BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) 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.     

Different effects of subchronic clozapine and haloperidol on dye-coupling between neurons in the rat striatal complex

Atypical antipsychotic drugs, such as clozapine, are distinguished from classical antipsychotics (e.g. haloperidol) by their lower liability for producing motor side-effects. Although initial studies suggested that the clinical efficacy of antipsychotic drugs is related to their affinity for the D2 dopamine receptor, the delayed onset of both the therapeutic effects and the extrapyramidal symptoms associated with these drugs implicates a more complex mechanism of action. In this study, we found that continuous (but not acute) treatment of rats with either drug caused an increase in dye coupling between neurons in the limbic component of the rat striatal complex (i.e. the shell region of the nucleus accumbens) after withdrawal of the drugs. Furthermore, continuous treatment with haloperidol, but not clozapine, also increased dye coupling in the motor-related part of the striatal complex (i.e. the dorsal striatum). Thus, both therapeutically effective drugs show a delayed effect on dye coupling between neurons in the accumbens shell, whereas only the drug associated with motor side effects altered coupling between cells in the dorsal striatum. Antipsychotic drugs may therefore alleviate the profound disturbances in cognitive function of schizophrenics by producing sustained alterations in the way signals from the cortex are integrated within these brain regions.     

Modification of haloperidol-induced pattern of c-fos expression by serotonin agonists

Acute challenge with clozapine and haloperidol produce different anatomical patterns of c-fos expression in the forebrain. The pharmacological profile of atypical antipsychotics suggests that serotonin might contribute to the unique therapeutic benefits of these drugs. In order to test this possibility, we examined the abilities of 5-HT1A and 5-HT2A/2c agonists to modify the pattern of c-fos expression induced by haloperidol and clozapine. Various groups of rats were pretreated with either saline, DOI, 8-OH-DPAT, and 8-OH-DPAT + DOI 30 min prior to haloperidol or clozapine administration. Rats were killed 90 min after antipsychotic administration. In saline-pretreated rats, haloperidol produced intense Fos-LI in all four striatal quadrants while the effect of clozapine was restricted to the medial part of the striatum. Prior administration of 8-OH-DPAT significantly reduced haloperidol-induced Fos-LI in all four striatal quadrants while DOI and 8-OHDPAT + DOI significantly reduced Fos-LI only in dorso- and ventrolateral quadrants. In the nucleus accumbens, haloperidol induced intense Fos-LI in the core and the shell regions whereas clozapine induced c-fos expression only in the shell. Pretreatment with 8-OHDPAT in haloperidol treated rats reduced Fos-LI in the core region yielding to a c-fos pattern similar to that induced by clozapine. In the prefrontal cortex of saline-pretreated rats, haloperidol produced a moderate c-fos expression compared with the intense expression produced by clozapine. Pretreatment with serotonin agonists before haloperidol brought the number of FOS-positive neurons to the same level as in clozapine treated rats. These results show the ability of 5-HT agonists to transform the typical pattern of c-fos expression induced by haloperidol into a pattern resembling that of clozapine.     

Effect of scopolamine on the efflux of dopamine and its metabolites after clozapine, haloperidol or thioridazine

The extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum and the nucleus accumbens were measured in awake, freely-moving rats. Clozapine (20 mg/kg, i.p.) increased extracellular DA and HVA in both regions but increased DOPAC only in the striatum. Scopolamine (1 mg/kg), although it had no effect by itself in the striatum or nucleus accumbens, inhibited the ability of clozapine to increase extracellular DA, DOPAC and HVA concentrations in the striatum. The clozapine-induced increase in DA in the frontal cortex was not blocked by scopolamine. Haloperidol (1 mg/kg, i.p.) and thioridazine (10 mg/kg, i.p.) also increased extracellular DA, DOPAC and HVA in the striatum, but scopolamine pretreatment did not inhibit these increases. The results suggest that clozapine differs from haloperidol and thioridazine in that the effect of clozapine, but not that of the two neuroleptic drugs, to increase DA release in the striatum acutely depends on muscarinic receptor stimulation. These results suggest that clozapine, despite its strong muscarinic antagonist properties, does not produce full blockade of muscarinic receptors in vivo in the striatum. The interaction of clozapine with the cholinergic system in the striatum could be relevant to its lack of ability to produce extrapyramidal symptoms or tardive dyskinesia.     

