Dopamine Blockade Research Articles

Rate and Level of Dopamine Blockade Achieved by MPH

Although methylphenidate (MPH) has been used for decades for treating hyperactivity disorders in children, there has been concern about the possibility of addiction with oral dosing because rapid occupancy of dopamine transporter sites has been associated with craving. To examine the addiction potential of oral MPH, this study measured dopamine transporter blockade in seven adults. …

Pimozide Does Not Shift Palatability: Separation of Anhedonia from Sensorimotor Suppression by Taste Reactivity

PECIÑA, S., K. C. BERRIDGE AND L. A. PARKER. Pimozide does not shift palatability: separation of anhedonia from sensorimotor suppression by taste reactivity. PHARMACOL BIOCHEM BEHAV 58(3) 801–811, 1997.—Several “taste reactivity” studies of dopamine and reward have concluded that pimozide suppresses the hedonic reaction patterns normally elicited by sucrose but enhances aversive reaction patterns elicited by quinine. However, other taste reactivity studies have failed to find hedonic/aversive shifts in reaction patterns after dopamine antagonists or dopamine lesions. The divergent conclusions have come from two different laboratories. To resolve the controversy regarding dopamine blockade and palatability, the present study joined the two laboratories to investigate the effect of pimozide on taste reactivity patterns elicited by sucrose and quinine. The results replicated many (but not all) of the earlier findings and identified procedural factors responsible for different outcomes. Overall, the results provide evidence for sensorimotor effects of pimozide on taste reactivity but not for a hedonic shift in palatability. Pimozide suppressed both hedonic and aversive reaction patterns in a gradual sensorimotor fashion when the eliciting taste stimulus was repeated or continued for several minutes. The general suppression typically did not alter the initial reaction to a taste but emerged only after an oral infusion of sucrose or quinine continued for several minutes or trials. Aversive reactions were never enhanced. The balance between hedonic and aversive reaction patterns was not shifted by pimozide. We conclude that pimozide produces a sensorimotor impairment of taste reactivity patterns but does not shift taste palatability toward anhedonia or aversion.

Modulation of basal ganglia neurotransmission by the classical antipsychotic fluphenazine is due in part to the blockade of dopamine D 1-receptors

Classical antipsychotics, such as fluphenazine, influence neurotransmission by blocking both dopamine D 1- and D 2-receptors which in turn results in widespread adaptive changes in the neurochemistry of the basal ganglia. The purpose of the present study was to determine the role of D 1-receptors in mediating some of these neurochemical events, including changes in D 1- and D 2-receptor binding, and the expression of preproenkephalin and glutamic acid decarboxylase mRNAs. For these experiments, rats were given a depot injection of fluphenazine decanoate or injected twice daily for 21 days with the D 1-receptor antagonist SCH-23390. An additional group received both fluphenazine and SCH-23390 and controls were given saline. Fluphenazine administration decreased D 2-receptor binding throughout the basal ganglia while SCH-23390 was without effect. In contrast to the uniform reduction in D 2-receptor binding, fluphenazine altered D 1-receptor binding in a region-dependent manner. Region-dependent changes were also observed in animals given SCH-23390 which increased binding in the entopeduncular nucleus and posterior caudate-putamen without affecting other brain regions. Both fluphenazine and SCH-23390 significantly enhanced preproenkephalin and glutamic acid decarboxylase (GAD) mRNA expression in the anterior striatum. Fluphenazine also increased GAD mRNA levels in the entopeduncular nucleus. Together, these results indicate that the attenuation of D 1-receptor-mediated neurotransmission modulates a number of clinically relevant neurochemical processes in the basal ganglia.

