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D2 dopamine receptors in the short- and long-term modulation of corticostriatal transmission
S-9 Advances in the Treatment of Schizophrenia: Into the 21st Century
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not activated by globus pallidu s (GP) stimulation. However, in the other neuron s, where an antidromi c spike was evoked by GP stimulation, it was polysynapt ically activated by compacta stimulation. The orthodromic spikes were inhibited by microiontoph oretically applied atropine, but not by domperidone. The firing of domperid one-sensitive neurons was dose-dependently increased by both microiontophoretic and intravenous admin istrations of ~ or D 21O , agonists such as talipexole, brornocriptine, and quinpirole. In whole -cell patch-clamp studies, talipexole and 7-0H-DPAT (a D, agon ist) induced dose-dependent depolarizat ion with concomitant increases in firing of striatal large neurons. However, in some medium -size neurons, talipexole produced hyperpolarization with a decrease in firing. These result s suggest that DA from pars compacta either activates the large cholinergic interneuron project ing to the GP via the D2 and/or D, receptors, or inhibits some of the medium-size neurons via the Dz receptors .
[s-8-41
02 Dopamine Receptors in the Short- and Long-Term Modulation of Corticostriatal Transmission
P. Calabresi , A. Pisani, D. Centonze, M. De Murta s, G. Bernardi. Clinica Neurologica, Dip. Sanita, Univers ita "Tor Vergata " Roma, Italy We have investigated the role of D2 dopamine (DA) receptors on the modulation of corticos triatal excitatory transm ission by utilizing extracellular and intracellular recordings from a rat corticostriatal slice preparation. In slices obtained from naive animals, bath-application of the D2 receptor agonist qu inpirole, did not significantly affect the excitatory postsynaptic poten tials (EPSPs) recorded from the striatum and induced by a single cortical stimulation. In contrast, in preparations obtained either from DA-denervated rats (unilateral injection of 6-0 HDA) or from haloperidol-treated animals, quinpirole produced a dose-dependent inhibition of the EPSP s amplitude . Th is effect was fully reversed by sulpiride, and was not coupled with changes of postsynaptic responses to exogenously applied glutamate, suggesting a presy naptic site for this action. We also studied the role of D2 receptors in the generation of two forms of synaptic plasticity in the striatum: long-term synaptic depression (LTD) and long-term synaptic potentiation (LTP). Under physiological conditions ( 1.2 mM magnesium), repetitive cortical activation produced LTD. LTP was observed only when magnesium ions were omitted from the bathing solution, in order to deinactivate NMDA receptors. Incubation of the slices with sulpiride prevented the generation of striatal LTD, while it enhanced the amplitude of striatal LTP. In addition. LTP was not observed when the slice was pre incubated with quinpirole. These data indicate that D2 DA receptors exert an opposite control on the generation of these two forms of synaptic plasticity : inhibition of D2 DA receptors blocks LTD, while it favours the generation ofLTP.
@-8-sl Cholinergic and GABAergic Interneurons in the Striatum
Y. Kawaguch i, T. Aosaki , Y. Kubota. Bio-mimetic Control Research Center, RIKEN. Nagoya, Japan In the striatum, intemeurons have not been as well characterized physiologically as the spiny projection cells. We found that the neostriatal interneurons can be divided at least into three classes by physiological, chemical and morpholo gical criteria. The first was FS cells (fast-spiking cells) which fired very short-duration action potentials at constant spike frequency durin g depolarizin g pulses, were immunoreactive for parvalbumin (calcium-binding protein), and had axons with very dense collateralization within or near their dendr itic fields. Another class was identified as those which fired low-threshold spikes (LTS cells) from hyperpolari zed potent ials, were positive for somatostatin and nitric oxide synthase (NOS), and had the largest axonal fields. The other class of interneurons had longer-lastin g afterhyperpolarizations (LA cells), were positive for choline acetyltransferase, and were mostly large aspiny cells. Glutam ic acid decarboxylase (GAD67 ) or GABA immunoreactivity was detected at the somata or terminals of parvalbumin FS cells and somatostatin/NOS LTS cells , but not of cholinergic LA cells. Substance P, probably released from the collateral s of cells projecting to the substantia nigra, excited LA cells and LTS cells, but not FS cells. These results suggest that the striatum has at least one type of cholinergic and two
types of GABAergic cells which are different in physiolog ical, chemical and pharmacological characteristics. It has been revealed that GABAergic intemeurons in the frontal cortex are also classed by the similar criteria into four subtypes immun oreactive for parvalbum in, somatostatin, vasoactive intestinal polypeptide or none of them. These results suggest that intemeuron s in the striatum and frontal cortex may be functionall y heterogeneous.