The microcirculation and survival of experimental flow-through venous flaps

We assessed the effects of chronic (21 day) administration of antipsychotic drugs on the density of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in rat brain. We used two typical antipsychotic drugs, haloperidol and pimozide, and two atypical antipsychotic drugs, risperidone and clozapine. Antipsychotic drugs as a group significantly elevated the density of the AMPA receptor measured with an AMPA receptor agonist ([3H]AMPA), but not with an AMPA receptor antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione ([3H]CNQX). In all regions studied, the magnitude of the increase seen with chronic typical antipsychotic drugs was significantly greater than that seen with chronic atypical antipsychotic drugs. In frontal cortex and striatum, typical antipsychotics but not atypical antipsychotics elevated AMPA receptor binding over control. These findings suggest that antipsychotic drugs alter the agonist affinity of the AMPA receptor without altering the number of AMPA receptors. Typical antipsychotic drugs may be more potent in this effect than atypical antipsychotic drugs, especially in critical corticostriatal circuits.     

A hemagglutinin-based multipeptide construct elicits enhanced protective immune response in mice against influenza A virus infection

The effect of the muscarinic antagonist, scopolamine, was examined for a change in the increase in extracellular dopamine, dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA), induced by haloperidol or clozapine in the striatum and nucleus accumbens of anaesthetised and awake rats, monitored using in vivo cerebral microdialysis. Rats received scopolamine (1 mg kg(-1); s.c.) or vehicle followed by haloperidol (1 mg kg(-1); s.c.) or clozapine (20 mg kg(-1); s.c.). Dopamine, DOPAC, HVA and 5-HIAA overflow into striatal or accumbens perfusates was determined using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Scopolamine failed to modify the clozapine- or haloperidol-induced efflux of dopamine or its metabolites in either the striatum or nucleus accumbens following systemic administration in anaesthetised or awake rats. Although pretreatment with scopolamine tended to produce a smaller increase in the clozapine-induced efflux of DOPAC in striatal perfusates than following clozapine treatment alone, this was not statistically significant. Furthermore, local infusion of scopolamine (100 microM) with clozapine (1 mM) via the microdialysis probe did not attenuate the elevated efflux of dopamine observed following clozapine alone, in either the striatum or nucleus accumbens, in anaesthetised rats. This treatment did prevent the clozapine-induced increase in DOPAC and HVA in the striatum but not the nucleus accumbens. Carbachol (50 microM) infused into the dorsolateral striatum or nucleus accumbens raised extracellular dopamine levels 200% and 150%, respectively above baseline. Our data suggest that the increased efflux of dopamine and its metabolites in the rat basal ganglia following clozapine administration is not significantly dependent upon the interaction of clozapine with muscarinic receptors.     

Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence

The pharmacological properties of the novel antipsychotic drugs (APDs) risperidone, sertindole, olanzapine, quetiapine, ziprasidone, remoxipride, and amperozide are reviewed and compared with haloperidol and clozapine. Focus is made on their receptor profiles, their effects in animal models used for evaluation of antipsychotic activity, and extrapyramidal side effects (EPS). In addition, the contrasting actions of these compounds on animal models of cognition, anxiety, and depression are briefly reviewed. The available evidence indicates that novel APDs and clozapine can be differentiated from haloperidol, particularly in models of EPS and cognitive side effects. However, among the group of novel APDs there are many individual differences in models reflecting limbic versus striatal inhibition of dopamine function: clozapine and sertindole show the largest limbic selectivity, followed by quetiapine, ziprasidone, olanzapine and remoxipride, whereas risperidone in many respects has a profile that resembles haloperidol. To date, the results of clinical studies have confirmed the predictions of lower incidence or absence of EPS after administration of novel APDs in doses which demonstrate antipsychotic efficacy.     

Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats

Behavioral sensitization resulting from repeated, intermittent exposure to psychostimulants such as amphetamine (Amp) is hypothesized to model pathophysiology of psychotic disorders. The present study was designed to characterize the effects of a typical and an atypical antipsychotic drug, haloperidol and clozapine, respectively, on the induction of context-independent sensitization to Amp. Peripheral Amp treatment for five days (2 mg/kg/day, s.c.) produced an augmented stimulant response to an acute Amp challenge (2 mg/kg, s.c.) given seven days after the last pretreatment injection. Interestingly, preexposure to high doses of either clozapine (20 mg/kg) or haloperidol (0.5 mg/kg) alone also led to a sensitized behavioral response to an acute Amp challenge. The cross-sensitization between Amp and high doses of the haloperidol and clozapine may have occluded any blockade of Amp behavioral sensitization by the antipsychotics. Indeed, administration of a lower dose of clozapine (4 mg/kg) or haloperidol (0.1 mg/kg) with Amp during the preexposure phase clearly blocked the induction of behavioral sensitization. In addition to the behavioral sensitization, Amp-pretreated rats showed a reduction in the ability of the acute Amp challenge to induce c-fos mRNA in the medial prefrontal cortex and neurotensin/neuromedin N (NT/N) mRNA in the nucleus accumbens-shell. At doses that blocked the initiation of behavioral sensitization to Amp, clozapine fully and haloperidol partially restored the capacity of acute Amp to induce c-fos and NT/N gene expression. These data lend support to the psychostimulant-sensitization model of psychosis and a role of dopamine D2-like receptors in the phenomenon.     

Evidence that an OX-2-positive cell can inhibit the stimulation of type 1 cytokine production by bone marrow-derived B7-1 (and B7-2)-positive dendritic cells

The present study was designed to compare the effects of typical and atypical antipsychotic drugs on extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis with dual probe implantation in awake, freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical antipsychotics, produced greater increases in extracellular DA levels in the mPFC than in the NAC. Olanzapine (1 mg/kg), risperidone (0.1 and 1 mg/kg), also an atypical antipsychotic, and S-(-)-sulpiride (25 mg/kg), a typical antipsychotic, produced comparable increases in extracellular DA levels in the mPFC and the NAC. S-(-)-sulpiride (10 mg/kg) and haloperidol (0.1 and 1 mg/kg), another typical antipsychotic, significantly increased extracellular DA levels in the NAC but not in the mPFC. The effects of the six antipsychotic drugs to increase extracellular DA levels in the mPFC relative to those in the NAC was positively correlated with the difference between their pKi values for serotonin (5-hydroxytryptamine, 5-HT2A) and DA-D2 receptors and was inversely correlated to their pKi values for D2 or D3 receptors, but was not for 5-HT2A receptors alone. These results are consistent with the hypothesis that the ability of antipsychotic drugs to produce a greater increase in prefrontal compared with NAC extracellular DA levels may be related, in part, to weak D2 and D3 receptor affinity relative to 5-HT2A receptor antagonism.     

Distinct and interactive effects of d-amphetamine and haloperidol on levels of neurotensin and its mRNA in subterritories in the dorsal and ventral striatum of the rat

Striatal tissue concentrations of neurotensin, expression of neurotensin/neuromedin N (NT/N) mRNA, and numbers of neurotensin-immunoreactive neurons are increased by d-amphetamine (amph), which stimulates dopamine release in the striatum, and haloperidol (hal), a dopamine receptor antagonist with high affinity for D2-like receptors. The possibility that the effects of these drugs involve distinct subpopulations of striatal neurons was addressed in this study, in which the relative numbers and distributions of striatal neuron profiles containing neurotensin immunoreactivity and/or NT/N mRNA were compared following administrations of hal, amph, hal and amph co-administered, and vehicle. Fourteen striatal subterritories in caudate-putamen, nucleus accumbens, and olfactory tubercle were evaluated. Amph produced increases in the expression of neurotensin preferentially in the ventromedial and caudodorsal subterritories of the caudate-putamen, the rostrobasal cell cluster and lateral shell of the nucleus accumbens, and the olfactory tubercle. Haloperidol produced increased neurotensin expression in much of dorsal and ventral striatum, most prominently in the rostral, dorsomedial and ventrolateral quadrants of the caudate-putamen, and in the rostrobasal cell cluster, rostral pole, medial and lateral shell of the nucleus accumbens and the olfactory tubercle. The numbers of neurons responding to amph and hal in all subterritories following co-administration of the two drugs were significantly less than the summed numbers responding individually to amph and hal. Furthermore, in the subterritories where immunohistochemically detectable responses elicited by amph exceeded those produced by hal, co-administration of the two drugs resulted in responses comparable to those elicited by hal given alone. It is suggested that some of the reported anti-dopaminergic behavioral effects of basal ganglia neurotensin may be attenuated in conditions of reduced dopamine neurotransmission.     

