Clozapine Pretreatment Research Articles

Examination of clozapine and haloperidol in improving ketamine-induced deficits in an incremental repeated acquisition procedure in BALB/c mice.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, causes locomotor hyperactivity, aberrant prepulse inhibition and impaired reversal learning among other deficits. There are numerous clinical and pre-clinically uses of NMDAR antagonists and a growing need to characterize their neurobehavioral effects. The present study was designed to characterize 1) ketamine's effect on incremental repeated acquisition (IRA), a procedure that taps multiple neurobehavioral functions and has performance measures correlated with IQ in humans, and 2) the extent to which clozapine (CLZ) and haloperidol (HAL) block ketamine's detrimental effects. In experiment 1 (Exp. 1), BALB/c mice nose-poked under an IRA procedure for sucrose pellets. Systemic ketamine (1-30 mg/kg) dose-dependently decreased measures of cognitive and motor function. CLZ pretreatment (CLZ 0.1-4.0 mg/kg) dose-dependently attenuated ketamine-induced (30 mg/kg) deficits; the effective dose range of CLZ was 0.3-1.0 mg/kg. HAL pretreatment (0.01-0.1 mg/kg) did not attenuate any ketamine-induced deficits. In experiment 2 (Exp. 2), BALB/c mice lever-pressed under an IRA procedure for sweetened condensed milk. Ketamine (30 mg/kg) produced a global impairment in the IRA procedure and CLZ pretreatment (0.3-1.0 mg/kg) dose-dependently attenuated that impairment; motor-based performance recovered to a greater extent than cognitive performance. When tested alone, these doses of CLZ had little effect on IRA performance. These findings support the notion that CLZ is more effective than HAL at blocking ketamine-induced deficits. The IRA procedure may be beneficial for distinguishing the efficacy of drugs that seek to alleviate deficits in complex behavior that result from acute NMDAR antagonism.

Clozapine pre-treatment has a protracted hypolocomotor effect on the induction and expression of amphetamine sensitization

Amphetamine locomotor sensitization is an animal model for the study of addiction and schizophrenia. The antipsychotic clozapine blocks the hyperlocomotion induced by an acute injection of amphetamine, but its effect on locomotor sensitization after repeated amphetamine administration remains unknown. In the present study we investigate the effect of repeated administration of clozapine on the induction and expression of amphetamine locomotor sensitization. We propose that repeated administration of clozapine blocks the induction and expression of amphetamine sensitization. Male Sprague-Dawley rats were classified according to their locomotor response to an acute saline injection in high responder saline (HRS) or low responder saline (LRS). Rats from both groups were injected once daily with amphetamine for 5 consecutive days. Horizontal locomotor activity was measured during 40 min. Four days after the last injection, an acute dose of amphetamine was administered to assess the expression of sensitization. Clozapine was injected once daily for 4 consecutive days before (pre-treatment) or after (treatment) induction of sensitization. Pre-treatment with clozapine significantly decreases both acute amphetamine-induced hyperlocomotion and the induction and expression of amphetamine sensitization only in LRS rats, showing a protracted hypolocomotor effect. On the other hand, clozapine treatment had no effect over locomotor response on the expression of amphetamine sensitization in either LRS or HRS rats. These data suggest that clozapine effect on amphetamine locomotor response depends on individual differences. Also, our results suggest that clozapine pre-treatment attenuates the neuroplasticity underlying amphetamine sensitization, but clozapine treatment is unable to reverse these changes once amphetamine sensitization has been induced.

Reversal of scopolamine-induced disruption of prepulse inhibition by clozapine in mice

Prepulse inhibition (PPI) of the acoustic startle reflex refers to the reduction of the startle response to an intense acoustic pulse stimulus when it is shortly preceded by a weak non-startling prepulse stimulus and provides a cross-species measure of sensory-motor gating. PPI is typically impaired in schizophrenia patients, and a similar impairment can be induced in rats by systemic scopolamine, a muscarinic cholinergic receptor antagonist that can evoke a range of cognitive and psychotic symptoms in healthy humans that are commonly referred to as the “anti-muscarinic syndrome” resembling some clinical features of schizophrenia. Scopolamine-induced PPI disruption has therefore been proposed as an anti-muscarinic animal model of schizophrenia, but parallel investigations in the mouse remain scant and the outcomes are mixed and often confounded by an elevation of startle reactivity. Here, we distinguished the PPI-disruptive and the confounding startle-enhancing effects of scopolamine (1 and 10mg/kg, i.p.) in C57BL/6 wild-type mice by showing that the latter partly stemmed from a shift in spontaneous baseline reactivity. With appropriate correction for between-group differences in startle reactivity, we went on to confirm that the PPI-disruptive effect of scopolamine could be nullified by clozapine pre-treatment (1.5mg/kg, i.p.) in a dose-dependent manner. This is the first demonstration that scopolamine-induced PPI disruption is sensitive to atypical antipsychotic drugs. In concert with previous data showing its sensitivity to haloperidol the present finding supports the predictive validity of the anti-muscarinic PPI disruption model for both typical and atypical antipsychotic drug action.

