Acute Effects of Typical and Atypical Antipsychotic Drugs on the Release of Dopamine from Prefrontal Cortex, Nucleus Accumbens, and Striatum of the Rat: An In Vivo Microdialysis Study

In vivo microdialysis has been used to study the acute effects of antipsychotic drugs on the extracellular level of dopamine from the nucleus accumbens, striatum, and prefrontal cortex of the rat. (-)-Sulpiride (20, 50, and 100 mg/kg i.v.) and haloperidol (0.1 and 0.5 mg/kg i.v.) enhanced the outflow of dopamine in the striatum and nucleus accumbens. In the medial prefrontal cortex, (-)-sulpiride at all doses tested did not significantly affect the extracellular level of dopamine. The effect of haloperidol was also attenuated in the medial prefrontal cortex; 0.1 mg/kg did not increase the outflow of dopamine and the effect of 0.5 mg/kg haloperidol was of shorter duration in the prefrontal cortex than that observed in striatum and nucleus accumbens. The atypical antipsychotic drug clozapine (5 and 10 mg/kg) increased the extracellular concentration of dopamine in all three regions. In contrast to the effects of sulpiride and haloperidol, that of clozapine in the medial prefrontal cortex was profound. These data suggest that different classes of antipsychotic drugs may have distinct effects on the release of dopamine from the nigrostriatal, mesolimbic, and mesocortical terminals.     

BIMG 80, a Novel Potential Antipsychotic Drug: Evidence for Multireceptor Actions and Preferential Release of Dopamine in Prefrontal Cortex

Abstract: In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT_1A, 5-HT_2A, 5-HT₆), dopamine (D₁, D_2L, D₄), and noradrenergic (α₁) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.     

Antipsychotic drugs reverse the AMPA receptor-stimulated release of 5-HT in the medial prefrontal cortex

The prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. PFC neuronal activity is modulated by monoaminergic receptors for which antipsychotic drugs display moderate-high affinity, such as 5-HT(2A) and alpha(1)-adrenoceptors. Conversely, PFC pyramidal neurons project to and modulate the activity of raphe serotonergic neurons and serotonin (5-HT) release. Under the working hypothesis that atypical antipsychotic drugs may partly exert their action in PFC, we assessed their action on the in vivo 5-HT release evoked by increasing glutamatergic transmission in rat medial PFC (mPFC). This was achieved by applying S-AMPA in mPFC (reverse dialysis) or by disinhibiting thalamic excitatory afferents to mPFC with bicuculline. The application of haloperidol, chlorpromazine, clozapine and olanzapine in mPFC by reverse dialysis (but not reboxetine or diazepam) reversed the S-AMPA-evoked local 5-HT release. Likewise, the local (in mPFC) or systemic administration of these antipsychotic drugs reversed the increased prefrontal 5-HT release produced by thalamic disinhibition. These effects were shared by the 5-HT(2A) receptor antagonist M100907 and the alpha(1)-adrenoceptor antagonist prazosin. However, raclopride (DA D2 antagonist) had very modest effects. These results suggest that, besides their action in limbic striatum, antipsychotic drugs may attenuate glutamatergic transmission in PFC, possibly by interacting with 5-HT(2A) and/or alpha(1)-adrenoceptors.     

Comparative study of sulpiride and haloperidol on dopamine turnover in the rat brain

The effects of the neuroleptics, sulpiride and haloperidol, on dopamine (DA) turnover were compared following the acute and chronic administration of these drugs alone or in combination with levodopa or apomorphine. In the acute treatment, the increase in DA metabolites in the striatum and nucleus accumbens was more marked in the haloperidol-treated rats than in the sulpiridetreated rats. Following the additional administration of levodopa, however, the potency of the neuroleptics in elevating DA metabolites was reversed. A low dose of apomorphine induced a marked reduction in the striatal DA metabolite levels by approximately 50%. When rats were pretreated with the neuroleptics, haloperidol was more effective in preventing an apomorphine-induced reduction in DA metabolites. On repeated administration of the neuroleptics, a tolerance occurred in the striatum and nucleus accumbens, but not in the prefrontal cortex. This differential development of tolerance was observed in the different brain regions and with the different drugs administered. These results suggests that the pharmacological mechanism of sulpiride on DA turnover differs from that of haloperidol.     

The effect of the antipsychotic drug mosapramine on the expression of Fos protein in the rat brain: comparison with haloperidol, clozapine and risperidone

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects.     