S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-Yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: I. Receptorial and neurochemical profile in comparison with clozapine and haloperidol

S 16924 showed a pattern of interaction at multiple (>20) native, rodent and cloned, human (h) monoaminergic receptors similar to that of clozapine and different to that of haloperidol. Notably, like clozapine, the affinity of S 16924 for hD2 and hD3 receptors was modest, and it showed 5-fold higher affinity for hD4 receptors. At each of these sites, using a [35S]GTPgammaS binding procedure, S 16924, clozapine and haloperidol behaved as antagonists. In distinction to haloperidol, S 16924 shared the marked affinity of clozapine for h5-HT2A and h5-HT2C receptors. However, an important difference to clozapine (and haloperidol) was the high affinity of S 16924 for h5-HT1A receptors. At these sites, using a [35S]GTPgammaS binding model, both S 16924 and clozapine behaved as partial agonists, whereas haloperidol was inactive. In vivo, the agonist properties of S 16924 at 5-HT1A autoreceptors were revealed by its ability to potently inhibit the firing of raphe-localized serotoninergic neurones, an action reversed by the selective 5-HT1A receptor antagonist, WAY 100,635. In contrast, clozapine and haloperidol only weakly inhibited raphe firing, and their actions were resistant to WAY 100,635. Similarly, S 16924 more potently inhibited striatal turnover of 5-HT than either clozapine or haloperidol. Reflecting its modest affinity for D2 (and D3) autoreceptors, S 16924 only weakly blocked the inhibitory influence of the dopaminergic agonist, apomorphine, upon the firing rate of ventrotegmental area-localized dopaminergic neurones. Further, S 16924 only weakly increased striatal, mesolimbic and mesocortical turnover of dopamine (DA). Clozapine was, similarly, weakly active in these models, whereas haloperidol, in line with its higher affinity at D2 (and D3) receptors, was potently active. In the frontal cortex (FCX) of freely moving rats, S 16924 dose-dependently reduced dialysate levels of 5-HT, whereas those of DA and NAD were dose-dependently increased in the same samples. In contrast, although S 16924 also suppressed 5-HT levels in the striatum and nucleus accumbens, DA levels therein were unaffected. Clozapine mimicked this selective increase in DA levels in the FCX as compared to striatum and accumbens. In contrast, haloperidol modestly increased DA levels in the FCX, striatum and accumbens to the same extent. In distinction to S 16924, clozapine and haloperidol exerted little influence upon 5-HT levels. Finally, the influence of S 16924 upon FCX levels of 5-HT, DA (and NAD) was attenuated by WAY 100,635. In conclusion, S 16924 possesses a profile of interaction at multiple monoaminergic receptors comparable to that of clozapine and distinct to that of haloperidol. In addition, S 16924 is a potent, partial agonist at 5-HT1A receptors. Correspondingly, acute administration of S 16924 decreases cerebral serotoninergic transmission and selectively reinforces frontocortical as compared to subcortical dopaminergic transmission. In line with these actions, S 16924 shows a distinctive profile of activity in functional (behavioral) models of potential antipsychotic activity (companion paper).     

Discriminative stimulus properties in rats of the novel antipsychotic quetiapine.

Rats discriminated the novel antipsychotic quetiapine (Seroquel). Full generalization was seen with the novel ("atypical") antipsychotics, clozapine, olanzapine, and risperidone. Generalization was not seen with the older "typical" antipsychotics, haloperidol, chlorpromazine, and loxapine, or with the novel atypical antipsychotic, amisulpride. The pattern of generalization resembled that seen in rats trained to discriminate a low dose (1.25 mg/kg) of clozapine, which dissociates most novel antipsychotics from typical antipsychotics. However, the failure of the novel antipsychotic amisulpride to generalize demonstrates that this bioassay does not detect all novel antipsychotics. These data suggest that the discrimination of antipsychotics such as quetiapine may be of value in the development of novel antipsychotics, although the relationship between the discriminative properties of such drugs and their clinical actions is unclear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Medial prefrontal cortical D2 and striatolimbic D4 dopamine receptors: common targets for typical and atypical antipsychotic drugs