Clozapine Protects Dopaminergic Neurons from Inflammation-Induced Damage by Inhibiting Microglial Overactivation

Increasing evidence suggests a possible involvement of neuroinflammation in some psychiatric disorders, and also pharmacological reports indicate that anti-inflammatory effects are associated with therapeutic actions of psychoactive drugs, such as anti-depressants and antipsychotics. The purpose of this study was to explore whether clozapine, a widely used antipsychotic drugs, displays anti-inflammatory and neuroprotective effects. Using primary cortical and mesencephalic neuron-glia cultures, we found that clozapine was protective against inflammation-related neurodegeneration induced by lipopolysaccharide (LPS). Pretreatment of cortical or mesencephalic neuron-glia cultures with clozapine (0.1 or 1 μM) for 24 h attenuated LPS-induced neurotoxicity. Clozapine also protected neurons against 1-methyl-4-phenylpyridinium(+) (MPP(+))-induced neurotoxicity, but only in cultures containing microglia, indicating an indispensable role of microglia in clozapine-afforded neuroprotection. Further observation revealed attenuated LPS-induced microglial activation in primary neuron-glia cultures and in HAPI microglial cell line with clozapine pretreatment. Clozapine ameliorated the production of microglia-derived superoxide and intracellular reactive oxygen species (ROS), as well as the production of nitric oxide and TNF-α following LPS. In addition, the protective effect of clozapine was not observed in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for superoxide production in immune cells. Further mechanistic studies demonstrated that clozapine pretreatment inhibited LPS-induced translocation of cytosolic subunit p47(phox) to the membrane in microglia, which was most likely through inhibiting the phosphoinositide 3-kinase (PI3K) pathway. Taken together, this study demonstrates that clozapine exerts neuroprotective effect via the attenuation of microglia activation through inhibition of PHOX-generated ROS production and suggests potential use of antipsychotic drugs for neuroprotection.

Clozapine inhibits development and expression of nicotine‐induced locomotor sensitization in rats

It has been shown that clozapine, the prototype of atypical antipsychotics, significantly reduces daily cigarette use and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of clozapine on nicotine abuse is limited. Aim of this study was to determine whether clozapine would inhibit the development and expression of nicotine-induced locomotor sensitization in rats. To investigate the effect of clozapine on the development of nicotine-induced locomotor sensitization, rats were pretreated with clozapine (2.5-10 mg/kg) 30 min before the nicotine (0.5 mg/kg), and locomotor activity was recorded for 15 min. This procedure was repeated every day for eight sessions. After a 3-day drug-free period, rats were challenged with nicotine (0.5 mg/kg). To reveal effect of clozapine on the expression of nicotine-induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 3-day drug-free period, rats were pretreated with clozapine (2.5-10 mg/kg) or vehicle 30 min before the nicotine (0.5 mg/kg) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Clozapine pretreatment (2.5-10 mg/kg) blocked the development and the expression of nicotine-induced locomotor sensitization in rats. Our results suggest that atypical antipsychotic clozapine can prevent the effects of nicotine in an animal model of dependence, which represents early adaptations in initiation and continuation of addictive behavior.