Effects of dopamine and alpha-2 adrenoreceptor blockade on l-dopa and cholecystokinin-induced gastroprotection

Dopamine and cholecystokinin have been colocalized in neurons and represent endogenous enteric neurotransmitters. Both peptides posses potent protective actions against gastric injury when given exogenously. This study was undertaken in conscious female rats to test the hypothesis that cholecystokinin may exert its protective actions via release of dopamine. Experiments were designed to ascertain whether l-dopa, a dopamine precursor, could prevent gastric injury with the same degree of efficacy as cholecystokinin and to determine what role alpha-2 adrenoreceptors and dopamine receptors play in mediating the protective actions of these peptides. Intraperitoneal administration of l-dopa (1 to 25 mg/kg) in a dose-dependent manner prevented the type of macroscopic injury to the acid-secreting portion of the stomach that is caused by 1 ml of orogastric acidified ethanol (150 mmol/L hydrochloric acid/50% ethanol), an effect corroborated by histologic examination. Administration of either the alpha-2 adrenoreceptor antagonist yohimbine (0.1 to 1.0 mg/kg) or the dopamine receptor antagonist haloperidol (1 to 5 mg/kg) caused a partial reversal of l-dopa—induced protection but not the protective actions of subcutaneous cholecystokinin (100 μg/kg). Simultaneous administration of both receptor antagonists had an additive effect and completely reversed the protective actions of l-dopa. The dopamine precursor l-dopa was just as effective in maintaining the integrity of the gastric epithelium in the face of a damaging insult as the gut peptide cholecystokinin. However, the data indicate that l-dopa initiates its protective actions through activation of both alpha-2 adrenoreceptors and dopamine receptors, whereas the protective effects of cholecystokinin are elicited by means of a different mechanism.

The dopamine D 3 receptor antagonist, (+)-S 14297, blocks the cataleptic properties of haloperidol in rats

In contrast to haloperidol, the selective dopamine D 3 receptor antagonist, (+)-S 11566 {(±)-[7-( N, N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3 b)dihydro,2,3-furane]} and its active isomer, (+)-S 14297, induced neither catalepsy nor reduced conditioned avoidance responses in rats. (+)-S 11566 and (+)-S 14297 did, however, dose-dependently abolish the cataleptic actions of haloperidol. This action was expressed stereospecifically inasmuch as (−)-S 17777, the inactive distomer of (+)-S 14297, was ineffective. Further, the influence of haloperidol upon conditioned avoidance responses was not affected by (+)-S 14297. These data suggest that blockade of dopamine D 3 receptors may inhibit the extrapyramidal but not – as based on the conditioned avoidance response paradigm – antipsychotic actions of neuroleptics. © 1997 Elsevier Science B.V. All rights reserved.

Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D 4 receptor

We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D 4 receptor. Both compounds, 3-ethoxy- N-methyl- N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinylamine (U-99363E), and its 3-isopropoxy analog (U-101958), were found through a routine receptor binding screen. The determined affinities ( K i) of these compounds for the cloned human dopamine D 4 receptor were 2.2 and 1.4 nM, respectively. They exhibited at least 100-fold lower affinities for dopamine D 2 and for other dopaminergic, serotonergic and adrenergic receptors. Both compounds were found to antagonize quinpirole-induced mitogenesis in Chinese hamster ovary cells expressing the human dopamine D 4 receptor. In spite of their poor metabolic stability and low bioavailability, U-99363E and U-101958 appear to be among the first high-affinity, highly selective dopamine D 4 receptor antagonists reported, and may have utility in in vitro investigations requiring selective tagging or blockade of dopamine D 4 sites. © 1997 Elsevier Science B.V. All rights reserved.