1. In vitro receptor autoradiography was used to examine the long-term effects of a typical (fluphenazine), atypical (clozapine), or potential atypical antipsychotic (S[+]-N-n-propylnorapomorphine; [+]-NPA) on different dopamine (DA) receptor subtypes. 2. D1-Like and D3 receptor levels were not changed with any treatment in any brain region examined. 3. D2 Receptors in caudate-putamen (CPu), nucleus accumbens (NAc) and olfactory tubercle (OT) were significantly increased by long-term treatment with fluphenazine, but not with clozapine or S[+]-NPA. 4. D2 Receptor levels in medial prefrontal cortex (MPC), but not dorsolateral frontal cortex (DFC), were elevated after repeated daily administration of fluphenazine, clozapine, and S[+]-NPA. 5. D4-Like receptors, assayed under D4-selective conditions, were increased by fluphenazine, clozapine and S(+)-NPA in both NAc and CPu, but by none of these treatments in OT, DFC or MPC. 6. These results support a common role for medial prefrontal cortical D2 and striatolimbic D4 receptors in mediating the clinical actions of typical and atypical antipsychotic drugs.     

Na+,K+-ATPase activity in cultured bovine retinal pigment epithelium

Ibogaine (Endabuse) is a psychoactive indole alkaloid found in the West African shrub, Tabernanthe iboga. This drug interrupts cocaine and amphetamine abuse and has been proposed for treatment of addiction to these stimulants. However, the mechanism of action that explains its pharmacological properties is unclear. Since previous studies demonstrated differential effects of psychotomimetic drugs (cocaine and methamphetamine) on neuropeptides such as neurotensin (NT), the present study was designed to determine: (1) the effects of ibogaine on striatal, nigral, cortical, and accumbens neurotensin-like immunoreactivity (NTLI); (2) the effects of selective dopamine antagonists on ibogaine-induced changes in NT concentrations in these brain areas; and (3) the effects of ibogaine pretreatment on cocaine-induced changes in striatal, nigral, cortical and accumbens NTLI content. Ibogaine treatments profoundly affected NT systems by increasing striatal, nigral, and accumbens NTLI content 12 h after the last drug administration. In contrast, NTLI concentrations were not significantly increased in the frontal cortex after ibogaine treatment. The ibogaine-induced increases in NTLI in striatum, nucleus accumbens and substantia nigra were blocked by coadministration of the selective D1 receptor antagonist, SCH 23390. The D2 receptor antagonist, eticlopride, blocked the ibogaine-induced increase in nigral NTLI, but not in striatum and nucleus accumbens. Ibogaine pretreatment significantly blocked the striatal and nigral increases of NTLI resulting from a single cocaine administration. Whereas many of the responses by NT systems to ibogaine resembled those which occur after cocaine, there were also some important differences. These data suggest that NT may contribute to an interaction between ibogaine and the DA system and may participate in the pharmacological actions of this drug.     

Identification of the populations of enteric neurons that have NK1 tachykinin receptors in the guinea-pig small intestine

In the present study we have compared the effects of the classical antipsychotic drug haloperidol and four different atypical antipsychotics (clozapine, risperidone, olanzapine, ziprasidone) on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex (MPFC) of conscious rats. Haloperidol (10, 100 and 800 nmol/kg), clozapine (0.3, 1, 10 and 30 micromol/kg), risperidone (100, 500 and 5000 nmol/kg), olanzapine (10, 100 and 500 nmol/kg) and ziprasidone (10, 100 and 1000 nmol/kg) were administered subcutaneously to rats. All compounds induced increases in dialysate levels of dopamine and noradrenaline in the medial prefrontal cortex. The increases induced by the four antipsychotic agents in extracellular levels of dopamine and noradrenaline displayed a striking co-variation both in dose and time. A similar co-variation was seen in the decrease of dopamine and noradrenaline, after administration of a low dose (30 nmol/kg, s.c.) of the dopamine D2/3 receptor agonist (+)-7-hydroxy-2-(N,N-di-n-propylamino) tetralin ((+)-7-OH-DPAT). It is concluded that there is a close coupling between the release of dopamine and noradrenaline in the medial prefrontal cortex. The mechanism of action of this interaction, that might be of importance for a better understanding of the mechanism of action of antipsychotic drugs, is discussed.     

Relative predispositional effects and mode of inheritance of HLA-DRB1 alleles among community-based Caucasian females with rheumatoid arthritis

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.     