IS-8-61 Do '02-Like' Dopamine Receptors Mediate Neuronal Excitation or Inhibition: Some Functional-Behavioural Implications J.L. Waddington. Royal College of Surgeons in Ireland, Dubl in, Ireland Few controversies in contemporary neuroscience have endured as long as that concerning the immediate neurophysiological effect(s) of 'D zlike' dopamine receptor activation. While the issue is of fundamental importance, it could be argued that the matter is more abstract and of less consequence than clarifying receptor-mediated actions at other, more functional levels from second messenger neurochemistry through to behaviour. Yet it is not possible to define fully these processes without insight into the immediate neurophysiological action. This necessity has been accentuated by a number of recent development s, including (i) recognition of multiple. complex forms of functional interactions between 'Dj-like' and 'Dj-like' receptor families which ultimately regulate so many forms of behaviour and (ii) the ongoing debate as to the extent to which members of 'Dj -like' and 'Dj -Iike' recep tor families might be colocalized on the same neuronal membrane to subserve such interactions. Full specification of these phenomen a requires a clear understanding of the relevant neuroph ysiological events. Supported by the Royal College of Surgeons in Ireland.
Is-91 Advances in the Treatment of Schizophrenia: Into the 21 st Century
IS-9-1 I Developing NewAntipsychotic Drugs andTreatment Strategies: An Overview D.L. Copolov. The Mental Health Research Institute of Victoria The validated efficacy of a growing number of atypical antipsychotic drugs has created opportuniti es for the development of both related and unrelated novel antipsychotic compound s. At the most banal level, the drugs have provided chemical templates which may be modified in an attempt to obtain more desirable pharmacological profiles. Addit ionally, the effects of these drugs on region-specific immediate-earl y gene expression and electrophysiological activity and on animal mode ls, such as the ternporo-Iimbic disconnection model, have led to a diversification of the methods available to screen for potentially useful antipsychotic drugs which may not bear structural similarities to those currently available. The ability to identify and investigate highly recep tor-selective drugs has been enhanced by the use of transfected cell lines which express individual receptor types and improvements in molecular modellin g. In the absence of x-ray crystallographic data, however, the precise topograph y of neurotransmitter receptors remains undefined. Challenges and requirements for the next phase of drug development and testing include the need to characterize the optimum and minimum receptor occupancy requirements for effective antipsychotic action, to clarify the relative place of the new and soon -to-be-introduced cohorts of atypical drugs in psychiatric practice, to improve the predic tion of the response to drug administration and discontinuation and to develop better drugs and treatment strategies for treatment-resistant patients, especially those with primary negative symptoms.
24
not activated by globus pallidu s (GP) stimulation. However, in the other neuron s, where an antidromi c spike was evoked by GP stimulation, it was polysynapt ically activated by compacta stimulation. The orthodromic spikes were inhibited by microiontoph oretically applied atropine, but not by domperidone. The firing of domperid one-sensitive neurons was dose-dependently increased by both microiontophoretic and intravenous admin istrations of ~ or D 21O , agonists such as talipexole, brornocriptine, and quinpirole. In whole -cell patch-clamp studies, talipexole and 7-0H-DPAT (a D, agon ist) induced dose-dependent depolarizat ion with concomitant increases in firing of striatal large neurons. However, in some medium -size neurons, talipexole produced hyperpolarization with a decrease in firing. These result s suggest that DA from pars compacta either activates the large cholinergic interneuron project ing to the GP via the D2 and/or D, receptors, or inhibits some of the medium-size neurons via the Dz receptors .
[s-8-41
02 Dopamine Receptors in the Short- and Long-Term Modulation of Corticostriatal Transmission
P. Calabresi , A. Pisani, D. Centonze, M. De Murta s, G. Bernardi. Clinica Neurologica, Dip. Sanita, Univers ita "Tor Vergata " Roma, Italy We have investigated the role of D2 dopamine (DA) receptors on the modulation of corticos triatal excitatory transm ission by utilizing extracellular and intracellular recordings from a rat corticostriatal slice preparation. In slices obtained from naive animals, bath-application of the D2 receptor agonist qu inpirole, did not significantly affect the excitatory postsynaptic poten tials (EPSPs) recorded from the striatum and induced by a single cortical stimulation. In contrast, in preparations obtained either from DA-denervated rats (unilateral injection of 6-0 HDA) or from haloperidol-treated animals, quinpirole produced a dose-dependent inhibition of the EPSP s amplitude . Th is effect was fully reversed by sulpiride, and was not coupled with changes of postsynaptic responses to exogenously applied glutamate, suggesting a presy naptic site for this action. We also studied the role of D2 receptors in the generation of two forms of synaptic plasticity in the striatum: long-term synaptic depression (LTD) and long-term synaptic potentiation (LTP). Under physiological conditions ( 1.2 mM magnesium), repetitive cortical activation produced LTD. LTP was observed only when magnesium ions were omitted from the bathing solution, in order to deinactivate NMDA receptors. Incubation of the slices with sulpiride prevented the generation of striatal LTD, while it enhanced the amplitude of striatal LTP. In addition. LTP was not observed when the slice was pre incubated with quinpirole. These data indicate that D2 DA receptors exert an opposite control on the generation of these two forms of synaptic plasticity : inhibition of D2 DA receptors blocks LTD, while it favours the generation ofLTP.