Modulation of [ 3H]dopamine release by neuropeptide Y in rat striatal slices

Neuropeptide Y, a 36-amino-acid peptide, has a wide and specific distribution in the central nervous system. In this study we examined the regulatory mechanisms of neuropeptide Y on dopamine release in the rat central nervous system. The effects of neuropeptide Y on the electrically stimulated [ 3H]dopamine release were investigated in superfused striatal slices of Sprague-Dawley rats, spontaneously hypertensive rats and Wistar-Kyoto rats. Neuropeptide Y (1 × 10 −8 – 1 × 10 −7 mol/l) reduced the stimulation (1 Hz)-induced [ 3H]dopamine release by a comparable amount in Sprague-Dawley rats. The blockade of dopamine D 2 receptors by the dopamine D 2 receptor antagonist, sulpiride, diminished the inhibitory effects of neuropeptide Y on the stimulation-evoked [ 3H]dopamine release. Pretreatment of slices with pertussis toxin (a potent inhibitor of G i-proteins) attenuated the suppression of the stimulation-evoked [ 3H]dopamine release by neuropeptide Y. Unlabelled dopamine itself reduced the stimulation-evoked [ 3H]dopamine release, and the inhibitory effect was also attenuated in the pertussis toxin-pretreated slices. In spontaneously hypertensive rats, the inhibitory effect of neuropeptide Y on the stimulation-evoked [ 3H]dopamine release was more pronounced than that in Wistar-Kyoto rats. The results of the present study showed that neuropeptide Y inhibited the stimulation-evoked dopamine release partially mediated by dopamine D 2 receptors and the pertussis toxin-sensitive G i-proteins in rat striatum. Furthermore, the greater effect of neuropeptide Y on dopamine release in spontaneously hypertensive rats suggests a possible involvement of the peptide in regulating the central dopaminergic nerve activity in hypertension.

Atypical Antipsychotics and the Pharmacology of Olanzapine

Atypical antipsychotics present exciting opportunities to improve the quality of life for many individuals who are experiencing the debilitating impact of schizophrenia, a syndrome with complex symptom presentations and unclear cause. In the past the antipsychotic efficacy was thought to correlate with the degree of dopamine blockade; this hypothesis has several limitations. Atypical antipsychotics hold promise for reduced side effects and improved efficacy in treating negative symptoms, possibly through the interactions of neurotransmitters such as serotonin and dopamine. Similar to clozapine, olanzapine (Zyprexa) has a bigh affinityfor a number of subtypes of dopamine receptors and other neurotransmitters. The interrelationship of its actions at multiple receptor sites may account for its improved efficacy in treating negative symptoms and its unique side effect profile.

Atypical antipsychotics and the pharmacology of olanzapine

Abstract Atypical antipsychotics present exciting opportunities to improve the quality of life for many individuals who are experiencing the debilitating impact of schizophrenia, a syndrome with complex symptom presentations and unclear cause. In the past the antipsychotic efficacy was thought to correlate with the degree of dopamine blockade; this hypothesis has several limitations. Atypical antipsychotics hold promise for reduced side effects and improved efficacy in treating negative symptoms, possibly through the interactions of neurotransmitters such as serotonin and dopamine. Similar to clozapine, olanzapine (Zyprexa) has a high affinity for a number of subtypes of dopamine receptors and other neurotransmitters. The interrelationship of its actions at multiple receptor sites may account for its improved efficacy in treating negative symptoms and its unique side effect profile.

Methodological issues in the design of clinical studies of new drugs for the treatment of obsessive compulsive disorder

Obsessive Compulsive Disorder (OCD) is increasingly recognised to be relatively common and responsive to some drug treatments (serotonin reuptake inhibitors). Clinical studies utilising recognised diagnostic criteria have identified some relevant negative prognostic factors: early age at disease onset, severe baseline disease, and failure of previous drug treatments all of which reduce the apparent success rates of SRI drugs. Furthermore, patients with comorbid tics seem to respond best to a combination of SRI activity and dopamine blockade. Short term efficacy studies are best performed with a parallel group design and a duration of around 3 months. Long term efficacy studies should probably use the relapse prevention design, with open label responders randomised to double blind continuation or placebo. Does finding has not been properly explored, and any one fixed dose will only be optimal for some patients. Efficacy can be reliably measured using the YBOCs, NIMH-OC and CGI rating scales.

