Atypical antipsychotic drugs block selective components of amphetamine-induced stereotypy

Individual items of behavior produced by 1.0 or 5.0 mg/kg d-amphetamine were monitored in rats pretreated 15 minutes earlier with vehicle or with behaviorally relevant doses of haloperidol (0.1 or 0.25 mg/kg), clozapine (1.0 or 5.0 mg/kg), or thioridazine (1.0 or 5.0 mg/kg). Unlike haloperidol, the atypical antipsychotics failed to block all components of either the low- or high-dose response to amphetamine. These drugs, however, did block selective items of amphetamine-induced stereotyped behavior. Clozapine significantly attenuated the sniffing produced by 1.0 mg/kg d-amphetamine as well as the oral behavior (licking and/or biting) produced by 5.0 mg/kg d-amphetamine. Thioridazine, at a dose of 5.0 mg/kg, also reduced oral behavior and selectively blocked repetitive head bobbing. Taken together, these results suggest that although atypical antipsychotic drugs exert some common effects on the amphetamine behavioral response, these drugs do not influence all amphetamine-induced behaviors equally.     

Central noradrenaline depletion antagonizes aspects ofd-amphetamine-induced hyperactivity in the rat

The effects of noradrenaline (NA) depletion upon amphetamine-induced hyperactivity were examined in five experiments. Central NA depletion via either systemic DSP4 or neonatal 6-OHDA antagonised the amphetamine-induced (2 mg/kg SC) increase in rearing behaviour, whereas lesions of the dorsal noradrenergic bundle using 6-hydroxydopamine antagonised the increase in locomotor activity. Peripheral NA depletion following systemic 6-hydroxydopamine to adult rats did not cause any changes in motor activity after acute amphetamine administration. Desipramine, the selective NA uptake inhibitor, blocked the effects of DSP4 upon amphetamine-induced rearing. NA depletion antagonised hyperactivity produced by the 2 mg/kg dose of amphetamine, but not the hyperactivity (rearing or locomotion) effects of amphetamine at 1, 4 or 8 mg/kg.     

Repeated treatment with ascorbate or haloperidol,but not clozapine,elevates extracellular ascorbate in the neostriatum of freely moving rats

Acute administration of neuroleptic drugs alters the extracellular level of ascorbate in the neostriatum, and increasing evidence suggests a role for this vitamin in the behavioral, and possibly therapeutic, effects of these drugs. To shed further light on this issue, extracellular ascorbate was recorded in the neostriatum and nucleus accumbens of awake, behaving rats following chronic treatment with either classical (haloperidol) or atypical (clozapine) neuroleptics or ascorbate itself. Electrochemically modified, carbon-fiber microelectrodes were lowered in place the day after the last of 21 daily injections of either haloperidol (0.5 mg/kg, SC), clozapine (20 mg/kg, IP), sodium ascorbate (500 mg/kg, IP) or vehicle. Voltammetric measurements were obtained during quiet rest and following administration ofd-amphetamine (2.5 mg/kg). Repeated treatment with either haloperidol or ascorbate elevated basal extracellular ascorbate and potentiated the amphetamine-induced increase in ascorbate release in neostriatum but not nucleus accumbens. Both treatment groups also showed a significant increase in amphetamine-induced sniffing and repetitive head movements compared to vehicle-treated animals. In contrast, repeated clozapine had no effect on extracellular ascorbate in either neostriatum or nucleus accumbens, but increased the locomotor response to an amphetamine challenge. Thus, to the extent that increases in neostriatal ascorbate exert neuroleptic-like effects, such effects are likely to parallel haloperidol rather than clozapine.     

