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: peakforce 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 antipsychotic agent.     

Acute and subchronic effects of clozapine on licking in rats: tolerance to disruptive effects on number of licks,but no tolerance to rhythm slowing

In order to assess the effects of the atypical neuroleptic clozapine on orolingual competence in rats, tongue function was measured by quantitating the rhythm of tongue movements after acute (1.0, 3.0, 6.0 mg/kg) or subchronic intraperitoneal treatment (1.5, 3.0, 4.5 mg/kg, each dose for at least 7 days) with the drug. Thirsty rats were trained to lick water from a force-sensing disk by thrusting the tongue through a 12-mm-diameter hole to strike the horizontal disk located 5 mm below the hole. Number of licks in 2 min and rhythm of tongue movements (as determined by Fourier analysis of the force-time signal) were each dose dependently reduced in the acute dose-effect phase of the study. In the subchronic study number of licks exhibited tolerance, but the slowing of lick rhythm did not show tolerance. An acute dose range of the serotonin antagonist ritanserin (0.5, 1.0, 2.0, 4.0 mg/kg) was also studied in the same rats. Ritanserin had no effect on any of the measures of orolingual function. The clozapine result was replicated in a second study using younger, drug naive rats. The results for clozapine were contrasted with previous reports indicating that haloperidol has little effect on lick rhythm. Additional discussion evaluated the possible contribution of neurotransmitter receptors on motor neurons of the hypoglossal nucleus to the observed rhythm slowing induced by clozapine.     

Chronic haloperidol produces a time- and dose-related slowing of lick rhythm in rats: implications for rodent models of tardive dyskinesia and neuroleptic-induced parkinsonism

 In order to characterize the development of orolingual motor effects of chronic haloperidol treatment in rats, this typical neuroleptic was administered for 102 days while daily measurements of tongue movement dynamics (peak force, lick rhythm, number of licks) during water licking were recorded. After chronic haloperidol dosing (vehicle, 0.06. 0.12, 0.24 mg/kg for four separate groups) for 32 days and continuing every second or third day of the chronic dosing period, the effects of cholinergic (scopolamine: 0.05–0.20 mg/kg; trihexyphenidyl: 0.15–1.0 mg/kg) or serotonergic (ritanserin: 0.5–4.0 mg/kg; quipazine: 0.5–4.0 mg/kg) probe drugs were examined for their capacity to antagonize the alterations in licking behavior induced by haloperidol. Haloperidol dose-dependently reduced peak force and number of licks, effects which were apparent within 2 or 3 days of the start of treatment. Significant effects of haloperidol on lick rhythm first emerged on day 13 and gradually increased in magnitude through the remaining treatment period. Scopolamine, trihexyphenidyl, and quipazine reduced haloperidol’s effects on at least one measure of licking behavior. During a 7-day haloperidol withdrawal period, the four dosage groups were similar on all measures of tongue dynamics. Overall, the results exhibited features suggesting the co-occurrence of Parkinson-like and tardive dyskinesia-like effects. Received: 3 July 1997 / Final version: 22 October 1997     

Acute and subchronic effects of neuroleptics on quantitative measures of discriminative motor control in rats

Operant-conditioning methods were used to train rats to reach through an opening in an operant chamber to exert forces on a silent, neraly isometric force-sensing manipulandum. The reinforcement contingency required the rat to hold forelimb force at 20–50 g for a minimum of 2 s. Once established, this hold-in-the-band behavior yielded three measures of performance (time on task, number of reinforcers, variance of in-band force). Variance of in-band force was presumed to reflect steadiness of forelimb control. Acute drug effects on the three dependent variables were assessed for dose ranges of haloperidol (HAL), chlorpromazine (CPZ), clozapine (CLZ), and chlordiazepoxide (CDP). Moreover, the effects of HAL (0.5 mg/kg) and CLZ (5.0 mg/kg) were examined in a subchronic (28 day) dosing regimen. The acutely administered neuroleptics (HAL, CPZ, CLZ) produced dose-related decreases in time on task and number of reinforcers, but did not significantly affect variance of in-band force. The subchronic paradigm produced similar results. CDP did not significantly affect variance of in-band force and the 5.0 mg/kg dose produced a slight, but non-significant increase in time on task while significantly decreasing number of reinforcers; a trend opposite to that seen for the neuroleptics, which produced parallel effects on these two measures. The results suggest that the neuroleptics impaired performance by affecting the tendency to initiate responding instead of affecting the capacity to maintain steady forelimb force once a response was started.     

