are synergistic in causing other behaviours (e.g. locomotor activity and some types of stereotypy). The precise clinical importance of these interactions is unclear. The densities and functional activities of dopamine receptors have been shown to change in response to chronic drug treatment and in disease. Thus an increase in the dopamine receptor density in the nigrostriatal pathway appears to be related to the behavioural supersensitivity observed following unilateral destruction of the dopaminergic system in the striatum. Dopamine receptor antagonists, such as the ‘‘classical’’ neuroleptics like chlorpromazine, are also known to increase the density of dopamine receptors in the striatal region. This contributes to the extrapyramidal side effects of such drugs, which frequently follows their prolonged use and reflects the drug-induced functional deficit of dopamine in the brain. Abrupt withdrawal of a neuroleptic following its prolonged administration is frequently associated with tardive dyskinesia, a disorder which may be partly due to the sudden activation of supersensitive dopamine receptors. Despite the appeal of this hypothesis, it should be emphasized that many other factors, such as brain damage and prior exposure to tricyclic antidepressants, may also predispose patients to this condition.With regard to the change in dopamine receptor activity in disease, there is some evidence from post-mortem studies that the density of D2 receptors is increased in the mesocortical areas of the schizophrenic brain, and in the putamen and caudate nucleus in neuroleptic-free patients. Positron emission tomography of schizophrenic patients has, however, failed to confirm these findings. There is also evidence that the link between the D1 and D2 receptors is defective in some patients with diseases in which the dopaminergic system might be involved. Thus the well-known loss of dopaminergic function in patients with Parkinson’s disease is associated with a compensatory rise in the density of postsynaptic D1 and D2 receptors. The long-term treatment of Parkinson’s disease with L-dopa reduces the receptor density to normal (socalled receptor ‘‘down-regulation’’). Similarly, the densities of D1 and D2 receptors are reduced in the striata of patients with Huntington’s chorea, as is the linkage between these receptors. Dopamine has been implicated in a number of psychiatric conditions of which schizophrenia and the affective disorders are the most widely established. Five major subtypes of dopamine receptors have now been cloned. These are divided into two main groups, D1 and D2 respectively. The D1 receptors consist of D1 and D5 types and are positively linked to the adenylate cyclase second messenger system, while the D2 group consists of the D2, D3 and D4 receptors which are negatively linked to the adenylate cyclase system. The D1 receptors have been subdivided into the D1A and D1B types and are coded by genes located on chromosomes 5 and 4 respectively. Several selective antagonists of the D1 receptors have been developed (for example, SCH 31966, SCH 23390 and SKF 83959), none of which have so far been developed for therapeutic use. Apomorphine is an agonist at both the D1 and D2 receptors. From the pathological viewpoint, a malfunction of the D1 receptors has been implicated in the negative symptoms of schizophrenia but as there is a close interaction between these receptor types it is difficult to conclude whether the changes seen in schizophrenia are attributable to a primary decrease in D1 receptor function or an increase in D2 receptor function. The function of the D5 receptors is unclear; these receptors, though widely distributed in the brain, are only present in a relatively low density in comparison to the other dopamine receptor types. The D2 receptor types, besides being subdivided into D3 and D4 types, are further divided into the D2 long and D2 short forms. D2 antagonists, in addition to virtually all therapeutically active neuroleptics, also include such novel drugs as raclopride, eticlopride and sniperone while quinpirole is an example of a specific D2 receptor agonist. The latter drugs are not available for therapeutic use. A malfunction of the D2 receptors has been associated with