Effects of AMPA receptor antagonists on dopamine-mediated behaviors in mice

 Current data indicate that dopaminergic and glutamatergic neurotransmitter systems interact. The role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor subtypes in modulating dopamine neurotransmission, however, remains unclear. The noncompetitive AMPA antagonists, GYKI 52466 (5–40 mg/kg) and LY300164 (1–6 mg/ kg), and the competitive AMPA antagonists, LY326325 (5–80 mg/kg) and NBQX (10–80 mg/kg), were compared to the dopamine antagonist, haloperidol (0.03– 1.0 mg/kg), for their ability to inhibit dopamine-mediated behaviors after IP administration in mice. The behavioral paradigms included amphetamine- or dizocilpine-induced hyperactivity, amphetamine-induced stereotyped sniffing, and apomorphine-induced climbing and stereotyped sniffing. All four AMPA antagonists and haloperidol attenuated amphetamine- and dizocilpine-induced hyperactivity and decreased spontaneous locomotion. Haloperidol and GYKI 52466 were more potent against amphetamine than against dizocilpine. In contrast, LY326325 was more potent against dizocilpine than against amphetamine. The hyperactivity decreases by LY300164 and NBQX were most likely due to non-specific effects on motor behavior. The AMPA antagonists and haloperidol also attenuated amphetamine- induced stereotypy. Unlike haloperidol, however, GYKI 52466, LY300164, and NBQX failed to attenuate apomorphine-induced climbing and stereotyped sniffing. LY326325, on the other hand, attenuated apomorphine-induced stereotypy, but not climbing. These results indicate that AMPA receptor antagonists can attenuate the behavioral effects of drugs, such as amphetamine and dizocilpine, that increase dopamine neurotransmission. However, the behavioral effects of the direct dopamine agonist apomorphine are not consistently attenuated by AMPA antagonists. The competitive AMPA receptor antagonist LY326325 appears to have a profile distinct from both haloperidol and the other AMPA antagonists tested. Received: 23 December 1996/Final version: 8 September 1997     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.     

Effects of typical,atypical, and novel antipsychotic drugs on amphetamine-induced place conditioning in rats

Because amphetamine-induced place conditioning is believed to be mediated by dopamine (DA) receptors within the nucleus accumbens, this behavioral model may be useful for detecting drugs with antipsychotic efficacy. To test the selectivity and specificity of the model, the present study examined whether amphetamine-induced place conditioning is reversible in rats pretreated with the classical antipsychotic haloperidol, the atypical antipsychotic clozapine, and the novel antipsychotics raclopride and risperidone. The non-antipsychotic drugs baclofen and prazosin were also tested. Male Sprague-Dawley rats received d-amphetamine (5.4 μmol/kg ip) paired with one side of a two-compartment box and saline paired with the other side. During these pairings, locomotor activity was measured. On the test day, the amount of time drug-free rats spent in each compartment was determined. Rats trained with amphetamine alone showed a significant increase in time spent on the drug-paired side from pre- to postconditioning, indicating a place preference. Pretreatment with the highest dose of either haloperidol (0.026, 0.13, 0.26 μmol/kg sc), clozapine (3, 15, 30, 60 μmol/kg sc), raclopride (0.1, 0.2, 1.0 μmol/kg), or risperidone (0.12, 0.24, 1.2 μmol/kg sc) prior to amphetamine significantly blocked the establishment of place conditioning. Treatment with the antipsychotic alone did not support place conditioning (preference or aversion). On conditioning days, haloperidol, clozapine, raclopride, and risperidone significantly decreased amphetamine-induced locomotor activity. Pretreatment with either baclofen or prazosin failed to disrupt amphetamine-induced place conditioning despite significant decreases in locomotor activity on the conditioning days. These data provide preliminary support for amphetamine place conditioning as a rodent model for detecting drugs with antipsychotic efficacy. © 1995 Wiley-Liss, Inc.     

Effects of antipsychotic drugs on the long-term effects of amphetamine on nigro-striatal dopamine neurons in iprindole-treated rats