Subchronic effects of clozapine and haloperidol on rats’ forelimb force and duration during a press-while-licking task

 In order to compare and contrast the behavioral effects of the typical neuroleptic haloperidol with the atypical neuroleptic clozapine, ten daily doses of these drugs were administered to separate groups of rats trained to extend the forelimb through a rectangular hole and to exert downward pressure on a force transducer to gain access to water. Doses were individually titrated daily for each rat in an attempt to achieve a 50% reduction in time on task (analogous to response rate) during 8-min daily sessions. Clozapine-treated rats exhibited dramatic tolerance to the drug’s suppressive effect on time on task. In contrast, haloperidol rats displayed little tolerance on this measure. Despite the tolerance reflected by time on task, no tolerance was seen in clozapine’s marked slowing of the dominant frequency of oscillations in forelimb force as measured by Fourier analysis of the force-time recordings. Haloperidol did not slow the dominant frequency. No tolerance was seen for clozapine’s effects on forelimb force or tremor measures. Haloperidol did not significantly affect forelimb force. Both haloperidol and clozapine produced increases in the duration of long-duration forelimb responses, and no tolerance was seen for either drug on this measure of behavior. For clozapine, the dissociation between the tendency to respond (time on task) and the observed slowing of the dominant frequency may reflect effects peculiar to atypical neuroleptics, while the lengthening of long-duration responses by both drugs may reflect a more general behavioral effect that is characteristic of both typical and atypical antipsychotic drugs. Received: 27 June 1996 / Final version: 12 November 1996     

Effects of clozapine,olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat

Rationale. Antipsychotic drugs, particularly the newer atypical compounds, have been associated with rapid weight gain in a clinical setting. However, there are few reported animal models producing reliable hyperphagia correlating with the human weight gain liability of these drugs. Objective. To compare the effects of the classic neuroleptic haloperidol with the atypical antipsychotics clozapine and olanzapine on the microstructure of ingestive behaviour in rats. Methods. Male hooded Lister rats drank a palatable high-calorie fat emulsion (10% Intralipid) during 30-min test sessions and microstructural analyses were made following administration of each drug over a range of doses. Results. Clozapine (0.3 mg/kg) and olanzapine (0.1, 0.3, 1 mg/kg) significantly increased intake, whilst haloperidol (0.05, 0.1, 0.2 mg/kg) significantly decreased drinking. No significant changes in the latency to the first lick were observed following any of the drugs tested. Median interlick intervals showed small, dose-related increases after clozapine (3.0 mg/kg), olanzapine (0.3, 1.0 mg/kg) and haloperidol (0.1, 0.2 mg/kg). Olanzapine (1.0 mg/kg) significantly elevated the number of clusters of licking (bouts of licking separated by pauses greater than 500 ms), whilst clozapine and haloperidol did not. Mean cluster size (licks per cluster) was not affected by clozapine or olanzapine, but haloperidol (0.025, 0.05, 0.1, 0.2 mg/kg) produced marked, significant decreases in cluster size. Conclusions. Clozapine and olanzapine increased fat intake whereas haloperidol did not, and this resembles the greater weight gain liability of atypical antipsychotics in humans. A delay or reduction of the post-ingestive satiety signal combined with preserved palatability appears to be the mechanism responsible for fat hyperphagia in rats treated with clozapine and olanzapine. Conversely, haloperidol leaves satiety unaffected but reduces the palatability of the fat emulsion resulting in reduced intake. Electronic Publication     

Effects of haloperidol and clozapine on tongue dynamics during licking in CD-1, BALB/c and C57BL/6 mice

