- Email: [email protected]
Dopamine D2 receptor and obesity
CORRESPONDENCE
their study were diagnosed on PEF criteria rather than the need for oral corticosteroids. Our criteria are broadly similar to those used in everyday practice and that the benefit seen with formoterol compared with terbutaline would differ to any extent if exacerbations were defined differently seems unlikely. A much larger study is underway that will show whether use of formoterol rather than short acting -agonists for asthma treatment will reduce exacerbations that are diagnosed only on the need for oral corticosteroids. C-G Löfdahl, D S Potma, A Eivindson, A J M Schreurs, A Rasidakis, T Ekström contributed to the writing of the letter.
A E Tattersfield Division of Respiratory Medicine, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK 1
2
Taylor DR, Town GI, Herbison GP, et al. Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998; 53: 744–52. Wong CA, Walsh LJ, Smith CJP, et al. Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet 2000; 355: 1399–403.
mesolimbic dopamine system is activated by foods. Patients treated with typical and atypical antipsychotic drugs showed significant bodyweight gain.3 One of the key target sites for the antipsychotic drugs is dopamine D2 receptor. Blockade of D2 receptor by the antipsychotic drugs increases neuronal activity in the mesolimbic dopamine system.4 Patients probably had low availability dopamine-D2-receptor because of blockade, and were more sensitive to the rewarding effect of foods. However, the antipsychotic drugs act on many target sites other than dopamine D2 receptor, and their effect on bodyweight gain might be more complicated. Abnormality in dopamine D2 receptor could be general in all compulsive behaviours, including drug abuse, gambling, binge eating, and compulsive shopping. Therapeutic drugs that target the dopamine D2 receptor and restore the brake of the dopaminergic transmission could be used to treat compulsive behaviours. Jingshan Chen
Dopamine D2 receptor and obesity Sir—Gene-Jack Wang and colleagues (Feb 3, p354)1 report an interesting observation on striatal dopamine-D2receptor availability in obese individuals. They showed that decrease of dopamine-D2-receptor availability correlated negatively with body-mass index (BMI) in obese people. I agree with the authors’ suggestion that the brain reward system plays a part in eating behaviour, but disagree with their interpretation that the decrease of dopamine-D2-receptor availability is a dopamine deficiency and might decrease activation of brain reward and motivation circuits in obese individuals. Dopamine D2 receptor plays an inhibitory role in dopaminergic transmission in mesolimbic dopamine system,2 a natural rewarding system in the human body. The presynaptic and postsynaptic dopamine D2 receptors provide two “brakes” for the dopaminergic transmission. Presynaptic dopamine D2 receptor mediates the negative feedback loop in the dopaminergic transmission. Postsynaptic dopamine D2 receptor couples with inhibitory G protein, and exerts opposite effect of dopamine D1 receptor, which couples with excitatory G protein. Therefore, lower dopamine D2 receptor availability in obese individuals will result in more dopamine release and stronger rewarding effect when the
THE LANCET • Vol 357 • June 9, 2001
Yale Genes and Behavior Center, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA 1
2
3
4
Wang G-J, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet 2001; 357: 354–57. Nestler EJ. Hard target: understanding dopaminergic neurotransmission. Cell 1994; 79: 923–26. Wetterling T. Bodyweight gain with atypical antipsychotics: a comparative review. Drug Saf 2001; 24: 59–73. Atkins JB, Chlan-Fourney J, Nye HE, Hiroi N, Carlezon WA Jr, Nestler EJ. Region-specific induction of delta-FosB by repeated administration of typical versus atypical antipsychotic drugs. Synapse 1999; 33: 118–28.
Sir—Gene-Jack Wang and colleagues1 raise intriguing issues about the relation between brain dopamine and obesity. According to their data in obese individuals, fewer D2 receptors were available in brain striatum and lower numbers of such receptors were negatively correlated with body-mass index (BMI). The investigators suggest that strategies aimed at improving dopamine function might be beneficial in the treatment of obese individuals. Many years ago I studied familial cases of Parkinson’s disease, the pathological hallmark of which is striatal dopamine deficiency because of degeneration of the nigral dopaminergic neurons. I noticed that some probands were affected by diabetes mellitus type 2. I questioned whether the concomitant presence of type 2 diabetes in some patients with Parkinson’s disease was coincidental.