Summary The decrease in striatal dopamine (DA) at 1 week after the administration of a single injection of (+)-amphetamine sulfate (9.2 mg/kg) to iprindole-treated (10 mg/kg of iprindole hydrochloride) rats was prevented by haloperidol (0.2 mg/kg), sulpiride (32 mg/kg), pimozide (2 mg/kg), chlorpromazine hydrochloride (3.5 mg/kg), fluphenazine 2-hydrochloride (0.25 mg/kg) and (+)-butaclamol hydrochloride (1 mg/kg) but not by (–)-butaclamol hydrochloride (1 mg/kg) or clozapine (40 mg/kg). The same dose of sulpiride did not significantly attenuate the rotational behavior induced by the administration of (+)-amphetamine sulfate (9.2 mg/kg) to iprindole-treated rats with unilateral aspiration lesions of the striatum. The concentration of amphetamine in the brains of iprindole-treated rats at 8 h after (+)-amphetamine sulfate (9.2 mg/kg) administration was not altered by the coadministration of haloperidol (1 mg/kg), sulpiride (32 mg/kg), pimozide (2 mg/kg) or clozapine (40 mg/kg). Recovery of striatal DA after depletion by -methyl-m-tyrosine (MMT) (50 mg/kg) was facilitated by haloperidol (0.2 mg/kg) and sulpiride (32 mg/kg) but not by clozapine (40 mg/kg). The possibility that neuroleptic drugs antagonize both the shortterm depletion of striatal DA produced by MMT and the long-term depletion of striatal DA produced by amphetamine in iprindole-treated rats by an effect on the nerve impulsemediated release of vesicular transmitter is discussed.     

Functional reactivity of the dopaminergic system following acute and chronic ketamine treatments

This study examined the effects of acute (15 mg/kg, i.p.) and chronic subanesthetic (15 mg/kg, i.p., t.i.d, for 6 days) doses of ketamine [a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist] on amphetamine (presynaptic dopamine releasing agent; 10 mg/kg, i.p.) and apomorphine (a D₂ receptor agonist; 1 mg/kg, i.p.)-induced stereotyped behaviors. The effect of acute and chronic ketamine on haloperidol (a D₂ receptor antagonist; 1.6 mg/kg, i.p.)-induced catalepsy was also examined. Acute ketamine and chronic ketamine pretreatment increased amphetamine-induced stereotyped sniffing and locomotion compared with control groups. Acute ketamine significantly increased apomorphine-induced stereotyped sniffing. However, chronic ketamine had no significant effect on apomorphine-induced stereotyped sniffing. Acute, but not chronic ketamine treatment abolished haloperidol-induced catalepsy. The increase in amphetamine-induced stereotyped behaviors and the reversal of haloperidol-induced catalepsy by acute ketamine suggest that blockade of NMDA receptors by ketamine facilitates dopaminergic transmission. The absence of significant effect of chronic ketamine on apomorphine-induced stereotyped sniffing and haloperidol-induced catalepsy suggests that chronic ketamine does not modulate postsynaptic dopaminergic D₂ receptors. It is suggested that chronic ketamine increased amphetamine-induced behaviors by causing hypersensitivity of presynaptic dopamine releasing mechanisms on dopaminergic terminals.     

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     

Atypical neuroleptics clozapine and thioridazine enhance amphetamine-induced stereotypy

The effects of the atypical neuroleptics clozapine and thioridazine and the typical neuroleptic pimozide on amphetamine-induced behavior were examined. Pimozide, as expected, blocked both amphetamine-induced locomotion and stereotypy. Thioridazine and clozapine antagonized the increases in locomotiom produced by amphetamine, but produced increases in amphetamine-induced stereotypy and lowered the threshold dose for stereotypy. It is suggested that the increased stereotypy might partly account for the decreased locomotion, and that this might be a primary effect of these atypical neuroleptics. The data would also suggest that the use of amphetamine-induced stereotypy as a model for psychosis is inappropriate, as clozapine and thioridazine, which enhance stereotypy, are antipsychotic.     

A novel procedure for dissociating the anatomical bases of the behavioral effects of amphetamine

A novel operative procedure is described in which the same cannula may be used to administer drugs either to the caudate nucleus (CN) or to the nucleus accumbens (NAcc) of the rat. Microinjections of amphetamine (10 or 20 micrograms) into the CN produced a reliable and robust stereotyped response; when administered to the NAcc of the same animal the higher dose increased locomotor activity. The stereotypy following peripheral administration of amphetamine (5 mg/kg) was antagonised by infusions of haloperidol (30 micrograms) into the CN but not into the NAcc. Conversely, the locomotor activity following a lower dose of amphetamine (1 mg/kg) was antagonised by infusions of haloperidol (5 micrograms) into the NAcc but not into the CN. The results confirm earlier reports that different anatomical structures mediate the behavioral effects of low and high doses of amphetamine.     