Rationale: In an initial effort to describe how genetic background influences the differential motor effects of haloperidol, a drug with high extrapyramidal side effect (EPS) liability, and clozapine, an antipsychotic low in EPS, both drugs were studied in inbred strains of mice (BALB/c and C57BL/6) previously shown to have differential sensitivities to haloperidol. Objectives: Behavioral differences in lick dynamics for male BALB/c, C57BL/6 and CD-1 (an outbred strain) were characterized. Effects of dose ranges of haloperidol and clozapine were then evaluated in the three strains. Methods: The mice learned to lick milk from a force-sensing disk during daily 2-min sessions, while a computer counted the number of licks and measured lick peak force and lick rhythm. After training, acute doses of haloperidol (0.08–2.0 mg/kg) or clozapine (0.5–8.0 mg/kg) were administered i.p. 45 min before sessions. Results: Prior to drug treatment, substantial quantitative strain differences in licking behavior were observed: C57BL/6 mice made fewer licks, licked with lower peak force per lick, and had a slower lick rhythm than the BALB/c and CD-1 mice. As in rats, clozapine slowed the lick rhythm in all three mouse strains much more than haloperidol did. Haloperidol produced a 50% greater suppression of number of licks in BALB/c than in C57BL/6 mice (ED₅₀ values were 0.82 mg/kg and 1.22 mg/kg, respectively). For clozapine, lick suppression was greater in the C57BL/6 than in the BALB/c strain (ED₅₀ values were 1.88 mg/kg and 2.65 mg/kg, respectively). Among the three strains examined, CD-1 was the most sensitive to haloperidol’s suppression of licking, while its sensitivity to clozapine’s lick-suppressing effect was similar to C57BL/6 mice. Clozapine lowered the lick peak force in the CD-1 and BALB/c strains more than in the C57BL/6 strain. Conclusions: Overall, the results suggest that genetic variables may influence both mice’s tongue dynamics and their alteration by both typical and atypical antipsychotic drugs. In addition, while the BALB/c strain was more sensitive to haloperidol’s lick-disruptive effects than the C57BL/6 strain, the size of the difference between strains was much smaller than the reported difference between the strains in the catalepsy test. Received: 19 October 1998 / Final version: 3 June 1999     

Dantrolene diminishes forelimb force-related tremor at doses that do not decrease operant behavior in the rat

A behavioral preparation that affords concurrent measurement of forelimb force and tremor in rats was used to assess the effects of dantrolene sodium, a muscle relaxant and potential neuroprotective drug. Rats that were trained to press downward on an isometric force transducer while simultaneously licking water reinforcement were administered dantrolene (5.0 mg/kg, 7.5 mg/kg, and 10.0 mg/kg). Dantrolene diminished force output at the 7.5 mg/kg and 10.0 mg/kg doses and decreased tremor at all three doses. Dantrolene decreased the ratio of forelimb tremor to force output at all three doses. Dantrolene did not suppress operant behavioral output at these doses. These results suggest that dantrolene may affect fine motor control and decrease tremor at doses that do not produce behavioral suppression.     

Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents.

The neuroactive steroid allopregnanolone is a potent gamma-aminobutyric acid type A (GABA(A)) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.     

Unlike haloperidol,clozapine slows and dampens rats' forelimb force oscillations and decreases force output in a press-while-licking behavioral task

In order to detect putative differences in the behavioral effects of clozapine and haloperidol, rats were trained to use a single forelimb to exert continuous pressure on a force-sensing operandum. Behavior was maintained by presenting a water-filled dipper for consumption only as long as the force remained above a specified level (the water fountain task). Effects of clozapine (2.0, 4.0, 8.0 mg/kg) and haloperidol (0.02, 0.04, 0.08, 0.12 mg/kg) on the forelimb force oscillations manifested during the operandum pressing episodes were analyzed with power spectral analysis and other quantitative methods. All rats exhibited force oscillations with a fundamental frequency near 7 Hz. Clozapine shifted the frequency to lower values (i.e., oscillation slowing), while haloperidol shifted oscillations to slightly higher frequencies. Moreover, clozapine reduced power in the region of the spectrum above 5 Hz. In contrast, haloperidol tended to increase power in these regions. Time domain analyses of the force-time waveforms indicated that haloperidol increased force emission during the hold phase of the forelimb response, and clozapine decreased this measure. The results are congruent with the high extrapyramidal side effects of haloperidol and the lack of such effects of clozapine in the clinic. In addition, clozapine may have antitremor effects in rats as it does in humans.     