Neonatal neurosteroid administration results in development-specific alterations in prepulse inhibition and locomotor activity

Early life exposure to stress and to GABAA receptor modulators have well-defined and persistent behavioral effects. A single neonatal injection of the GABAergic neurosteroid allopregnanolone (3alpha-hydroxy,5alpha-pregnane-20-one, 10 mg/kg, i.p.) alters the localization of prefrontal cortex (PFC) interneurons in adulthood. Such displacement could result in disinhibited behavior associated with impaired development of the mesocortical dopamine system. To determine if there is a critical window in which allopregnanolone levels may impact the development and mature function of the mesocorticolimbic circuitry. Behavioral measures, including prepulse inhibition (PPI) and total locomotor activity, after amphetamine exposure were assessed at postnatal day 20 (P20) (prepuberty), P40 (puberty), P60 (postpuberty), and P80 (adulthood) in animals previously exposed to allopregnanolone (10 mg/kg) on P2 and P5. PFC tyrosine hydroxylase immunoreactivity was stereologically measured. P2 administration of allopregnanolone resulted in an increased locomotor response to amphetamine (14, 28% on P20 and P80, respectively) and reduced PPI (28, 22% on P20 and P80, respectively) at P20 and P80, whereas allopregnanolone administration on P5 increased locomotor response to amphetamine (20%) and reduced PPI (37%) at P80. Clozapine (7.5 mg/kg) pretreatment reversed the PPI deficit in P2-exposed animals. The total length of tyrosine hydroxylase immunopositive fibers in PFC was not altered by neonatal neurosteroid exposure, but more fibers were located in layers V/VI vs I-III. Altering neonatal allopregnanolone levels disrupts PFC-dependent behavior, indicating that allopregnanolone might be important for normal PFC circuitry development. The temporal exposure differences (P2 vs P5) and ontological-dependent effects (P20 and P80, but not P40 or P60) suggest critical windows of vulnerability to neurosteroid insult across development.

Apomorphine-induced disruption of prepulse inhibition that can be normalised by systemic haloperidol is insensitive to clozapine pretreatment.

Prepulse inhibition (PPI) of startle refers to the phenomenon in which a weak prepulse attenuates the startle response to a succeeding intense stimulus. PPI can be disrupted by systemic apomorphine in animals, and reduced PPI has been consistently reported in schizophrenia patients. The ability of the atypical antipsychotic clozapine to reverse apomorphine-induced PPI deficit has been demonstrated in the rat, but has not yet been tested in the mouse. The present study was designed to fill this gap. We investigated the efficacy of clozapine in reversing apomorphine-induced (2.0 or 2.5 mg/kg, s.c.) PPI deficit in C57BL6 mice. Clozapine failed to restore PPI disruption in apomorphine-treated mice in two independent laboratories across two dose ranges (1-3 mg/kg, i.p., or 3-30 mg/kg, p.o.), whereas the typical antipsychotic haloperidol (1 mg/kg, i.p.) completely normalised PPI performance. Unlike the rat, apomorphine-induced PPI disruption in mice might be instrumental in distinguishing between typical and atypical antipsychotic drugs. This also lends further support to the suggestion that the neuropharmacology of PPI is not identical in the two rodent species.

Clozapine enhances breakpoint in common marmosets responding on a progressive ratio schedule.

Motivational effects of psychotropic drugs may contribute to their therapeutic profile and progressive ratio (PR) schedules provide a method of measuring these effects in animals. Determine effects of selected antipsychotic, psychotomimetic, anxiolytic and antidepressant drugs on PR performance in common marmosets. Marmosets were trained to lever press for banana milkshake reinforcement using a PR schedule, in which the number of lever presses to achieve successive reinforcements increased by one until responding ceased (breakpoint). Clozapine administered intramuscularly (0.01-2 mg/kg IM; 30 min pretreatment time (ptt) or by oral gavage (0.1-4 mg/kg PO; 60 min ptt) significantly increased the breakpoint. Independent tests of fluid consumption failed to show enhanced fluid intake after clozapine pretreatment, suggesting this effect was not due to drug induced polydipsia. Neither haloperidol (0.005-0.1 mg/kg PO; 60 min ptt) nor risperidone (0.0025-0.05 mg/kg PO; 60 min ptt) altered breakpoint. Olanzapine (0.01-1 mg/kg PO; 60 min ptt) significantly enhanced the breakpoint at 0.05 mg/kg PO, but the effect was not robust. Amphetamine (0.2-2 mg/kg SC; 30 min ptt) significantly reduced the breakpoint at 2 mg/kg and fluoxetine (0.1-1 mg/kg PO; 60 min ptt) was without effect. Diazepam significantly increased the breakpoint at 0.5 mg/kg PO. Drug-induced polydipsia might play a role in this response as independent tests showed increased fluid consumption following diazepam. These results demonstrate that, unlike other antipsychotics, clozapine over a wide dose range increased the motivational state of marmosets to respond for banana milkshake. This motivational aspect of clozapine's actions may contribute to its unique clinical profile and the PR procedure may provide a method for detecting novel antipsychotics with a clozapine-like profile.