SKF 38393 and apomorphine modify locomotion and exploration in rats placed on a holeboard by separate actions at dopamine D-1 and D-2 receptors

Horizontal motor activity, rearing and head dipping were recorded automatically in rats placed on a holeboard and taken as indices of locomotion and exploration. Other behaviours were assessed visually using a video camera. SKF 38393, 15-30 mg/kg (D-1 agonist), suppressed all three behavioural measures more effectively in habituated than in naive rats. These actions were blocked by SCH 23390 (0.05 mg/kg, D-1 antagonist) but not by haloperidol (0.05 mg/kg, D-2 antagonist). Apomorphine modified behaviour biphasically, causing haloperidol-resistant sedation at a low, presynaptic dose (0.05 mg/kg) and haloperidol-sensitive hyperactivity and stereotyped sniffing at a larger, postsynaptic dose (0.5 mg/kg, especially after habituation). Neither action was antagonised by SCH 23390. The results support the conclusion that D-1 and D-2 dopamine recognition sites can separately influence the processes controlling locomotion and exploratory activity in normal rats.     

The effects of kainic acid lesions on locomotor responses to haloperidol and clozapine

 Spontaneous and amphetamine-elicited locomotor activity in rats is reduced by most clinically effective antipsychotic drugs. We have recently demonstrated that intracerebroventricular infusion of kainic acid (KA), which produces cell loss in the hippocampus and other limbic-cortical brain regions, increases spontaneous and amphetamine-elicited locomotion. The present study determined if KA lesions alter the suppressive effects of the antipsychotic drugs, haloperidol and clozapine, on spontaneous and amphetamine-elicited locomotor behavior. Young adult male rats (70 days of age) received intracerebroventricular infusions of vehicle or KA, which produced hippocampal pyramidal cell loss in each rat and more variable cell loss or gliosis in the amygdala, piriform cortex, and laterodorsal thalamus. Thirty days post-surgery, lesioned and control rats were tested once a week for locomotor responses to drug treatments. As observed previously, spontaneous locomotor activity and hyperactivity elicited by amphetamine (1.50 mg/kg SC) were greater in lesioned animals than controls. In addition, the level of spontaneous activity and/or amphetamine-elicited hyperlocomotion observed in lesioned rats after haloperidol treatment (0.13, 0.35, or 1.50 mg/kg SC) was greater than that found in controls. Locomotor responses to low (6.30 mg/kg) and moderate doses of clozapine (20 mg/kg) were similar in lesioned and control rats, although lesioned rats were more active than controls following the administration of a high dose of clozapine (30 mg/kg). These data indicate that the hyperactivity associated with limbic-cortical lesions may be insensitive to reversal by haloperidol, yet uniquely sensitive to suppression by clozapine. Received: 1 April 1997/Final version: 6 August 1997     

Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation

Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has been associated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypical antipsychotics such as olanzapine. In rodents, early life exposure to stressful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg s.c.), olanzapine (5 mg/kg s.c.), and haloperidol (0.5 mg/kg s.c.) on dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of the mPFC in group- and isolation-reared rats. Rats reared in isolation showed significant and robust deficits in prepulse inhibition of the acoustic startle. In group-reared animals, both clozapine and olanzapine produced a significant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics compared with group-reared animals. In contrast, the administration of haloperidol failed to modify dialysate DA levels in mPFC in either group- or isolation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D2 or D3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate, GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA responsiveness to the atypical antipsychotic drugs clozapine and olanzapine may explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, namely hyperactivity and attention deficit.     