Changes in extracellular dopamine in the rat globus pallidus induced by typical and atypical antipsychotic drugs

Typical antipsychotic drugs with a high extrapyramidal motor side-effects liability markedly increase extracellular dopamine in the caudate-putamen, while atypical antipsychotic drugs with a low incidence of extrapyramidal motor side-effects have less pronounced stimulating actions on striatal dopamine. Therefore, it has been suggested that the extrapyramidal motor side-effects liability of antipsychotic drugs (APD) is correlated with their ability to increase extracellular dopamine in the caudate-putamen. The globus pallidus (GP) is another basal ganglia structure probably mediating extrapyramidal motor side-effects of typical antipsychotic drugs. Therefore, the present study sought to determine whether extracellular dopamine in the globus pallidus might be a further indicator to differentiate neurochemical actions of typical and atypical antipsychotic drugs. Using in vivo microdialysis we compared effects on pallidal dopamine induced by typical and atypical antipsychotic drugs in rats. Experiment I demonstrated that systemic administration of haloperidol (1 mg/kg; i.p.) and clozapine (20 mg/kg; i.p.) induced a significant pallidal dopamine release to about 160 and 180% of baseline, respectively. Experiment II revealed that reverse microdialysis of raclopride and clozapine using a cumulative dosing regimen did not stimulate extracellular dopamine in the globus pallidus if low (1microM) or intermediate (10 and 100 microM) concentrations were used. Only at a high concentration (1,000 microM), raclopride and clozapine induced a significant pallidal dopamine release to about 130 and 300% of baseline values, respectively. Thus, effects of typical and atypical antipsychotic drugs on pallidal dopamine were similar and thus, may not be related to their differential extrapyramidal motor side-effects liability. Furthermore, the finding that reverse microdialysis of raclopride over a wide range of concentrations did not stimulate pallidal dopamine concentrations tentatively suggests that pallidal dopamine release under basal conditions is not regulated by D2 autoreceptors.     

Regulation of Extracellular Dopamine by the Norepinephrine Transporter

Abstract: There is growing evidence of an interaction between dopamine and norepinephrine. To test the hypothesis that norepinephrine terminals are involved in the uptake and removal of dopamine from the extracellular space, the norepinephrine uptake blocker desmethylimipramine (DMI) was infused locally while the extracellular concentrations of dopamine were simultaneously monitored. DMI increased the extracellular concentrations of dopamine in the medial prefrontal cortex and nucleus accumbens shell but had no effect in the striatum. The combined systemic administration of haloperidol and the local infusion of DMI produced an augmented increase in extracellular dopamine in the cortex compared with the increase produced by either drug alone. This synergistic increase in dopamine overflow is likely due to the combination of impulse-mediated dopamine release produced by haloperidol and blockade of the norepinephrine transporter. No such synergistic effects were observed in the nucleus accumbens and striatum. Local perfusion of the α₂-antagonist idazoxan also increased the extracellular concentrations of dopamine in the cortex. Although the stimulation of extracellular dopamine by idazoxan and DMI could be due to the increased extracellular concentrations of norepinephrine produced by these drugs, an increase in dopamine also was observed in lesioned rats that were depleted of norepinephrine and challenged with haloperidol. This contrasted with the lack of an effect of haloperidol on cortical dopamine in unlesioned controls. These results suggest that norepinephrine terminals regulate extracellular dopamine concentrations in the medial prefrontal cortex and to a lesser extent in the nucleus accumbens shell through the uptake of dopamine by the norepinephrine transporter.     

ON THE RELEVANCE OF PREFERENTIAL INCREASES OF MESOLIMBIC VERSUS STRIATAL DOPAMINE TURNOVER FOR THE PREDICTION OF ANTIPSYCHOTIC ACTIVITY OF PSYCHOTROPIC DRUGS