Limited participation of 5-HT 1A and 5-HT 2A/2C receptors in the clozapine-induced Fos-protein expression in rat forebrain regions

Through the development of tolerance following long-term clozapine treatment, we investigated whether 5-HT 1A and 5-HT 2A/2C receptors participate in the clozapine-induced Fos-protein expression in the rat forebrain. Tolerance exists when the acutely increased Fos responses to a challenge dose of the 5-HT 1A and 5-HT 2A/2C agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-hydrochloride (DOI) and 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), respectively, given simultaneously to rats, are attenuated after 3-week clozapine (20 mg kg −1 day −1 i.p.) pretreatment. As compared to the acute effects of clozapine, the Fos responses to concomitant administration of the 5-HT receptor agonists DOI (2.5 mg kg −1 i.p.) and 8-OH-DPAT (2.5 mg kg −1 i.p.) were more pronounced in the prefrontal cortex, the nucleus accumbens core and the dorsomedial and ventromedial striatum, areas in which clozapine (20 mg kg −1 i.p.) exhibited marginal effects. In the hypothalamic paraventricular nucleus, both clozapine and DOI/8-OH-DPAT induced a remarkably high number of Fos-positive nuclei. Long-term clozapine pretreatment attenuated the acutely induced Fos expression of the 5-HT receptor agonists in the nucleus accumbens core, the dorsomedial and ventromedial parts of the striatum and the lateral septum, indicating (partial) common sites of action of the agents in these brain regions. No tolerance was found in the nucleus accumbens shell and the hypothalamic paraventricular nucleus and the central amygdala, suggesting that the clozapine-induced Fos responses, though distinct in these regions, are independent of 5-HT receptors. The prefrontal cortex and the dorsolateral striatum indicated only a tendency towards tolerance. In addition, the involvement of the tested 5-HT receptor agonists in the clozapine-enhanced release of plasma corticosterone became apparent. The present results indicate that the clozapine-induced patterns of Fos expression in the rat forebrain can only be in part attributed to an interaction with 5-HT 1A/2A/2C receptors.

Low-dose clozapine pretreatment partially prevents haloperidol-induced deficits in conditioned active avoidance.

The effectiveness of neuroleptics in disrupting conditioned active avoidance has led to the widespread use of this test as an index of antipsychotic efficacy, whereas the tendency for these drugs to induce catalepsy is believed to reflect their propensity to cause extrapyramidal motor side-effects. Although the typical neuroleptic haloperidol produces catalepsy as well as profound deficits in conditioned active avoidance, the atypical neuroleptic clozapine does not induce catalepsy and is less effective than haloperidol in disrupting active avoidance. Furthermore, clozapine pretreatment prevents haloperidol-induced catalepsy. We investigated whether clozapine pretreatment might also reduce the disruptive effects of haloperidol on two-way active avoidance. We assessed the avoidance acquisition of the following drug treatment groups in which all animals received two injections prior to testing: vehicle + vehicle, vehicle + haloperidol (0.1 mg/kg, i.p.), clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + haloperidol (0.1 mg/kg, i.p.), or clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + vehicle. Haloperidol-pretreated animals showed markedly impaired active avoidance, deficits which were improved by 2.5 and 5 mg/kg but not by 10 mg/kg clozapine pretreatment. These data suggest that the disruptive effects of haloperidol on conditioned active avoidance partially mirror its capacity to induce catalepsy and extrapyramidal motor symptoms. Furthermore, this study indicates that clozapine may be effective in reducing motor side-effects caused by typical neuroleptics.

Significant interaction between clozapine and cocaine in cocaine addicts

Because clozapine may be prescribed to cocaine abusing patients with schizophrenia, we studied cocaine–clozapine interactions in a controlled setting. Eight male cocaine addicts underwent four oral challenges with ascending doses of clozapine (12.5, 25 and 50 mg) and placebo followed 2 h later by a 2-mg/kg dose of intranasal cocaine. Subjective and physiological responses, and serum cocaine levels were measured over a total 4-h period. Clozapine pretreatment increased cocaine levels during the study and significantly increased the peak serum cocaine levels in a dose dependent manner. In spite of this elevation in blood levels, clozapine pretreatment had a significant diminishing effect upon subjective responses to cocaine, including ‘expected high’, ‘high’ and ‘rush’, notably at the 50 mg dose. There was also a significant effect upon ‘sleepiness’, ‘paranoia’ and ‘nervous’. Clozapine caused a significant near-syncopal episode in one subject in the study, requiring his removal from the study. Clozapine had no significant effect on baseline pulse rate and systolic blood pressure, but it attenuated the significant pressor effects of the single dose of intranasal cocaine. These data suggested a possible therapeutic role for clozapine in the treatment of cocaine addiction in humans, but also suggests caution due to the near-syncopal event and the increase in serum cocaine levels.

