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Antipsychotic drugs and amphetamine: direct evidence for an action on dopaminergic neurons
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ABSTRACTS
Thus, chronic stimulation of brain at subconvulsant levels gradually creates a state wherein convulsive responses not only occur, but result in a permanent plastic change in neural excitability which transcends synaptic barriers. A crucial feature of the model is the discovery that intermittent stimulation is more effective than continuous afferent barrage. Indeed, continuous stimulation led to elevation of the convulsive threshold as though a kind of adaptation of habituation were taking place. The discussion will be centered around two issues: (1) the significance of this model for analysis of mechanisms of plasticity at the neuronal level and, (2) the possible implications of these findings to those researches involving chronic stimulation of the human brain.
Antipsychotic drugs and amphetamine: direct evidence for an action on dopaminergic neurons* BENJAMINS. BUNMEYand GEORGEK. AGHAJANIAN Department
of psychiatry, Yale University School of Medicine, New Haven, Connecticut,
U.S.A.
The therapeutic effects as well as extrapyramidal side effects of the major antipsychotic phenothiazines and butyrophenones have been hypothesized to result from a blockade of dopamine (DA) receptors in the neostriatum or portions of the limbic system. It has been proposed that the paranoid psychosis induced by amphetamine and reversed by antipsychotic drugs results from an excessive release of DA onto these receptor sites. Antipsychotic drugs have been shown to increase DA metabolite concentration and turnover in the CNS. Amphetamine has been shown to promote the release and block the reuptake of catecholamines at presynaptic terminals. To evaluate directly the effects of these drugs upon dopaminergic neurons, extracellular recordings were made to determine the effect of various phenothiazines, haloperidol, and amphetamine on the firing rate of DA-containing cells in the substantia nigra and ventral tegmental area of the rat midbrain. Both anesthetized and gallamine paralyzed animals were used. D-Amphetamine greatly decreased the spontaneous activity of dopaminergic neurons in these areas. The antipsychotic phenothiazines and haloperidol reversed the d-amphetamine depression and when administered alone increased the firing rate of these cells. Promethazine, a phenothiazine lacking antipsychotic efficacy and extrapyramidal side effects, had no effect on the activity of dopaminergic neurons. These findings provide further evidence for a correlation between the antipsychotic properties and extrapyramidal side effects of various phenothiazines and their ability to affect DA cell activity. The phenothiazines and haloperidol being structurally related to DA have been hypothesized to&ave an affinity for postsynaptic DA receptor sites. Thus, a receptor blockade by these drugs might lead to a compensatory increase in activity of the DA-containing cells via a neuronal feedback mechanism. Gur findings support this hypothesis. In an effort to elucidate further the mode of action of amphetamine, its effect on dopaminergic unit activity was studied in the presence of alpha-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis at the rate limiting step. AMPT reversed or prevented amphetamine-induced inhibition. L-Dopa, the immediate precursor of DA and a drug which in high doses can produce psychosis in some patients, as well as dyskinesias that resemble stereotyped behavior, reversed the effect of AMPT on amphetamine depression of DAcontaining cells. Pretreatment with high doses of an aromatic amino acid decarboxylase inhibitor (RO4-4602) antagonized the depressant effect of L-Dopa on dopaminergic cells by preventing the conversion of L-Dopa to DA centrally. This antagonism could be overcome by apomorphine, a drug which appears to stimulate DA receptors directly. Thus, ongoing synthesis of DA appears necessary for amphetamine and L-Dopa (but not apomorphine) to have an effect on the bring rate of DA cells. Haloperidol, a presumed DA receptor blocker, could prevent and reverse the depressant effect of L-Dopa and apomorphine as well as amphetamine. Amphetamine and L-Dopa in high doses cause various behavioral effects in man (e.g., stereotypes) that have been attributed to enhancement of DA activity. Both of these agents as well as apomorphine produce stereotyped behavior in rats and other animals. This behavior is blocked or reversed by haloperidol. In rats, AMPT blocks amphetamine induced stereotypy. Thus, there is a direct parallel between the effect of these drugs on DA cell bring rate and their ability to induce or block DA-linked behaviors. *This research was done in collaboration with Judith R. Walters and Robert H. Roth. This research was supported in part by NIMH Grants l-ROl-MH-17871, MH-4092 and the State of Connecticut.