Abstract— Drugs possessing (chlorpromazine, haloperidol, clozapine, thioridazine and sulpiride) or lacking (benzoctamine and perlapine) antipsychotic activity were compared with respect to their ability to enhance x-methyl-p-tyrosine-induced dopamine disappearance from the mesolimbic area and corpus striutum of rat brain. In addition, their effects on the endogenous concentrations of homovanillic (HVA) and 3.4-dihydroxyphenylacetic (DOPAC) acids in these two brain areas were determined. Some of the drugs enhanced dopamine disappearance in the mesolimbic area more than in the striatum. The most active in this respect were sulpiride. perlapine and chlorpromazine. By contrast, haloperidol was slightly more active in the striatum than in the mesolimbic area. None of the drugs was more efficient in elevating HVA levels in the mesolimbic area than in the striatum. However, there were large differences in the relative extent of the HVA increases in the two regions. Benzoctamine, perlapine and chlorpromazine increased HVA concentrations in the mesolimbic area nearly as much as in the striatum. Thioridazine and haloperidol, however, elevated striatal HVA much more effectively. Haloperidol and clozapine increased the DOPAC concentration in both areas to about the same extent. The other drugs were more active in the striatum. The largest difference between both regions was shown by chlorpromazine. Perlapine and benzoctamine, both lacking antipsychotic activity, produced much larger increases of HVA than of DOPAC. This is in contrast to the results obtained with true neuroleptics and may reflect an involvement of release phenomena in the action of these two drugs on dopamine metabolism. These results suggest that a preferential increase of dopamine turnover in the mesolimbic area is not necessarily linked to a better ratio of antipsychotic activity vs. extrapyramidal side effects. Moreover, an antiacetylcholine component of dopamine receptor blocking drugs does not seem to be a prerequisite for preferential activity on dopamine turnover in the mesolimbic system.     

Effects of N-acetylaspartylglutamate (NAAG) peptidase inhibition on release of glutamate and dopamine in prefrontal cortex and nucleus accumbens in phencyclidine model of schizophrenia

The "glutamate" theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3.     

Repeated exposure to methamphetamine, cocaine or morphine induces augmentation of dopamine release in rat mesocorticolimbic slice co-cultures

Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1-1000 μM), cocaine (0.1-300 μM) or morphine (0.1-100 μM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1-1000 μM) had little effect. Following repeated exposure to methamphetamine (10 μM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1-300 μM) or morphine (10 and 100 μM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 μM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA receptors and the medial prefrontal cortex play an essential role in the dopaminergic sensitization. This in vitro sensitization model provides a unique approach for studying mechanisms underlying behavioral sensitization to drugs of abuse.     

Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3

Protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and members of the Wnt signal transduction pathway were recently found to be altered in schizophrenia and targeted by antipsychotic drugs. In the current study, selected Wnt signalling proteins were investigated to determine if they are altered by the antipsychotics clozapine or haloperidol in the rat prefrontal cortex. Pheochromocytoma (PC12) and neuroblastoma (SH-SY5Y) cells were also used to elucidate how antipsychotics generated the pattern of changes observed in vivo . Western blotting (WB) revealed that treatment with haloperidol or clozapine caused an up-regulation of Wnt-5a, dishevelled-3, Axin, total and phosphorylated GSK-3 and β-catenin protein levels. Treatment of PC12 and SH-SY5Y cells with a variety of pharmacological agents as well as the over-expression of several Wnt related proteins failed to mimic the pattern observed in vivo following antipsychotic treatment. However, the over-expression of dishevelled-3 nearly perfectly duplicated the changes observed in vivo . Immunoprecipitations (IP) conducted using protein isolated from the rat prefrontal cortex indicated that dishevelled-3 is associated with the D₂ dopamine receptor thereby suggesting that antipsychotics may act on dishevelled-3 via D₂ dopamine receptors to initiate a cascade of downstream changes involving Axin, GSK-3 and β-catenin that may help to alleviate psychosis in schizophrenic patients.     

Alterations in regional brain neurotensin concentrations produced by atypical antipsychotic drugs.

Classical antipsychotic drugs, such as haloperidol, have been shown to increase the concentrations of neurotensin (NT) selectively in the nucleus accumbens and caudate nucleus of the rat. Several novel, putative antipsychotic drugs have also been found to produce increases in NT content in one or both of these brain regions. The present study sought to compare the effects of chronic treatment with three clinically efficacious atypical antipsychotic drugs, sulpiride, rimcazole and remoxipride, on regional brain NT concentrations to those of haloperidol. The concentrations of NT in five discrete brain regions were determined by a sensitive and specific radioimmunoassay. As previously reported, haloperidol increased NT concentrations in both the nucleus accumbens and caudate nucleus. Sulpiride and rimcazole produced significant increases in the concentration of NT in the caudate. NT concentrations were unaltered in any brain region by remoxipride at either of the doses tested. These data provide additional evidence for specific increases in regional brain NT concentrations produced by antipsychotic drugs.     