psychosis, extrapyramidal side effects and hyperprolactinaemia.The human D3 gene has produced two variants, D3 and D3s. So far there do not appear to be any selective agonists or antagonists of the D3 receptor which enable the function of this receptor to be clearly distinguished from that of the D2 receptor. The D3 receptors are located in the ventral and limbic regions of the brain but absent from the dorsal striatum. This suggests that specific antagonists of the D3 receptors may be effective antipsychotics but without causing extrapyramidal side effects. The D4 receptor has eight polymorphic variants in the human. However, even though several specific antagonists of this receptor type have been developed and shown to have antipsychotic activity in animal models of schizophrenia, the clinical findings have been disappointing. Because of the high density of the D4 receptors in the limbic cortex and hippocampus, but their absence from the motor regions of the brain, it was anticipated that such drugs have antipsychotic efficacy without the motor side effects. In support of this view, it has been shown that the atypical antipsychotic clozapine has a high affinity for the D4 receptors; other studies have also indicated that many of the atypical, and some of the typical, antipsychotics have similar affinities for these receptors. In addition to the postsynaptic receptors, dopamine autoreceptors also exist on the nerve terminals, dendrites and cell bodies. Experimental studies have shown that stimulation of the autoreceptors in the somatodendritic region of the neuron slows the firing rate of the dopaminergic neuron while stimulation of the autoreceptors on the nerve terminal inhibits both the release and the synthesis of the neurotransmitter. Structurally, the autoreceptor appears to be of the D2 type. While several experimental compounds have been developed that show a high affinity for the autoreceptors, to date there is no convincing evidence for their therapeutic efficacy.
Two types of dopamine receptors have been characterized in the mammalian brain, termed D1 and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. Detailed studies of the binding of 3H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the D1 receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the D1 receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor; conversely, the D1 receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appea rs to have a high affinity for most therapeutically active neuroleptics.There is still some controversy over the precise anatomical location of the dopamine receptor subtypes, but there is now evidence that the D2 receptors are located presynaptically on the corticostriatal neurons and postsynaptically in the striatum and substantia nigra. Conversely, the D1 receptors are found presynaptically on nigrostriatal neurons, and postsynaptically in the cortex. It is possible to differentiate these receptor types on the basis of their agonist and antagonist affinities. In addition to these two subtypes, there is also evidence that the release of dopamine is partially regulated by feedback inhibition operating via the dopamine autoreceptor. With the development of D1 and D2 agonists, however, emphasis has become centred on the pharmacological characteristics of the specific drug in order to determine whether an observed effect is mediated by D1 or D2 receptors. It is now apparent that dopamine receptors with the same pharmacological characteristics do not necessarily produce the same functional responses at the same receptor. For example, D2 receptors are present in both the striatum and the nucleus accumbens, but cause an inhibition of adenylate cyclase only in the striatum. Furthermore, recent studies indicate that dopamine receptors can influence cellular activities through mechanisms other than adenylate cyclase. These may include direct effects on potassium and calcium channels, as well as modulation of the phosphatidyl inositol cycle. D1 and D2 receptors have opposite effects on some behaviours (e.g. chewing in rats) but are synergistic in causing other behaviours (e.g. locomotor activity and some types of stereotypy). The precise clinical importance of these interactions is unclear. The densities and functional activities of dopamine receptors have been shown to change in response to chronic drug treatment and in disease. Thus an increase in the dopamine receptor density in the nigrostriatal pathway appears to be related to the behavioural supersensitivity observed following unilateral destruction of the dopaminergic system in the striatum. Dopamine receptor antagonists, such as the ‘‘classical’’ neuroleptics like chlorpromazine, are also known to increase the density of dopamine receptors in the striatal region. This contributes to the extrapyramidal side effects of such drugs, which frequently follows their prolonged use and reflects the drug-induced functional deficit of dopamine in the brain. Abrupt withdrawal of a neuroleptic following its prolonged administration is frequently associated with tardive dyskinesia, a disorder which may be partly due to the sudden activation of supersensitive dopamine receptors. Despite the appeal of this hypothesis, it should be emphasized that many other factors, such as brain damage and prior exposure to tricyclic antidepressants, may also predispose patients to this condition.With regard to the change in dopamine receptor activity in disease, there is some evidence from post-mortem