TiPS - S e p t e m b e r 1990 [Vol. 11]
357
Pharmacology shows inter- not intraspecies differences
Subtypes of the
dopamine receptor
A n d e r s e n et al. (TIPS, June 1990) 1 have m a d e a persuasive case for w i d e n i n g the D1/D2 d o p a m i n e receptor classification to further subclasses of each receptor. Here I w i s h to c o m m e n t only on central D2 d o p a m i n e receptors w h e r e a variety of evidence, some cited b y A n d e r s e n et al. ~, hints at p h a r m a cologically distinct s u b t y p e s of this receptor (see Refs 2--4 for further discussion). Differences are s u g g e s t e d particularly between D2 d o p a m i n e receptors in limbic a n d striata] b r a i n regions in in v i v o b i n d i n g studies; substituted b e n z a m i d e drugs (e.g. sulpiride) a n d d i b e n z a z e p i n e d r u g s (e.g. clozapine) stand out as potentially d i s c r i m i n a t o r y agents. W h i l e I d o not wish to q u e n c h
the e n t h u s i a s m of those, including myself, w h o search for such s u b t y p e s , in v i t r o l i g a n d b i n d i n g studies w i t h these classes of drug in b o v i n e tissues 3'5 have not supp o r t e d their existence. The data s h o w little evidence for d i s c r i m i n a t i o n of receptor subt y p e s on the basis of differences in Ki values in different b o v i n e tissues i n c l u d i n g b o t h limbic and striatal regions of b r a i n a n d anterior pituitary. Since competition d a t a for a n t a g o n i s t s all fit to single b i n d i n g site models, there is also no evidence for s u b t y p e s w i t h i n each tissue. T h u s other explan a t i o n s such as differential p e n etration of d r u g s s h o u l d be cons i d e r e d for the d i s c r i m i n a t i o n data cited in the T i P S article.
Further evidence links EAAs to schizophrenia
Glutamate and schizophrenia The recent article b y Wachtel a n d Turski (TIPS, June 1990) I discusses the evidence for the 'glutamate h y p o t h e s i s ' of s c h i z o p h r e n i a 2, This h y p o t h e s i s proposes that a deficiency in glutamatergic neurot r a n s m i s s i o n a n d a resulting dist u r b e d balance b e t w e e n glutamatergic a n d d o p a m i n e r g i c systems w i t h i n the striatum m a y play a key role in the p a t h o p h y s i o l o g y of schizophrenia. There are also two other h y potheses l i n k i n g excitatory a m i n o acids a n d s c h i z o p h r e n i a w h i c h were not m e n t i o n e d b y Wachtel and Turski: • Etienne a n d Baudry have suggested that an abnormal genetic regulation of N M D A receptors m i g h t b e r e s p o n s i b l e for developm e n t of schizophrenic symptoms 3. e O n the basis of o b s e r v e d increased [3H]kain!c acid a n d [3H]Daspartate b i n d i n g in p o s t - m o r t e m orbital frontal cortex of schizophrenic patients, Deakin et al. 4 have s u g g e s t e d that schizophrenia • ay involve disturbances in the normal d e v e l o p m e n t of cortical glutamatergic n e u r o n s leading to an o v e r a b u n d a n t glutamatergic
However, similar studies in rats 4 do suggest interspecies differences between D2 d o p a m i n e receptors (bovine vs rat) and these differences are particularly notable for the substituted benza m i d e drugs. Such differences should ultimately be explicable in terms of the rather limited a m i n o acid differences between rat and b o v i n e receptors 6 revealed b y gene cloning. PHILIP G. STRANGE
Biological Laboratory, The University, Canterbury, Kent CT2 7N], UK.