@-8-sl Cholinergic and GABAergic Interneurons in the Striatum
Y. Kawaguch i, T. Aosaki , Y. Kubota. Bio-mimetic Control Research Center, RIKEN. Nagoya, Japan In the striatum, intemeurons have not been as well characterized physiologically as the spiny projection cells. We found that the neostriatal interneurons can be divided at least into three classes by physiological, chemical and morpholo gical criteria. The first was FS cells (fast-spiking cells) which fired very short-duration action potentials at constant spike frequency durin g depolarizin g pulses, were immunoreactive for parvalbumin (calcium-binding protein), and had axons with very dense collateralization within or near their dendr itic fields. Another class was identified as those which fired low-threshold spikes (LTS cells) from hyperpolari zed potent ials, were positive for somatostatin and nitric oxide synthase (NOS), and had the largest axonal fields. The other class of interneurons had longer-lastin g afterhyperpolarizations (LA cells), were positive for choline acetyltransferase, and were mostly large aspiny cells. Glutam ic acid decarboxylase (GAD67 ) or GABA immunoreactivity was detected at the somata or terminals of parvalbumin FS cells and somatostatin/NOS LTS cells , but not of cholinergic LA cells. Substance P, probably released from the collateral s of cells projecting to the substantia nigra, excited LA cells and LTS cells, but not FS cells. These results suggest that the striatum has at least one type of cholinergic and two
types of GABAergic cells which are different in physiolog ical, chemical and pharmacological characteristics. It has been revealed that GABAergic intemeurons in the frontal cortex are also classed by the similar criteria into four subtypes immun oreactive for parvalbum in, somatostatin, vasoactive intestinal polypeptide or none of them. These results suggest that intemeuron s in the striatum and frontal cortex may be functionall y heterogeneous.
IS-8-61 Do '02-Like' Dopamine Receptors Mediate Neuronal Excitation or Inhibition: Some Functional-Behavioural Implications J.L. Waddington. Royal College of Surgeons in Ireland, Dubl in, Ireland Few controversies in contemporary neuroscience have endured as long as that concerning the immediate neurophysiological effect(s) of 'D zlike' dopamine receptor activation. While the issue is of fundamental importance, it could be argued that the matter is more abstract and of less consequence than clarifying receptor-mediated actions at other, more functional levels from second messenger neurochemistry through to behaviour. Yet it is not possible to define fully these processes without insight into the immediate neurophysiological action. This necessity has been accentuated by a number of recent development s, including (i) recognition of multiple. complex forms of functional interactions between 'Dj-like' and 'Dj-like' receptor families which ultimately regulate so many forms of behaviour and (ii) the ongoing debate as to the extent to which members of 'Dj -like' and 'Dj -Iike' recep tor families might be colocalized on the same neuronal membrane to subserve such interactions. Full specification of these phenomen a requires a clear understanding of the relevant neuroph ysiological events. Supported by the Royal College of Surgeons in Ireland.
Is-91 Advances in the Treatment of Schizophrenia: Into the 21 st Century
IS-9-1 I Developing NewAntipsychotic Drugs andTreatment Strategies: An Overview D.L. Copolov. The Mental Health Research Institute of Victoria The validated efficacy of a growing number of atypical antipsychotic drugs has created opportuniti es for the development of both related and unrelated novel antipsychotic compound s. At the most banal level, the drugs have provided chemical templates which may be modified in an attempt to obtain more desirable pharmacological profiles. Addit ionally, the effects of these drugs on region-specific immediate-earl y gene expression and electrophysiological activity and on animal mode ls, such as the ternporo-Iimbic disconnection model, have led to a diversification of the methods available to screen for potentially useful antipsychotic drugs which may not bear structural similarities to those currently available. The ability to identify and investigate highly recep tor-selective drugs has been enhanced by the use of transfected cell lines which express individual receptor types and improvements in molecular modellin g. In the absence of x-ray crystallographic data, however, the precise topograph y of neurotransmitter receptors remains undefined. Challenges and requirements for the next phase of drug development and testing include the need to characterize the optimum and minimum receptor occupancy requirements for effective antipsychotic action, to clarify the relative place of the new and soon -to-be-introduced cohorts of atypical drugs in psychiatric practice, to improve the predic tion of the response to drug administration and discontinuation and to develop better drugs and treatment strategies for treatment-resistant patients, especially those with primary negative symptoms.