Binding of Typical and Atypical Antipsychotic Drugs to Multiple Neurotransmitter Receptors

As antipsychotic drugs appear to act mainly via blockade of central D2 dopamine (DA) receptors, the hypothesis that DA is primarily involved in the pathogenesis of schizophrenia has gained wide acceptance. In recent times atypical antipsychotic drugs, exemplified by clozapine, have been developed. These drugs do not have many of the toxic side effects of typical antipsychotic drugs such as tardive dyskinesia, Parkinsonism, dystonias, akathisia, and elevation of serum prolactin levels. Clozapine remains the prototype of atypical antipsychotic drugs, and no currently available atypical antipsychotic drug appears to have the spectrum of efficacy of clozapine. A large number of putative atypical antipsychotic drugs have been developed that include risperidone, olanzepine, sertindole, ziprasidone, seroquel, melperone, and others. The fact that atypical antipsychotic drugs, as a group, have relatively high affinity for a number of different receptors suggests that ascribing the unique effects of any one member of this group to a particular receptor is likely to be unproductive. It is more likely that the unique effects of clozapine, for instance, are because of a spectrum of binding to several receptors. This chapter investigates the spectrum of drug binding of clinically available atypical antipsychotic drugs to multiple DA and 5HT receptors and compares their binding spectrums with typical antipsychotic drugs. It is discovered that atypical antipsychotic drugs are, in general, characterized by low D2 dopamine receptor affinity and relatively high affinities for various 5HT receptors (5HT2A, 5HT2C, 5HT6, and 5HT7).

Effects of a range of dopamine receptor agonists and antagonists on ethanol intake in the rat

The aim of this study was to assess the effects of a range of dopaminergic agents on consumption of an ethanol solution (10% ethanol, 3% glucose) in rats. A two-bottle, free-choice paradigm was used following induction of ethanol consumption and preference in standard laboratory rats. The model used provides a robust and reliable level of ethanol oral administration in normal laboratory rats. Both ethanol intake and preference were reduced by a dopamine D 1 receptor partial agonist, SFK 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol hydrochloride), in a dose-dependent manner. The dopamine D 2/D 3 receptor agonist 7-OH-DPAT ((±)-7-hydroxy- N,N-(di- n-propyl-2-aminotetralin)) at the lowest dose of 0.01 mg/kg increased both ethanol intake and preference. At higher doses (0.03–0.1 mg/kg) no significant effects were found. The dopamine D 1 receptor antagonist SCH 23390 ( R-(+)-7-chloro-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1 H-3-3benzazepine-8-ol), dopamine D 2/D 3 receptor antagonist raclopride and 5-HT 2/D 2 receptor antagonist risperidone did not affect ethanol consumption, although all at high doses induced a significant decrease in water intake, indicating a non-specific decrease in consummatory behavior with these compounds. These results suggest the involvement of the dopaminergic system in ethanol intake and ethanol reinforcement with dopamine D 1 and D 2/D 3 receptors playing opposing roles. Blockade of dopamine D 2 receptors had no selective effect on ethanol consumption and ethanol preference.

Dopamine D 3 receptors are not involved in the induction of c- fos mRNA by neuroleptic drugs: comparison of the dopamine D 3 receptor antagonist GR103691 with typical and atypical neuroleptics

The effect of acute and chronic administration of dopamine receptor antagonists on the expression of mRNA encoding the cellular immediate-early gene c- fos was investigated in rat brain by in situ hybridization using 35S-labelled oligonucleotide probes. The selective dopamine D 3 receptor antagonist GR103691 had no effect on the level of c- fos mRNA after acute or chronic treatment. Acute treatment with haloperidol increased the level of c- fos mRNA in the caudate-putamen, nucleus accumbens shell and core, olfactory tubercle and parietal cortex. After chronic treatment with haloperidol increases in the level of c- fos mRNA in the caudate-putamen and nucleus accumbens core were no longer observed. The increase in the level of c- fos mRNA in the nucleus accumbens shell was attenuated but still significantly elevated above the level measured in vehicle-treated animals. In the olfactory tubercle, parietal cortex, frontal cortex and cingulate cortex the level of c- fos mRNA was decreased after chronic haloperidol treatment. Acute sulpiride treatment reduced the level of c- fos mRNA in the olfactory tubercle, parietal cortex and cingulate cortex. After chronic treatment with sulpiride the level of c- fos mRNA was reduced in the dorsal caudate-putamen only. Acute clozapine treatment increased the level of c- fos mRNA in the nucleus accumbens shell and islands of Calleja. After chronic treatment with clozapine the level of c- fos mRNA remained elevated in the islands of Calleja but not in the nucleus accumbens shell. These results indicate that acute and chronic blockade of dopamine D 3 receptors does not cause induction of c- fos transcription in limbic, striatal or cortical regions of rat brain. This study also demonstrated that acute blockade of dopamine receptors with haloperidol, sulpiride and clozapine induced different regionally specific patterns of c- fos expression which were altered after chronic blockade.