ABSTRACTS
Thus, chronic stimulation of brain at subconvulsant levels gradually creates a state wherein convulsive responses not only occur, but result in a permanent plastic change in neural excitability which transcends synaptic barriers. A crucial feature of the model is the discovery that intermittent stimulation is more effective than continuous afferent barrage. Indeed, continuous stimulation led to elevation of the convulsive threshold as though a kind of adaptation of habituation were taking place. The discussion will be centered around two issues: (1) the significance of this model for analysis of mechanisms of plasticity at the neuronal level and, (2) the possible implications of these findings to those researches involving chronic stimulation of the human brain.
Antipsychotic drugs and amphetamine: direct evidence for an action on dopaminergic neurons* BENJAMINS. BUNMEYand GEORGEK. AGHAJANIAN Department
of psychiatry, Yale University School of Medicine, New Haven, Connecticut,
U.S.A.
The therapeutic effects as well as extrapyramidal side effects of the major antipsychotic phenothiazines and butyrophenones have been hypothesized to result from a blockade of dopamine (DA) receptors in the neostriatum or portions of the limbic system. It has been proposed that the paranoid psychosis induced by amphetamine and reversed by antipsychotic drugs results from an excessive release of DA onto these receptor sites. Antipsychotic drugs have been shown to increase DA metabolite concentration and turnover in the CNS. Amphetamine has been shown to promote the release and block the reuptake of catecholamines at presynaptic terminals. To evaluate directly the effects of these drugs upon dopaminergic neurons, extracellular recordings were made to determine the effect of various phenothiazines, haloperidol, and amphetamine on the firing rate of DA-containing cells in the substantia nigra and ventral tegmental area of the rat midbrain. Both anesthetized and gallamine paralyzed animals were used. D-Amphetamine greatly decreased the spontaneous activity of dopaminergic neurons in these areas. The antipsychotic phenothiazines and haloperidol reversed the d-amphetamine depression and when administered alone increased the firing rate of these cells. Promethazine, a phenothiazine lacking antipsychotic efficacy and extrapyramidal side effects, had no effect on the activity of dopaminergic neurons. These findings provide further evidence for a correlation between the antipsychotic properties and extrapyramidal side effects of various phenothiazines and their ability to affect DA cell activity. The phenothiazines and haloperidol being structurally related to DA have been hypothesized to&ave an affinity for postsynaptic DA receptor sites. Thus, a receptor blockade by these drugs might lead to a compensatory increase in activity of the DA-containing cells via a neuronal feedback mechanism. Gur findings support this hypothesis. In an effort to elucidate further the mode of action of amphetamine, its effect on dopaminergic unit activity was studied in the presence of alpha-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis at the rate limiting step. AMPT reversed or prevented amphetamine-induced inhibition. L-Dopa, the immediate precursor of DA and a drug which in high doses can produce psychosis in some patients, as well as dyskinesias that resemble stereotyped behavior, reversed the effect of AMPT on amphetamine depression of DAcontaining cells. Pretreatment with high doses of an aromatic amino acid decarboxylase inhibitor (RO4-4602) antagonized the depressant effect of L-Dopa on dopaminergic cells by preventing the conversion of L-Dopa to DA centrally. This antagonism could be overcome by apomorphine, a drug which appears to stimulate DA receptors directly. Thus, ongoing synthesis of DA appears necessary for amphetamine and L-Dopa (but not apomorphine) to have an effect on the bring rate of DA cells. Haloperidol, a presumed DA receptor blocker, could prevent and reverse the depressant effect of L-Dopa and apomorphine as well as amphetamine. Amphetamine and L-Dopa in high doses cause various behavioral effects in man (e.g., stereotypes) that have been attributed to enhancement of DA activity. Both of these agents as well as apomorphine produce stereotyped behavior in rats and other animals. This behavior is blocked or reversed by haloperidol. In rats, AMPT blocks amphetamine induced stereotypy. Thus, there is a direct parallel between the effect of these drugs on DA cell bring rate and their ability to induce or block DA-linked behaviors. *This research was done in collaboration with Judith R. Walters and Robert H. Roth. This research was supported in part by NIMH Grants l-ROl-MH-17871, MH-4092 and the State of Connecticut.