Effects of neuroleptics on rate and duration of operant versus reflexive licking in rats

Operant conditioning techniques were used to train one group of nine rats to lick a dry horizontal metal disk on a fixed ratio 15 schedule with water reinforcement delivered at a different location. Another group of seven rats licked reflexively from a water reservoir positioned with the same spatial arrangements as the metal disk. The distance the rats' rongues traversed (10 mm) to contact the licking surface was the same in both the operant and reflexive lick conditions. The effects of three neuroleptics, haloperidol (0.06, 0.12, 0.24, 1.0, 2.0 mg/kg), chlorpromazine (0.5, 1.0, 2.0 mg/kg) and clozapine (2.5, 5.0, 7.5 mg/kg) on average lick rate and median lick duration were assessed for both groups. Dose related decreases in average lick rate were observed in both groups of rats as a function of dose of each of these neuroleptics. Moreover, operant lick rates were proportionately more affected by neuroleptic treatment than were reflexive lick rates. The dose-response effect for the duration variable was different for the two lick conditions in that reflexive lick duration was lengthened as dose increased, whereas operant lick duration was lengthened only at the lower doses of these drugs. The differential effect of these neuroleptics on operant vs. reflexive licking suggests that neuroleptics attenuate selectively those responses that require relatively more conditioning to acquire. These results may be analogous to the initiation deficit that has been suggested to account for neuroleptics' selective attenuation of avoidance, while leaving relatively intact the escape response in escape/avoidance procedures.     

Effects of cocaine and putative atypical antipsychotics on rat social behavior: an ethopharmacological study

The effects of cocaine, amperozide, clozapine, olanzapine and cocaine/atypical antipsychotic combinations on aggression, affiliation and defensive behaviors was examined. Acute cocaine (30.0 mg/kg) decreased basal aggression and affiliation yet increased basal defense. Amperozide (1.0, 3.0 and 5.0 mg/kg) decreased basal aggression, affiliation and defense had no effect on the cocaine-induced decrease in affiliation, and accentuated the cocaine-induced decrease in aggression. Near basal levels of defense were observed for animals treated with either amperozide, clozapine (3.0 and 10.0 mg/kg but not 30.0 mg/kg) or olanzapine followed by cocaine. Clozapine (3.0, 10.0 and 30.0 mg/kg) decreased basal aggression and affiliation. Clozapine (30.0 mg/kg but not 3.0 or 10.0 mg/kg) decreased basal defense. Clozapine attenuated the cocaine-induced decrease in aggression. Although 3.0 and 10.0 mg/kg clozapine attenuated the cocaine-induced decrease in affiliation, 30.0 mg/kg clozapine accentuated this cocaine-induced effect. Olanzapine (1.0, 3.0 and 10.0 mg/kg) decreased basal aggression, affiliation and defense. Olanzapine had no effect on the cocaine-induced decrease in aggression. Olanzapine (3.0 mg/kg but not 1.0 or 10.0 mg/kg) attenuated the cocaine-induced decrease in affiliation. Thus, acute cocaine administration had an antiaggressive effect, suppressed affiliative behavior and enhanced defensive behavior. Amperozide, clozapine and olanzapine have anticonflict and anxiolytic effects, as well as potent and specific antiaggressive effects.     

Effects of olanzapine, sertindole and clozapine on learning and memory in the Morris water maze test in naive and MK-801-treated mice

Cognitive dysfunction in schizophrenia is associated with functional disease symptoms. The beneficial effects of second generation antipsychotic drugs on cognitive function in schizophrenic patients are controversial. In this study, we investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on cognitive function in the Morris water maze task in naive or MK-801-treated animals. Male balb-c mice were treated subchronically with olanzapine (1.25, 2.5 and 5 mg/kg, i.p.), sertindole (0.63, 1.3, 2.5 mg/kg, s.c.) or clozapine (0.5 and 1 mg/kg, i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg, i.p.) administration. Water maze performance was expressed as escape latency to find the hidden platform, the time spent in target quadrant, the mean distance to platform and the swim speed. In naive mice olanzapine impaired water maze performance, whereas sertindole and clozapine had no effect while the MK-801-induced cognitive impairment was reversed by the second generation antipsychotics — olanzapine, sertindole and clozapine at the doses used. These results revealed that while olanzapine had some disturbing effects on cognitive functions in naive animals; olanzapine, sertindole and clozapine might improve cognitive deficits in schizophrenic patients.     

Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: Contrast with haloperidol and chlordiazepoxide

Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical anti-psychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22-kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22-kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical anti-psychotics as well as anxiolytics.     

Olanzapine,a novel atypical antipsychotic,reversesd-amphetamine-induced inhibition of midbrain dopamine cells

This study compared the ability of the novel atypical antipsychotic olanzapine with that of clozapine to reverse thed-amphetamine-induced inhibition of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA) cells. Extracellular single-unit recordings were made from A9 and A10 DA cells in anesthetized rats. When administered alone, neither olanzapine nor clozapine altered the firing rate of A9 or A10 DA cells. Administration ofd-amphetamine (0.5, 1.0 and 2.0 mg/kg, IV, decreased the firing rate of A9 and A10 DA cells. Olanzapine completely reversed the inhibitory effects ofd-amphetamine on A10 DA cells (ED₁₀₀=0.18 mg/kg, IV) and on A9 DA cells (ED₁₀₀=1.0 mg/mg, IV). Clozapine completely reversed the inhibitory effects ofd-amphetamine on A10 DA cells (ED₁₀₀=3.8 mg/kg, IV), but only partially reversed the effects ofd-amphetamine on A9 DA cells at the highest dose tested (8.0 mg/kg, IV). Thus, olanzapine, like clozapine, was more potent in reversing the effects ofd-amphetamine on A10 than A9 DA cells. In addition, olanzapine was more potent than clozapine in the reversal ofd-amphetamine effects on A9 and A10 DA cells. These results indicate that olanzapine and clozapine have similar effects on DA unit activity and predict that olanzapine should have an atypical antipsychotic profile in man.     

Discriminative-stimulus effects of clozapine in squirrel monkeys: comparison with conventional and novel antipsychotic drugs

 The effects of conventional and novel atypical antipsychotic drugs were compared to clozapine in squirrel monkeys that discriminated IM injections of clozapine (1.0 mg/kg) from saline in a two-lever drug discrimination procedure. Clozapine (0.03–3.0 mg/kg) produced dose-related increases in responding on the clozapine-associated lever with full substitution at the training dose in all monkeys. Dose-related increases in responding on the clozapine-associated lever and full substitution also were observed with structural analogues of clozapine including perlapine and fluperlapine (0.1–3.0 mg/kg), seroquel (0.1–5.6 mg/kg), and JL 5, JL 8 and JL 18 (0.1–3.0 mg/kg). Other clozapine analogues, including olanzapine, amoxapine, loxapine and clothiapine, and conventional antipsychotic drugs, including phenothiazines such as chlorpromazine and thioridazine, produced some clozapine-associated responding up to the highest doses that could be studied, but did not substitute for clozapine. Olanzapine did produce full clozapine-lever responding following pretreatment with the dopamine D₂-receptor agonist (+)-PHNO (0.003–0.01 mg/kg). Putatively atypical antipsychotics that are structurally unrelated to clozapine including risperidone (0.003–0.1 mg/kg), sertindole (0.03–1.0 mg/kg) and remoxipride (0.1–5.6 mg/kg) similarly failed to substitute for clozapine up to the highest doses. The present results indicate that some, but not all, structural analogs of clozapine have clozapine-like discriminative-stimulus effects and that novel antipsychotic drugs which purportedly have clozapine-like clinical efficacy may not produce its interoceptive stimulus effects. Received: 2 November 1996 / Final version: 13 January 1997     

Clozapine and prazosin slow the rhythm of head movements during focused stereotypy induced by <Emphasis Type="Italic">d</Emphasis>-amphetamine in rats