Morphologically distinct subpopulations of neurotensin-immunoreactive striatal neurons observed in rat following dopamine depletions and D 2 receptor blockade project to the globus pallidus

It has been reported in previous studies that perikaryal neurotensin immunoreactivity is largely absent in the rat striatum except following striatal dopamine depletion or blockade of dopamine D 2 receptors, after which, however, neurotensin immunoreactivity is elicited in at least two distinct subpopulations of striatal neurons [Zahm D. S. (1992) Neuroscience 46, 335–350]. One subpopulation of such cells (type I), prominent following D 2 receptor blockade, is located mainly in the matrix compartment in the rostral, dorsomedial and ventrolateral parts of the striatum, and comprises neurons at the large end of the medium-sized spectrum that exhibit intense neurotensin immunoreactivity in perikarya and proximal dendrites, but rarely display Fos immunoreactivity [Senger B. et al. (1993) Neuroscience 57, 649–660]. A second subpopulation (type II) resides predominantly in the patch (striosome) and matrix compartments in the dorsolateral quadrant of the striatum, and is prominent following administration of reserpine. These neurons are at the small end of the medium size range and exhibit very light neurotensin immunoreactivity, with little staining of dendrites. Fos immunoreactivity is frequently co-localized in striatal neurons that exhibit a type II striatal neurotensin response [Brog J. S. and Zahm D. S. (1995) Neuroscience 65, 71–86]. In the current study, neurotensin immunoreactivity was elicited in striatal neurons by ventral mesencephalic 6-hydroxydopamine lesions or administration of reserpine or haloperidol. Irrespective of which drug was given, retrogradely transported Fluoro-Gold was prominently co-localized with neurotensin-like immunofluorescence in the perikarya of striatal neurons following injections of the retrograde tracer into the globus pallidus. Few double-labeled neurons were observed following administration of any of these drugs and injections of Fluoro-Gold into the substantia nigra. It is concluded that two supopulations of neurotensin-immunoreactive striatal neurons project predominantly to the globus pallidus and minimally to the substantia nigra.

Behavioural effects of 7-OH-DPAT are solely due to stimulation of dopamine D 2 receptors in the shell of the nucleus accumbens; jaw movements

The goal of this study was to determine whether the dopamine D 3 receptor in limbic structures plays a role in the shell-specific and dopamine-dependent display of jaw movements in rats. When combined with the dopamine D 1 receptor agonist (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SKF 82958, 5 μg), the putative dopamine D 3 receptor agonist (±)-7-hydroxy- N,N-di- n-propyl-2-aminotetralin (7-OH-DPAT, 10 μg) produced repetitive jaw movements following injection into the shell, but not the core, of the nucleus accumbens. This behaviour was only partially inhibited by local blockade of dopamine D 1 receptors ( R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine, SCH 23390, 500 ng), dopamine D 2 receptors (domperidone, 50 and 100 ng) or dopamine D 2 3 receptors (l-sulpiride, 25 ng). Combined blockade of both dopamine D 1 and D 2 receptors in the shell completely antagonized the jaw movements elicited by the cocktail of SKF 82958 and 7-OH-DPAT. Replacing 7-OH-DPAT by another putative dopamine D 3 receptor agonist, S(+)-(4 aR, 10 bR)-3,4,4 a,10 b-tetrahydro-4-propyl-2 H,5 H-[1]benzopyrano[4,3- b]-1,4-oxazin-9-ol (PD 128,907, 10 μg), in the cocktail did not produce jaw movements, when administered into the shell. Injection of the cocktail of SKF 82958 and 7-OH-DPAT into the ventrolateral striatum, which contains nearly no dopamine D 3 receptors, also elicited jaw movements. It is concluded that mesolimbic dopamine D 3 receptors play no role in the dopamine-dependent and shell-specific jaw movements: the contribution of 7-OH-DPAT in the cocktail of SKF 82958 and 7-OH-DPAT to the display of jaw movements is solely due to its ability to activate dopamine D 2 receptors.