Differences in effects of sultopride and sulpiride on dopamine turnover in rat brain

Sultopride and sulpiride are both chemically similar benzamide derivatives and selective antagonists of dopamine D2 receptors. However, these drugs differ in clinical properties. We compared the effects of sultopride and sulpiride on dopamine turnover in rats following the administration of these drugs alone or in combination with apomorphine. The administration of sultopride or sulpiride markedly accelerated dopamine turnover in the rat brain. The increase in the level of dopamine metabolites in the striatum was more marked in the sultopride-treated rats. Sulpiride affected the limbic dopamine receptors preferentially, whereas sultopride affected the striatal and the limoic dopamine receptors equally. A low dose of apomorphine induced a reduction in the concentration of dopamine metabolites in the striatum and the nucleus accumbens by approximately 55%, but not in the medial prefrontal cortex. Sultopride was more effective in preventing an apomorphine-induced reduction in dopamine metabolite levels. These results from rat experiments would model the pharmacological differences observed between sultopride and sulpiride in clinical use.     

Dopamine Autoreceptors Modulate Dopamine Release from the Prefrontal Cortex

Electrical stimulation (at 0.3, 1, or 10 Hz, 120 pulses each) produced a calcium-dependent overflow of radioactivity from slices of the rabbit prefrontal cortex preloaded with [3H]3,4-dihydroxyphenylethylamine ([3H]DA, [3H]dopamine) in the presence of desipramine. Flat frequency-release curves were observed. Apomorphine and LY-171555 inhibited in a concentration-dependent fashion the evoked overflow of DA, an effect antagonized by haloperidol. Stimulation frequencies comparable to normal firing rates of mesocortical neurons (10 Hz) drastically reduced apomorphine-induced inhibition of DA overflow. Haloperidol produced greater facilitation of DA overflow at 10 than at 1 Hz. Nomifensine, a neuronal uptake inhibitor, enhanced DA overflow. These results indicate that mesocortical DA neurons projecting to the prefrontal cortex have release modulatory autoreceptors of the D2 subtype.     

Effect of chronic haloperidol treatment on dopamine-induced inositol phosphate formation in rat brain slices

The effects of chronic haloperidol administration on the accumulation of inositol phosphates were examined in rat brain slices pre-labeled with [³H]myo-inositol and incubated with various dopaminergic drugs. Rats were treated with haloperidol-decanoate or its vehicle (sesame oil) for two, four or six weeks. Dopamine and the selective D₁ agonist, SKF38393, induced a significant increase in lithium-dependent accumulation of [³H]inositol monophosphate (IP₁) in the frontal cortex, hippocampus and striatum of vehicle-treated animals, while the selective D₂ agonist quinpirole did not show any effect on IP₁ accumulation. The actions of dopamine and SKF38393 were blocked by the D₁ antagonist, SCH23390, but not by the D₂ antagonist, spiperone, in all three brain regions. Haloperidol treatment did not affect basal phosphoinositide turnover in the three brain regions. Four or six weeks of haloperidol treatment significantly decreased dopamine-induced IP₁ accumulation in the striatum (by 30% and 25%, respectively), but not in the frontal cortex and the hippocampus. Four weeks of treatment with haloperidol significantly decreased IP₁ levels in the striatal slices when measured in the presence of quinpirole. However, the accumulation of IP₁ measured in the presence of SKF38393 was not significantly altered after haloperidol treatment. The loss of dopamine-sensitive IP accumulation was not observed in the presence of spiperone after haloperidol treatment. The number, but not the affinity, of [³H]sulpiride binding sites in the striatum was significantly increased (by 34–46%) after chronic haloperidol treatment. A timecourse study suggests that the inhibition by chronic haloperidol treatment of dopamine-induced phosphoinositide hydrolysis may involve an effect secondary to an increase in the number of dopamine D₂ receptors in the striatum.     

Effects of Apomorphine on In Vivo Release of Dopamine and Its Metabolites in the Prefrontal Cortex and the Striatum, Studied by a Microdialysis Method

The effects of apomorphine (0.1-2.5 mg/kg) on release of endogenous dopamine and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex and the striatum were examined in vivo by a microdialysis method. Apomorphine significantly reduced release of dopamine and the extracellular levels of dopamine metabolites, DOPAC and HVA, not only in the striatum, but also in the prefrontal cortex. These findings indicate that dopamine autoreceptors modulate in vivo release of dopamine in the prefrontal cortex.     