References 1 Andersen, P. H. et al. (1990) Trends
Pharmacol. Sci. 11, 231-236 2 Strange, P. G. (1987) Neurochem. Int. 10, 27-33 3 Leonard, M. N., Macey, C. A. and Strange, P. G. (1987) Biochem. I. 248, 595-602 4 Leonard, M. N., Halliday, C. A., Marriott, A. S. and Strange, P. G. (1988) Biochem. Pharmacol. 37, 4335--4339 5 Simmonds, S. H., Strange, P. G., Hall, A. W. and Taylor, R. l- K. (1986) Biochem. Pharmacol. 35, 731-735 6 Chio, C. L., Hess, G. F., Graham, R. S. and Huff, R. M. (1990) Nature 343, 266-269 4 Deakin, J. F. W. etal. (1989) I. Neurochem. 52, 1781-1786 5 lanowsky, A. and Berger, S. P. (1989) ScMzophrenia Res. 2, 189
i n n e r v a t i o n of the orbital frontal cortex. The g r o w i n g e v i d e n c e for a d i s t u r b e d function of excitatory a m i n o a~ids in s c h i z o p h r e n i a m i g h t p r o v i d e a b a s i s for the d e v e l o p m e n t of n e w drugs. It is p o s s i b l e that w e have h a d such d r u g s available for m a n y years: it has been s h o w n that the atypical neuroleptic clozapine, b u t not haloperidol, interacts w i t h the N M D A receptor-coupled ion channel (Ki value in the high nanomolar range) s. H o w e v e r , it is not yet k n o w n w h e t h e r clozapine would act as an agonist or as an antagonist at this site. JOHANNES KORNHUBER
University of Wiirzburg, Department of Psychiatry, FiichsleinstraJ~e 15, D-8700 Wiirzburg, FRG. '
References 1 Wachtel, H. and Turski, L. (1990) Trends Pharmacol. Sci. 11, 219-220 2 Kim, J. S., Kornhuber, H. H., SchmidBurgk, W. and Holzmiiller, B. (1980) Neurosci. Lett. 20, 379-382 3 Etienne, P. and Baudry, M. (1987) Neurobiol. Aging 8, 362-366
News
.....
Pot receptor cloned The serendipitous cloning of the cannabinoid receptor has been reported in a recent issue of Nature (9th August 1990). Lisa Matsuda and Tom Bonner have cloned the receptor from rat cerebral cortex using a probe derived from the bovine substance K receptor sequence. It is a member of the G-protein coupled family of receptors and has seven hydrophobic domains. Its mRNA is found in cell lines and regions of the brain that have been shown biochemically to have cannabinoid receptors. The receptor has been expressed in a CHO-K1 cell line, where it has been shown to inhibit forskolin-stimulated accumulation of cAMP dose-dependently in response to psychoactive (but not non-psychoactive) cannabinoids. The endogenous ligand is not known. In next month's TIPS, Allyn Howlett reviews the details of the Nature paper and discusses its significance in relation to the mechanism of action of cannabinoids.
357
Pharmacology shows inter- not intraspecies differences
Subtypes of the
dopamine receptor
A n d e r s e n et al. (TIPS, June 1990) 1 have m a d e a persuasive case for w i d e n i n g the D1/D2 d o p a m i n e receptor classification to further subclasses of each receptor. Here I w i s h to c o m m e n t only on central D2 d o p a m i n e receptors w h e r e a variety of evidence, some cited b y A n d e r s e n et al. ~, hints at p h a r m a cologically distinct s u b t y p e s of this receptor (see Refs 2--4 for further discussion). Differences are s u g g e s t e d particularly between D2 d o p a m i n e receptors in limbic a n d striata] b r a i n regions in in v i v o b i n d i n g studies; substituted b e n z a m i d e drugs (e.g. sulpiride) a n d d i b e n z a z e p i n e d r u g s (e.g. clozapine) stand out as potentially d i s c r i m i n a t o r y agents. W h i l e I d o not wish to q u e n c h
the e n t h u s i a s m of those, including myself, w h o search for such s u b t y p e s , in v i t r o l i g a n d b i n d i n g studies w i t h these classes of drug in b o v i n e tissues 3'5 have not supp o r t e d their existence. The data s h o w little evidence for d i s c r i m i n a t i o n of receptor subt y p e s on the basis of differences in Ki values in different b o v i n e tissues i n c l u d i n g b o t h limbic and striatal regions of b r a i n a n d anterior pituitary. Since competition d a t a for a n t a g o n i s t s all fit to single b i n d i n g site models, there is also no evidence for s u b t y p e s w i t h i n each tissue. T h u s other explan a t i o n s such as differential p e n etration of d r u g s s h o u l d be cons i d e r e d for the d i s c r i m i n a t i o n data cited in the T i P S article.