Low-dose clozapine pretreatment partially reverses haloperidol-induced deficits in conditioned active avoidance

Low-dose clozapine pretreatment partially reverses haloperidol-induced deficits in conditioned active avoidance

Clozapine pre-treatment enhances raclopride catalepsy

The clinical replacement of clozapine by another antipsychotic sometimes causes extrapyramidal signs, including dystonia, to appear suddenly. The present study was done, therefore, to test whether clozapine pre-treatment of rats could affect raclopride-induced catalepsy. Clozapine, at 5 mg/kg, given 2 h before a catalepsy-threshold dose of 0.1 mg/kg raclopride, markedly enhanced raclopride-induced catalepsy in the rats. The results are compatible with earlier in vitro data where pre-exposure of human cloned dopamine D 2 receptors to clozapine resulted in an increased potency of raclopride in inhibiting the binding of [ 3 H ]clozapine to the receptors. The mechanism of clozapine potentiation of raclopride action may contribute to the clinically observed post-clozapine dystonia.

Clozapine pretreatment modifies haloperidol-elicited forebrain Fos induction: a regionally-specific double dissociation.

Acute administration of typical antipsychotic drugs, such as haloperidol, results in the induction of the immediate-early gene c-fos in the dorsolateral striatum. In contrast, the atypical antipsychotic drug clozapine, which lacks significant extrapyramidal side effect liability, does not induce Fos protein in the dorsal striatum. Several studies have attempted to define the mechanisms through which typical antipsychotic drugs induce striatal Fos, often by pretreating animals with specific receptor antagonists. Despite the broad receptor profile of clozapine, there has been no study of the effect of clozapine pretreatment on haloperidol-elicited striatal Fos expression. We examined the effects of clozapine pretreatment of rats on haloperidol-elicited forebrain Fos expression, using both immunoblot and immunohistochemical methods. The effects of clozapine pretreatment were assessed in the dorsal striatum and in the different nucleus accumbens compartments, the septum, and the prefrontal cortex. Clozapine pretreatment markedly decreased haloperidol-elicited striatal Fos induction and blocked haloperidol-induced catalepsy. Clozapine also attenuated haloperidol-elicited Fos expression in the nucleus accumbens, but in the prefrontal cortex and ventrolateral septum the effects of haloperidol and clozapine were additive. An emerging body of literature suggests a high incidence of rapid relapse in schizophrenic patients when clozapine treatment is discontinued. This psychosis is relatively resistant to haloperidol and other neuroleptics, even in patients who had previously responded well to neuroleptics. The present data may shed light on the central sites associated with and perhaps model certain aspects of the relapse associated with clozapine discontinuation.

Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex.

In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist, would cause a long-lasting behavioral sensitization associated with neuronal toxicity. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP. Following assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microscopy or terminal dUTP nick-end labeling (TUNEL). In study I, PCP challenge produced a much more robust and long-lasting increase in locomotor activity in rats chronically treated with PCP than in those chronically treated with saline. In study II, clozapine pretreatment blunted the degree of sensitization caused by PCP. In study I, a marked increase in TUNEL-positive neurons was found in layer II of the olfactory tubercle and piriform cortex of rats chronically treated with PCP. Many of these neurons had crescent-shaped nuclei consistent with apoptotic condensation and margination of nuclear chromatin under the nuclear membrane. Acute PCP had no effect. Electron microscopy revealed that PCP caused nuclear condensation and neuronal degeneration consistent with apoptosis. Cell counts in layer II of the piriform cortex revealed that chronic PCP treatment resulted in the loss of almost 25% of the cells in this region. However, an increase in glial fibrillary acidic protein (GFAP)-positive cells in the molecular layer suggests that this neurotoxicity also may involve necrosis. In study II, the PCP-induced neuronal degeneration was essentially completely abolished by clozapine pretreatment. This pattern of degeneration was found to coincide with the distribution of the mRNA of the NR1 subunit of the NMDA receptor. The relevance of these data to a PCP model of chronic NMDA receptor hypofunction is discussed.