Subcortical laminal heterotopia and lissencephaly: cerebral malformations of X-linked inheritance

The effects of single and repeated administration of amphetamine (5 mg/kg, i.p., twice a day for 14 days) on the thyrotropin-releasing hormone (TRH) level, release and receptors in the rat striatum and nucleus accumbens were evaluated. Both treatments decreased the TRH level in those structures at 2 h after the drug injection. These effects were accompanied with elevation of the basal release of TRH from the nucleus accumbens and striatal slices at the same time point, whereas the stimulated (K+, 56 mM) TRH release was attenuated following repeated amphetamine administration. Acute amphetamine had no effect on the density and affinity of TRH receptors. Repeated amphetamine increased the Bmax of TRH receptors in the striatum (by ca 49%) and nucleus accumbens (by ca 38%) at 2 h after the last drug injection. At 72 h after the last amphetamine administration, the Bmax of the TRH receptor in the striatum was still elevated (by ca 42%), whereas in the nucleus accumbens it returned to control level. No changes in the affinity of TRH receptors following repeated amphetamine were found. The obtained results indicate that repeated amphetamine evokes long- and short-term up-regulation of TRH receptors in the rat striatum and nucleus accumbens, respectively. Furthermore, it is suggested that these changes may be an adaptive response to the amphetamine-induced alterations in the TRH tissue level and release.     

Clozapine and olanzapine treatment decreases rat cortical and limbic GABA(A) receptors

The density of GABA(A) receptors in the hippocampus and the temporal cortex from rats treated for 28 days with either haloperidol, chlorpromazine, clozapine or olanzapine was measured. Compared to haloperidol (0.01 and 0.1 mg kg(-1) day(-1)) and chlorpromazine (0.1 and 1 mg kg(-1) day(-1)), clozapine and olanzapine (0.1 and 1 mg kg(-1) day(-1)) markedly decreased the density of GABA(A) receptors in these two brain regions. These data suggest that modulation of GABAergic transmission could be an important action of some antipsychotic drugs.     

Differential expression of c-fos mRNA in rat prefrontal cortex, striatum, N. accumbens and lateral septum after typical and atypical antipsychotics: an in situ hybridization study

The regional difference in the expression of c-fos mRNA induced by typical and atypical antipsychotics was determined in prefrontal cortex, striatum, N. accumbens and lateral septum in rats by in situ hybridization. Two typical antipsychotics, haloperidol (2 mg/kg) and fluphenazine (2 mg/kg), and three atypical antipsychotics, (-)sulpiride (100 mg/kg), clozapine (20 mg/kg) and OPC-14597 (40 mg/kg), were used. Brains were fixed with 4% paraformaldehyde 45 min after drug administration (i.p.). Brain sections of 30 microns-thickness were made in a cryostat and hybridized with 35S-labelled for c-fos oligonucleotide probe. These sections were apposed to X-ray films and the autoradiograms were semi-quantitatively analysed by computer-assisted densitometry. All antipsychotics used increased c-fos mRNA expression in N. accumbens shell, a region of the forebrain associated with limbic systems. On the other hand, two typical antipsychotics (haloperidol and fluphenazine) that cause a high incidence of acute motor side effects increased the expression of c-fos mRNA in the dorsolateral striatum, an extrapyramidal region primarily involved in motor control. Only clozapine induced c-fos mRNA in the medial prefrontal cortex and lateral septum. These results strongly suggest that the shell region of N. accumbens may be a common site of therapeutic action of antipsychotics.     

Similarity of clozapine's and olanzapine's acute effects on rats' lapping behavior

As a way of further comparing the behavioral effects of clozapine and olanzapine, dose ranges of these drugs were studied in a task emphasizing fine motor detail of rats' tongue movements during lapping behavior. Rats lapped drops of tap water from a force-sensing disk. From this behavior four variables were derived: peak-force of tongue strikes, duration of tongue contact, number of separate tongue contacts in 2 min, and the rhythm of the lapping behavior as quantified by Fourier analysis. Both clozapine (0.5-4.0 mg/kg, IP, 45 min) and olanzapine (0.25-2.0 mg/kg, IP, 45 min) dose dependently reduced all four measures of behavior. With respect to lick rhythm, a behavioral marker which clearly distinguishes haloperidol from clozapine in this behavioral paradigm, olanzapine was about twice as potent as clozapine, with the two drugs having parallel dose-effect functions. Within-session decrements in behavior previously reported for haloperidol in the lick task were not produced by clozapine nor by olanzapine. Taken together, these data strengthen the idea that the behavioral effects of clozapine and olanzapine are strikingly similar, and thereby emphasize the potential of olanzapine as an atypical anti-psychotic agent.