studies that the density of D2 receptors is increased in the mesocortical areas of the schizophrenic brain, and in the putamen and caudate nucleus in neuroleptic-free patients. Positron emission tomography of schizophrenic patients has, however, failed to confirm these findings. There is also evidence that the link between the D1 and D2 receptors is defective in some patients with diseases in which the dopaminergic system might be involved. Thus the well-known loss of dopaminergic function in patients with Parkinson’s disease is associated with a compensatory rise in the density of postsynaptic D1 and D2 receptors. The long-term treatment of Parkinson’s disease with L-dopa reduces the receptor density to normal (socalled receptor ‘‘down-regulation’’). Similarly, the densities of D1 and D2 receptors are reduced in the striata of patients with Huntington’s chorea, as is the linkage between these receptors. Dopamine has been implicated in a number of psychiatric conditions of which schizophrenia and the affective disorders are the most widely established. Five major subtypes of dopamine receptors have now been cloned. These are divided into two main groups, D1 and D2 respectively. The D1 receptors consist of D1 and D5 types and are positively linked to the adenylate cyclase second messenger system, while the D2 group consists of the D2, D3 and D4 receptors which are negatively linked to the adenylate cyclase system. The D1 receptors have been subdivided into the D1A and D1B types and are coded by genes located on chromosomes 5 and 4 respectively. Several selective antagonists of the D1 receptors have been developed (for example, SCH 31966, SCH 23390 and SKF 83959), none of which have so far been developed for therapeutic use. Apomorphine is an agonist at both the D1 and D2 receptors. From the pathological viewpoint, a malfunction of the D1 receptors has been implicated in the negative symptoms of schizophrenia but as there is a close interaction between these receptor types it is difficult to conclude whether the changes seen in schizophrenia are attributable to a primary decrease in D1 receptor function or an increase in D2 receptor function. The function of the D5 receptors is unclear; these receptors, though widely distributed in the brain, are only present in a relatively low density in comparison to the other dopamine receptor types. The D2 receptor types, besides being subdivided into D3 and D4 types, are further divided into the D2 long and D2 short forms. D2 antagonists, in addition to virtually all therapeutically active neuroleptics, also include such novel drugs as raclopride, eticlopride and sniperone while quinpirole is an example of a specific D2 receptor agonist. The latter drugs are not available for therapeutic use. A malfunction of the D2 receptors has been associated with
psychosis, extrapyramidal side effects and hyperprolactinaemia.The human D3 gene has produced two variants, D3 and D3s. So far there do not appear to be any selective agonists or antagonists of the D3 receptor which enable the function of this receptor to be clearly distinguished from that of the D2 receptor. The D3 receptors are located in the ventral and limbic regions of the brain but absent from the dorsal striatum. This suggests that specific antagonists of the D3 receptors may be effective antipsychotics but without causing extrapyramidal side effects. The D4 receptor has eight polymorphic variants in the human. However, even though several specific antagonists of this receptor type have been developed and shown to have antipsychotic activity in animal models of schizophrenia, the clinical findings have been disappointing. Because of the high density of the D4 receptors in the limbic cortex and hippocampus, but their absence from the motor regions of the brain, it was anticipated that such drugs have antipsychotic efficacy without the motor side effects. In support of this view, it has been shown that the atypical antipsychotic clozapine has a high affinity for the D4 receptors; other studies have also indicated that many of the atypical, and some of the typical, antipsychotics have similar affinities for these receptors. In addition to the postsynaptic receptors, dopamine autoreceptors also exist on the nerve terminals, dendrites and cell bodies. Experimental studies have shown that stimulation of the autoreceptors in the somatodendritic region of the neuron slows the firing rate of the dopaminergic neuron while stimulation of the autoreceptors on the nerve terminal inhibits both the release and the synthesis of the neurotransmitter. Structurally, the autoreceptor appears to be of the D2 type. While several experimental compounds have been developed that show a high affinity for the autoreceptors, to date there is no convincing evidence for their therapeutic efficacy.
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