The question prompted me to carefully assess the probands’ pedigrees. I studied 52 families of Parkinson’s disease patients and 68 relatives affected by various diseases (glaucoma, schizophrenia, migraine, epilepsy, &c). 25 relatives had type 2 diabetes, and in several families the disease was present in two to three generations. Of these 25 relatives, 14 had Parkinson’s disease. In addition, my observations showed that clinical course of Parkinson’s disease was more benign in probands who had type 2 diabetes, and these showed good response to treatment with levodopa.2 There is now no doubt that obesity and type 2 diabetes are associated. My study results are comparable with the results of Wang and colleagues and confirm the probability of the relation between brain dopamine and obesity. Based on published reports, low concentrations of dopamine D2 receptors are seen in individuals addicted to various types of drugs, including cocaine, alcohol, and opiates; obese individuals with binge-eating disorders are significantly more likely to have a family history of substance abuse than people in the general population; and genetic variants of the human obesity gene, which predict BMI, interact with the dopamine D2-receptor gene. I therefore postulate that the relation between brain dopamine and obesity is genetically determined. The role of genetic factors in Parkinson’s disease and type 2 diabetes are well known. On the basis of published data and our results, the relation between brain dopamine and insulin seems important, probably in the degree of interaction of the corresponding genes. The dopamine hypothesis has been the main neurochemical theory of schizophrenia for longer than 30 years. Although the details of that relation is elusive, Wang and colleagues’ findings show that its importance should not be doubted.3 Future advances in molecular genetics will help to clarify underlying mechanisms of dopamine metabolism, and its relation to physiology and pathology of the central nervous system. Masharip Atadzhanov Department of Clinical Medicine, School of Medicine, University of Zambia, 50110 Lusaka, Zambia (e-mail: [email protected]) 1
2
3
Wang G-J, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet 2001; 357: 354–57. Atadzhanov M. Diabetes mellitus in families with Parkinson’s disease. Clin Med (Rus) 1973; 5: 87–91. Harrison PJ. Dopamine and schizophrenia: proof at last? Lancet 2000; 356: 958–59.
1883
For personal use. Only reproduce with permission from The Lancet Publishing Group.
their study were diagnosed on PEF criteria rather than the need for oral corticosteroids. Our criteria are broadly similar to those used in everyday practice and that the benefit seen with formoterol compared with terbutaline would differ to any extent if exacerbations were defined differently seems unlikely. A much larger study is underway that will show whether use of formoterol rather than short acting -agonists for asthma treatment will reduce exacerbations that are diagnosed only on the need for oral corticosteroids. C-G Löfdahl, D S Potma, A Eivindson, A J M Schreurs, A Rasidakis, T Ekström contributed to the writing of the letter.
A E Tattersfield Division of Respiratory Medicine, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK 1
2
Taylor DR, Town GI, Herbison GP, et al. Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998; 53: 744–52. Wong CA, Walsh LJ, Smith CJP, et al. Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet 2000; 355: 1399–403.