Further evidence links EAAs to schizophrenia
Glutamate and schizophrenia The recent article b y Wachtel a n d Turski (TIPS, June 1990) I discusses the evidence for the 'glutamate h y p o t h e s i s ' of s c h i z o p h r e n i a 2, This h y p o t h e s i s proposes that a deficiency in glutamatergic neurot r a n s m i s s i o n a n d a resulting dist u r b e d balance b e t w e e n glutamatergic a n d d o p a m i n e r g i c systems w i t h i n the striatum m a y play a key role in the p a t h o p h y s i o l o g y of schizophrenia. There are also two other h y potheses l i n k i n g excitatory a m i n o acids a n d s c h i z o p h r e n i a w h i c h were not m e n t i o n e d b y Wachtel and Turski: • Etienne a n d Baudry have suggested that an abnormal genetic regulation of N M D A receptors m i g h t b e r e s p o n s i b l e for developm e n t of schizophrenic symptoms 3. e O n the basis of o b s e r v e d increased [3H]kain!c acid a n d [3H]Daspartate b i n d i n g in p o s t - m o r t e m orbital frontal cortex of schizophrenic patients, Deakin et al. 4 have s u g g e s t e d that schizophrenia • ay involve disturbances in the normal d e v e l o p m e n t of cortical glutamatergic n e u r o n s leading to an o v e r a b u n d a n t glutamatergic
However, similar studies in rats 4 do suggest interspecies differences between D2 d o p a m i n e receptors (bovine vs rat) and these differences are particularly notable for the substituted benza m i d e drugs. Such differences should ultimately be explicable in terms of the rather limited a m i n o acid differences between rat and b o v i n e receptors 6 revealed b y gene cloning. PHILIP G. STRANGE
Biological Laboratory, The University, Canterbury, Kent CT2 7N], UK.
References 1 Andersen, P. H. et al. (1990) Trends
Pharmacol. Sci. 11, 231-236 2 Strange, P. G. (1987) Neurochem. Int. 10, 27-33 3 Leonard, M. N., Macey, C. A. and Strange, P. G. (1987) Biochem. I. 248, 595-602 4 Leonard, M. N., Halliday, C. A., Marriott, A. S. and Strange, P. G. (1988) Biochem. Pharmacol. 37, 4335--4339 5 Simmonds, S. H., Strange, P. G., Hall, A. W. and Taylor, R. l- K. (1986) Biochem. Pharmacol. 35, 731-735 6 Chio, C. L., Hess, G. F., Graham, R. S. and Huff, R. M. (1990) Nature 343, 266-269 4 Deakin, J. F. W. etal. (1989) I. Neurochem. 52, 1781-1786 5 lanowsky, A. and Berger, S. P. (1989) ScMzophrenia Res. 2, 189
i n n e r v a t i o n of the orbital frontal cortex. The g r o w i n g e v i d e n c e for a d i s t u r b e d function of excitatory a m i n o a~ids in s c h i z o p h r e n i a m i g h t p r o v i d e a b a s i s for the d e v e l o p m e n t of n e w drugs. It is p o s s i b l e that w e have h a d such d r u g s available for m a n y years: it has been s h o w n that the atypical neuroleptic clozapine, b u t not haloperidol, interacts w i t h the N M D A receptor-coupled ion channel (Ki value in the high nanomolar range) s. H o w e v e r , it is not yet k n o w n w h e t h e r clozapine would act as an agonist or as an antagonist at this site. JOHANNES KORNHUBER
University of Wiirzburg, Department of Psychiatry, FiichsleinstraJ~e 15, D-8700 Wiirzburg, FRG. '
References 1 Wachtel, H. and Turski, L. (1990) Trends Pharmacol. Sci. 11, 219-220 2 Kim, J. S., Kornhuber, H. H., SchmidBurgk, W. and Holzmiiller, B. (1980) Neurosci. Lett. 20, 379-382 3 Etienne, P. and Baudry, M. (1987) Neurobiol. Aging 8, 362-366
News
.....
Pot receptor cloned The serendipitous cloning of the cannabinoid receptor has been reported in a recent issue of Nature (9th August 1990). Lisa Matsuda and Tom Bonner have cloned the receptor from rat cerebral cortex using a probe derived from the bovine substance K receptor sequence. It is a member of the G-protein coupled family of receptors and has seven hydrophobic domains. Its mRNA is found in cell lines and regions of the brain that have been shown biochemically to have cannabinoid receptors. The receptor has been expressed in a CHO-K1 cell line, where it has been shown to inhibit forskolin-stimulated accumulation of cAMP dose-dependently in response to psychoactive (but not non-psychoactive) cannabinoids. The endogenous ligand is not known. In next month's TIPS, Allyn Howlett reviews the details of the Nature paper and discusses its significance in relation to the mechanism of action of cannabinoids.