Rationale Clozapine is an efficacious, symptom-ameliorating, atypical antipsychotic drug with few extrapyramidal side effects. Clozapine has been reported either not to affect or to increase d-amphetamine-induced stereotypy, a behavior that is blocked by typical antipsychotic drugs. Objectives This work used a high-resolution measurement system to reassess clozapine’s effects on d-amphetamine-induced focused stereotypy (FS) in rats. Materials and methods A force-plate actometer permitted the quantitation of the rhythm and vigor of movements during FS. Eight rats received a sensitizing series of doses of 5.0 mg/kg d-amphetamine sulfate, and this dosing regimen induced head movements with a rhythm near 10 Hz. Thirty minutes after d-amphetamine treatment, rats received acute clozapine (2.5–10.0 mg/kg), followed by eight, daily clozapine injections (5.0 mg/kg) given with d-amphetamine on days 2, 5, and 8. Effects of acute doses of the α₁-noradrenergic antagonist prazosin (0.5–2.0 mg/kg) on the d-amphetamine response were also examined. Results Clozapine dose-dependently slowed the near 10-Hz rhythm and reduced the vigor of the d-amphetamine-induced FS. Clozapine significantly lengthened the duration of the FS phase, but the rhythm remained slowed. No evidence for tolerance to clozapine’s rhythm-slowing effects was seen in the subchronic phase. Prazosin dose-dependently reduced the near 10-Hz rhythm induced by d-amphetamine, but prazosin did not lengthen the FS phase. Conclusions The results show that clozapine diminished the rhythm and vigor of d-amphetamine-induced stereotyped head movements but, at the same time, lengthened the duration of the expression of the stereotypy. α₁ antagonism is a likely contributor to the rhythm-modulating effects of clozapine. Supported by MH43429 and HD02528     

Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: contrast with haloperidol and chlordiazepoxide

Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical anti-psychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22-kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22-kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical anti-psychotics as well as anxiolytics.     

Effects of olanzapine and clozapine on radial maze performance in naive and MK-801-treated mice

Attention, working memory and long-term memory dysfunctions are the most commonly seen cognitive impairments in schizophrenic patients. Conflicting results exist regarding the effects of antipsychotics on cognitive abnormalities. The aim of this study was to investigate the effects of atypical antipsychotic drugs olanzapine (0.4, 0.8 and 1.25?mg/kg, i.p.) and clozapine (0.5 and 1?mg/kg, i.p.) on spatial working memory in naive and MK-801 (0.2?mg/kg, i.p.) treated BALB-c mice in an 8-arm radial arm maze (RAM) task. None of the antipsychotic drugs studied altered number of errors in naive mice, whereas MK-801 significantly increased working memory errors in RAM test. Olanzapine and clozapine potently reversed MK-801 induced increasement of working memory errors. Olanzapine and clozapine prolonged latency of the animals in naive mice. The MK-801-induced enhancement in the speed of mice in performing the RAM task was blocked by olanzapine but not clozapine. Our study shows that atypical antipsychotics olanzapine and clozapine might improve cognitive deficits in schizophrenic patients.     

Effects of clozapine and chlorpromazine upon operant response measures in rats

Rats responded under a FR20 schedule of water reinforcement by paw-pressing a silent, isometric, force-sensing manipulandum. Two seven-animal groups differed in terms of the force requirement for reinforcer delivery, i.e., a low-force condition (4-g requirement for reinforcer delivery) or a high-force condition (32-g requirement for reinforcer delivery). Oral dose ranges of chlorpromazine (1.0, 3.0, 9.0 mg/kg) and clozapine (2.5, 5.0, 10.0 mg/kg) were evaluated for their effects on intensitive measures of response (i.e., peak force and duration), in addition to the conventional rate measure. Peak force, duration, and rate of response were recorded with a laboratory computer system. Conjoint examination of these three dependent variables revealed that clozapine, a new anti-psychotic agent which produces virtially no extrapyramidal side effects in man, affected FR responding in the same way as did chlorpromazine. More specifically, response rate and peak force declined as a function of dose for each drug. Duration of response tended to be increased at the highest dose for both clozapine and chlorpromazine, but this effect was limited primarily to the high-force condition.