Behavioural effects of 7-OH-DPAT are solely due to stimulation of dopamine D 2 receptors in the shell of the nucleus accumbens; turning behaviour

The goal of this study was to determine whether the dopamine D 3 receptor in limbic structures plays a role in the shell-specific and dopamine-dependent display of turning behaviour in rats. When combined with the dopamine D 1 receptor agonist (±)-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7,8-diol (SKF-38393, 5 μg), the putative dopamine D 3 receptor agonist (±)-7-hydroxy- N,N-di- n-propyl-2-aminotetralin (7-OH-DPAT, 1, 5 and 10 μg) elicited contralateral turning in a dose-dependent manner following unilateral injection into the shell, but not the core, of the nucleus accumbens. The turning pattern displayed was identical to that reported previously after intra-accumbens administration of the cocktail of SKF-38393 and the dopamine D 2 receptor agonist quinpirole. The behaviour under study was dose-dependently attenuated by local administration of the dopamine D 1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SCH 23390: 10 and 100 ng), the dopamine D 2 receptor antagonist domperidone (25 and 50 ng) or the dopamine D 2 3 receptor antagonist l-sulpiride (5 and 25 ng). Combined blockade of both dopamine D 1 and D 2 receptors in the shell with a dose of either antagonist alone that produced just a moderate reduction (10 ng SCH 23390 and 50 ng domperidone) completely antagonized the turning behaviour elicited by the cocktail of SKF-38393 and 7-OH-DPAT. Replacing 7-OH-DPAT by another putative dopamine D 3 receptor agonist, S(+)-(4 aR,10 bR)-3,4,4 a,10 b-tetrahydro-4-propyl-2 H,5 H-[1]benzopyrano[4,3- b]-1,4-oxazin-9-ol (PD 128,907, 10 μg), in the cocktail did produce no turning behaviour at all. It is concluded that mesolimbic dopamine D 3 receptors play no role in the dopamine-dependent and shell-specific turning behaviour: the contribution of 7-OH-DPAT in the cocktail of SKF-38393 and 7-OH-DPAT to the display of turning behaviour is solely due to its ability to activate dopamine D 2 receptors.

The effects of D- and L-fenfluramine (and their interactions with D-amphetamine) on psychomotor function and mood

This study reports the results on psychomotor functioning of D- and L-fenfluramine alone, and in combination with D-amphetamine, in a placebo-controlled trial on 12 normal male volunteers, in order to investigate their CNS activity in humans. The major findings were that D-amphetamine increased alertness, L-fenfluramine increased unhappiness whilst D-fenfluramine decreased hunger and increased the critical flicker fusion threshold. D-Amphetamine in combination with D-fenfluramine increased the critical flicker fusion threshold and in combination with L-fenfluramine the alerting action was diminished. The differing actions of the fenfluramine isomers and their interactions with D-amphetamine suggest that D-fenfluramine is predominantly serotonergic in its activity, whereas L-fenfluramine may be causing dopamine blockade, reducing certain actions of amphetamine possibly mediated by dopamine receptors. The significance of these results in relationship to the psychopharmacology of serotonin, dopamine, and noradrenaline is discussed.