In Vivo Assessment of Dopamine and Norepinephrine Release in Rat Neocortex: Gas Chromatography-Mass Spectrometry Measurement of 3-Methoxytyramine and Normetanephrine

A new method with the sensitivity and specificity required to measure regional levels of 3-methoxytyramine (3-MT) and normetanephrine (NMN) in the rat cortex is described. The method utilizes a liquid ion exchanger to isolate the parent amines, dopamine (DA) and norepinephrine (NE), along with their methylated metabolites. These samples are derivatized and analyzed by negative ion gas chromatography-mass spectrometry. Using this method, we examined a number of drug actions on steady-state levels as well as pargyline-induced increases in 3-MT and NMN. In the prefrontal cortex, cingulate cortex, striatum, and olfactory tubercle, nomifensine was found to increase 3-MT steady-state levels and accumulation rates. Similar actions of this drug were observed in the cingulate and prefrontal cortices with NMN. In contrast, clonidine decreased cortical NMN levels and accumulation. A unique action was observed with haloperidol, in that both 3-MT levels and accumulation after pargyline were increased in the nigrostriatal and mesolimbic dopaminergic projections, whereas only the accumulation rates were accelerated in the mesocortical projections. In summary, our data indicate that this new assay is a useful approach for the in vivo evaluation of DA and NE release in cortical regions of the rat. This approach is unique in that no surgery, restraint, or anesthetic is required, thereby permitting more complicated experimental paradigms to be utilized.     

Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits

Postmortem studies in schizophrenic patients revealed alterations in NMDA receptor binding and gene expression of specific subunits. Because most of the patients had been treated with antipsychotics over long periods, medication effects might have influenced those findings. We treated animals with haloperidol and clozapine in clinical doses to investigate the effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Rats were treated with either haloperidol (1,5 mg/kg/day) or clozapine (45 mg/kg/day) given in drinking water over a period of 6 months. Quantitative receptor autoradiography with [³H]-MK-801 was used to examine NMDA receptor binding. In situ hybridization was performed for additional gene expression studies of the NR1, NR2A, NR2B, NR2C, and NR2D subunits. [³H]-MK-801 binding was found to be increased after haloperidol treatment in the striatum and nucleus accumbens. Clozapine was shown to up-regulate NMDA receptor binding only in the nucleus accumbens. There were no alterations in gene expression of NMDA subunits in any of the three regions. However, the NR2A subunit was down-regulated in the hippocampus and prefrontal cortex by both drugs, whereas only clozapine induced a down-regulation of NR1 in the dorsolateral prefrontal cortex. NR2B, 2C, and 2D subunits did not differ between treatment groups and controls. Both altered NMDA receptor binding and subunit expression strengthen a hyperglutamatergic function after haloperidol treatment and may contribute to some of our postmortem findings in antipsychotically treated schizophrenic patients. Because the effects seen in different brain areas clearly vary between haloperidol and clozapine, they may also be responsible for some of the differences in efficacy and side effects.     

Dopamine receptor excess and mouse madness

The dopamine hypothesis of schizophrenia is based on evidence that the major antipsychotic drugs act by blocking dopamine D2 receptors and that dopamine-releasing drugs worsen symptoms. In this issue of Neuron, Kellendonk et al. report an elegant conditional transgenic mouse overexpressing dopamine D2 receptors selectively in the striatum. Strikingly, these animals display selective cognitive impairment typically associated with frontal cortical defects and abnormal dopamine markers in the prefrontal cortex, suggesting that striatal dopamine receptors can influence cortical dopamine function.     

Blockade of the Noradrenaline Carrier Increases Extracellular Dopamine Concentrations in the Prefrontal Cortex: Evidence that Dopamine Is Taken up In Vivo by Noradrenergic Terminals

The effect of systemic administration of desmethylimipramine (DMI) and oxaproptiline (OXA), two inhibitors of the noradrenaline (NA) reuptake carrier, on the in vivo extracellular concentrations of dopamine (DA) was studied by transcerebral dialysis in the prefrontal cortex and in the dorsal caudate of freely moving rats. In the NA-rich prefrontal cortex, either drug increased extracellular DA concentrations whereas in the dorsal caudate neither was effective. Haloperidol increased extracellular DA concentrations more effectively in the dorsal caudate than in the prefrontal cortex. Pre-treatment with DMI or OXA, which failed to modify the effect of haloperidol in the dorsal caudate, potentiated its action in the prefrontal cortex. 6-Hydroxydopamine lesioning of the dorsal NA bundle prevented the ability of OXA to increase DA concentrations. The results suggest that reuptake into NA terminals in an important mechanism by which DA is cleared from the extracellular space in a NA-rich area such as the prefrontal cortex. The elevated extracellular concentrations of DA resulting from blockade of such mechanism by tricyclic antidepressants may play a role in the therapeutic effects of these drugs.