Effects of phencyclidne (PCP) and (+)MK-801 on sensorimotor gating in CD-1 mice

1. 1. Male CD-1 mice were tested for prepulse inhibition (PPI) following admistration of PCP and the PCP site ligand, (+)MK-801, as well as the dopamine (DA) agonist (-)-apomorhine and DA releaser d-amphetamine. Similar to reports in rats, PCP (0.36 –36.0 μmol/kg), (+)MK-801 (0.03–3.0 umol/kg), (−)-apomorphine (3.3 and 10.0 umol/kg) and d-amphetamine (3.0 and 8.0 μmol/kg) significantly reduced PPI when administered prior to testing. 2. 2. Because PCP also binds to sigma receptors, the authors tested the sigma ligand (+)-3-PPP at (118 μmol/kg) which marginally increased the PPI. 3. 3. Haloperidol (1.1 μmol/kg) pretreatment attenuated the reduction in PPI following (−)-apomorphine (10.0 μmol/kg), however no effects of haloperidol or clozapine pretreatment on (+)MK-801 disruption of PPI were observed. 4. 4. Because of the pharmacological similarities between mouse data and previously published rat data, it is concluded that the mouse is a viable alternative to the rat for testing PPI.

THE EFFECTS OF THE ATYPICAL ANTIPSYCHOTICS CLOZAPINE, REMOXIPRIDE AND RISPERIDONE ON THE CONTRACTILE CHARACTERISTICS OF RAT SKELETAL MUSCLEIN VITRO

The therapeutic use of the atypical antipsychotics clozapine, remoxipride and risperidone has been reported to be associated with a reduced occurrence of the extrapyramidal side-effects seen during therapy with classical (or typical) antipsychotics such as trifluoperazine and haloperidol. The aim of this study was to determine the effects of the atypical antipsychotics clozapine, remoxipride and risperidone on rat skeletal musclein vitro. Remoxipride and risperidone did not produce contracture in muscle. Clozapine induced a small muscle contracture at high concentrations. Pre-treatment of muscle with trifluoperazine or haloperidolin vitrocaused the muscle to display contracture responses to halothane, and haloperidol also potentiated a contracture response to caffeine. Pre-treatment of muscle with remoxipride and risperidone did not induce contracture in response to halothane and did not potentiate caffeine contracture. Clozapine pre-treatment caused muscle fibre bundles to display a small halothane-induced contracture and caused significant potentiation of caffeine-induced contracture.

Prolonged treatment with haloperidol and clozapine in the rat: differential effects on spontaneous and theophylline-induced motor activity

Differences in striatal dopamine D 2 receptors and in spontaneous and theophylline-induced motor activity in rats withdrawn (for 72 h) from prolonged treatment with haloperidol or clozapine were studied. Haloperidol but not clozapine pretreatment increased the binding of the dopamine D 2 antagonist [ 3H]raclopride in striatal membrane preparations, due to an increased number of striatal dopamine D 2 receptors ( B max) without changes in affinity ( K d). Haloperidol induced a significant increase (in motility and locomotion) and clozapine a decrease (in locomotion) of the spontaneous motor activity. Haloperidol but not clozapine pretreatment was associated with a stronger theophylline-induced motor activation. These results suggest that prolonged treatment with typical but not with atypical antipsychotics are associated with adaptive changes at both dopamine and adenosine receptors.

Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.

Enkephalin-dopamine interactions in the central amygdalar nucleus during gastric stress ulcer formation in rats

Intra-amygdalar (i/am) microinjections of the enkephalin analog, ( d-Ala 2)-Met-enkephalinamide (DAMEA, 3, 10 and 30 μg) into the central amygdalar nucleus (CEA) produced a dose-related, naltrexone-reversible attenuation of cold restraint (3 h at 4°C)-induced gastric mucosal lesions in rats. Similarly, gastric stress ulcer formation was also inhibited by i/am dopamine (DA, 10 μg) - an effect which was reversed by the DA-antagonist, clozapine (5 mg/kg) pretreatment. Further, pretreatment of rats with clozapine or the DA-neurotoxin, 6-hydroxydopamine (6-OHDA, 10 μg, i/am) clearly reversed and/or antagonized the gastric cytoprotective effect of DAMEA (30 μg). The results indicate interactions between enkephalinergic and DAergic systems at the level of the CEA in the maintenance of gastric mucosal integrity during immobilization stress.