mesolimbic dopamine system is activated by foods. Patients treated with typical and atypical antipsychotic drugs showed significant bodyweight gain.3 One of the key target sites for the antipsychotic drugs is dopamine D2 receptor. Blockade of D2 receptor by the antipsychotic drugs increases neuronal activity in the mesolimbic dopamine system.4 Patients probably had low availability dopamine-D2-receptor because of blockade, and were more sensitive to the rewarding effect of foods. However, the antipsychotic drugs act on many target sites other than dopamine D2 receptor, and their effect on bodyweight gain might be more complicated. Abnormality in dopamine D2 receptor could be general in all compulsive behaviours, including drug abuse, gambling, binge eating, and compulsive shopping. Therapeutic drugs that target the dopamine D2 receptor and restore the brake of the dopaminergic transmission could be used to treat compulsive behaviours. Jingshan Chen
Dopamine D2 receptor and obesity Sir—Gene-Jack Wang and colleagues (Feb 3, p354)1 report an interesting observation on striatal dopamine-D2receptor availability in obese individuals. They showed that decrease of dopamine-D2-receptor availability correlated negatively with body-mass index (BMI) in obese people. I agree with the authors’ suggestion that the brain reward system plays a part in eating behaviour, but disagree with their interpretation that the decrease of dopamine-D2-receptor availability is a dopamine deficiency and might decrease activation of brain reward and motivation circuits in obese individuals. Dopamine D2 receptor plays an inhibitory role in dopaminergic transmission in mesolimbic dopamine system,2 a natural rewarding system in the human body. The presynaptic and postsynaptic dopamine D2 receptors provide two “brakes” for the dopaminergic transmission. Presynaptic dopamine D2 receptor mediates the negative feedback loop in the dopaminergic transmission. Postsynaptic dopamine D2 receptor couples with inhibitory G protein, and exerts opposite effect of dopamine D1 receptor, which couples with excitatory G protein. Therefore, lower dopamine D2 receptor availability in obese individuals will result in more dopamine release and stronger rewarding effect when the
THE LANCET • Vol 357 • June 9, 2001
Yale Genes and Behavior Center, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA 1
2
3
4
Wang G-J, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet 2001; 357: 354–57. Nestler EJ. Hard target: understanding dopaminergic neurotransmission. Cell 1994; 79: 923–26. Wetterling T. Bodyweight gain with atypical antipsychotics: a comparative review. Drug Saf 2001; 24: 59–73. Atkins JB, Chlan-Fourney J, Nye HE, Hiroi N, Carlezon WA Jr, Nestler EJ. Region-specific induction of delta-FosB by repeated administration of typical versus atypical antipsychotic drugs. Synapse 1999; 33: 118–28.
Sir—Gene-Jack Wang and colleagues1 raise intriguing issues about the relation between brain dopamine and obesity. According to their data in obese individuals, fewer D2 receptors were available in brain striatum and lower numbers of such receptors were negatively correlated with body-mass index (BMI). The investigators suggest that strategies aimed at improving dopamine function might be beneficial in the treatment of obese individuals. Many years ago I studied familial cases of Parkinson’s disease, the pathological hallmark of which is striatal dopamine deficiency because of degeneration of the nigral dopaminergic neurons. I noticed that some probands were affected by diabetes mellitus type 2. I questioned whether the concomitant presence of type 2 diabetes in some patients with Parkinson’s disease was coincidental.
The question prompted me to carefully assess the probands’ pedigrees. I studied 52 families of Parkinson’s disease patients and 68 relatives affected by various diseases (glaucoma, schizophrenia, migraine, epilepsy, &c). 25 relatives had type 2 diabetes, and in several families the disease was present in two to three generations. Of these 25 relatives, 14 had Parkinson’s disease. In addition, my observations showed that clinical course of Parkinson’s disease was more benign in probands who had type 2 diabetes, and these showed good response to treatment with levodopa.2 There is now no doubt that obesity and type 2 diabetes are associated. My study results are comparable with the results of Wang and colleagues and confirm the probability of the relation between brain dopamine and obesity. Based on published reports, low concentrations of dopamine D2 receptors are seen in individuals addicted to various types of drugs, including cocaine, alcohol, and opiates; obese individuals with binge-eating disorders are significantly more likely to have a family history of substance abuse than people in the general population; and genetic variants of the human obesity gene, which predict BMI, interact with the dopamine D2-receptor gene. I therefore postulate that the relation between brain dopamine and obesity is genetically determined. The role of genetic factors in Parkinson’s disease and type 2 diabetes are well known. On the basis of published data and our results, the relation between brain dopamine and insulin seems important, probably in the degree of interaction of the corresponding genes. The dopamine hypothesis has been the main neurochemical theory of schizophrenia for longer than 30 years. Although the details of that relation is elusive, Wang and colleagues’ findings show that its importance should not be doubted.3 Future advances in molecular genetics will help to clarify underlying mechanisms of dopamine metabolism, and its relation to physiology and pathology of the central nervous system. Masharip Atadzhanov Department of Clinical Medicine, School of Medicine, University of Zambia, 50110 Lusaka, Zambia (e-mail: [email protected]) 1
2
3
Wang G-J, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet 2001; 357: 354–57. Atadzhanov M. Diabetes mellitus in families with Parkinson’s disease. Clin Med (Rus) 1973; 5: 87–91. Harrison PJ. Dopamine and schizophrenia: proof at last? Lancet 2000; 356: 958–59.
1883
For personal use. Only reproduce with permission from The Lancet Publishing Group.