Chronic morphine increases hippocampal acetylcholine release: possible relevance in drug dependence

Previous studies have shown that cocaine and amphetamine stimulate acetylcholine release in the hippocampus via an action of endogenously released dopamine on dopamine D 1 and D 2 receptors. The present study was aimed at clarifying if the property of stimulating hippocampal acetylcholine release was shared by morphine. The acute administration of morphine (10 mg/kg i.p.) failed to modify acetylcholine release in the hippocampus. However, after repeated administration (10 mg/kg i.p. twice daily) morphine acquired the ability to stimulate hippocampal acetylcholine release. Thus, at days 5 and 7 of chronic morphine treatment, a challenge dose of morphine (10 mg/kg i.p.) increased acetylcholine release by 50 and 100%, respectively. Concomitantly with the development of the stimulant property on acetylcholine release, morphine also acquired that of producing behavioural stimulation and lost that of producing sedation and catalepsy. The morphine-induced increase in acetylcholine output was suppressed by the blockade of dopamine D 1 receptors with SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (0.1 mg/kg s.c.), which also suppressed the morphine-induced motor stimulation. Moreover, repeated morphine administration markedly potentiated the stimulant effect of the dopamine D 1 D 2 receptor agonist apomorphine (R(-)-10,11-dihydroxyaporphine) (0.1 or 0.5 mg/kg s.c.) both on hippocampal acetylcholine release and on behaviour. These results may suggest that the enhancement of hippocampal acetylcholine release as well as the development of behavioural sensitisation after chronic morphine could be related to the development of dopamine receptor supersensitivity. Moreover, increased acetylcholine transmission in the hippocampus may play a role in the ‘memory’ of the rewarding effects of drugs of abuse.

ICI 204636 (‘Seroquel’)—A putative new atypical antipsychotic: Results from phase III trials

As antipsychotic drugs appear to act mainly via blockade of central D2 dopamine (DA) receptors, the hypothesis that DA is primarily involved in the pathogenesis of schizophrenia has gained wide acceptance. In recent times atypical antipsychotic drugs, exemplified by clozapine, have been developed. These drugs do not have many of the toxic side effects of typical antipsychotic drugs such as tardive dyskinesia, Parkinsonism, dystonias, akathisia, and elevation of serum prolactin levels. Clozapine remains the prototype of atypical antipsychotic drugs, and no currently available atypical antipsychotic drug appears to have the spectrum of efficacy of clozapine. A large number of putative atypical antipsychotic drugs have been developed that include risperidone, olanzepine, sertindole, ziprasidone, seroquel, melperone, and others. The fact that atypical antipsychotic drugs, as a group, have relatively high affinity for a number of different receptors suggests that ascribing the unique effects of any one member of this group to a particular receptor is likely to be unproductive. It is more likely that the unique effects of clozapine, for instance, are because of a spectrum of binding to several receptors. This chapter investigates the spectrum of drug binding of clinically available atypical antipsychotic drugs to multiple DA and 5HT receptors and compares their binding spectrums with typical antipsychotic drugs. It is discovered that atypical antipsychotic drugs are, in general, characterized by low D2 dopamine receptor affinity and relatively high affinities for various 5HT receptors (5HT2A, 5HT2C, 5HT6, and 5HT7).

Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat

The present paper reviews a series of experiments aimed at elucidating the interaction between specific dopamine (DA) and 5-hydroxytryptamine (5-HT) receptors in the mediation of extrapyramidal motor functions in the rat. There is strong evidence to suggest that (1) the catalepsy produced by dopamine D 1 or D 2 receptor antagonists can be completely antagonized by the administration of 5-HT 1A receptor agonists acting at 5-HT autoreceptors in the median raphe nucleus; (2) the catalepsy produced by a dopamine D 2 receptor antagonist can be completely antagonized by treatment with a 5- HT 2 A C receptor agonist; and (3) the catalepsy produced by blockade of either dopamine D 1 or D 2 receptors is not affected by the administration of a 5- HT 2 A C receptor antagonist. The emerging picture of DA 5- HT receptor interactions in the mediation of extrapyramidal motor functions is of great interest in relation to present efforts to develop new atypical neuroleptics with affinity for brain 5-HT receptor subtypes, and also for the observations that new serotonin selective re-uptake inhibiting antidepressants can produce parkinson-like symptoms in vulnerable individuals.