Differential actions of classical and atypical antipsychotic drugs on spontaneous neuronal activity in the amygdaloid complex

Classical antipsychotic drugs such as haloperidol produce akinesia and catalepsy, whereas clozapine and related atypical antipsychotics fail to elicit these behaviors even at relatively high doses. Despite these behavioral differences, a cataleptic dose of haloperidol (2.0 mg/kg) produces changes in neuronal activity in the neostriatum and nucleus accumbens comparable to those produced by a non-cataleptic dose of clozapine (20.0 mg/kg). To further elucidate the brain mechanisms underlying the differential behavioral response to these drugs, an electrophysiological analysis was extended to neurons in the rat amygdaloid complex. Whereas an intraperitoneal injection of 2.0 mg/kg haloperidol generally failed to alter the firing rate of amygdaloid neurons, 20.0 mg/kg clozapine typically produced a prolonged increase in activity. Similarly, clozapine, but not haloperidol, reversed the depression of firing rate produced by 1.0 mg/kg d-amphetamine. The results suggest that neurons in the amygdaloid complex are more responsive to antipsychotic drugs devoid of extrapyramidal side effects than to antipsychotics which elicit parkinsonian-like motor dysfunctions.     

ST2472: a new potential antipsychotic with very low liability to induce side-effects

ST2472 was shown to bind to multiple receptors, thus resembling the affinity spectrum of atypical antipsychotics. The present study investigates its in-vivo potential antipsychotic effects. ST2472 is effective in the conditioned avoidance response (CAR) test in rats (ED50=1.5 mg/kg p.o.), a model sensitive to antipsychotics. It antagonizes amphetamine-induced hypermotility at dosages (minimal effective dose=0.7 mg/kg p.o.) that are lower than those necessary to antagonize amphetamine-induced stereotypy (minimal effective dose=30 mg/kg p.o.), in rats. This finding, together with the fact that ST2472 does not induce catalepsy in rodents at up to 100 mg/kg p.o., indicates that ST2472 has very low liability to induce extrapyramidal side-effects. ST2472 does not increase prolactinaemia after chronic treatment. In mice, ST2472 does not appear to alter blood pressure and heart rate in a significant fashion. In conclusion, ST2472 seems to be an antipsychotic with lower liability to produce side-effects than other antipsychotics, such as haloperidol, risperidone, olanzapine and clozapine, which were evaluated as reference drugs.     

The influence of clozapine treatment and other antipsychotics on the 18 kDa translocator protein, formerly named the peripheral-type benzodiazepine receptor, and steroid production.

It has been shown that the atypical antipsychotic drug clozapine increases the levels of the neurosteroid allopregnanolone in the rat brain. The 18 kDa translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, has been demonstrated to be involved in the process of steroid biosynthesis, in peripheral steroidogenic tissues as well as in glia cells in the brain. In the current study, we investigated the influence of chronic treatment with clozapine and other antipsychotics (thioridazine,sulpiride and risperidone) on TSPO binding in cell cultures and rat tissues. Clozapine significantly increased TSPO binding density in C6 rat glioma cells and in MA-10 mouse Leydig tumor cells, while the antipsychotic sulpiride had no effect on TSPO binding density in both cell lines. In addition, clozapine, but not sulpiride, significantly increased progesterone synthesis by MA-10 Leydig tumor cells. In an animal experiment, male Sprague-Dawley rats were treated with clozapine (20 mg/kg), risperidone (0.5 mg/kg), thioridazine (20 mg/kg), or sulpiride (20 mg/kg) for 21 days, followed by 7 days of withdrawal. Clozapine induced significant increases in TSPO binding in brain and peripheral steroidogenic tissues, whereas the other antipsychotics did not show such pronounced effects on TSPO binding. Our results suggest that TSPO may be involved in the modulation of steroidogenesis by clozapine.     

Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex

Recent neuroanatomical and functional investigations focusing on dopamine (DA) D(3) receptors have suggested a potential role of this receptor in psychiatric diseases such as schizophrenia and drug dependence. In line with the key role of the prefrontal cortex in psychiatric disorders, the present study aimed at assessing the effects of the acute systemic administration of the selective DA D(3) receptor antagonist SB-277011-A on the in vivo extracellular levels of monoamines (DA, norepinephrine (NE), and serotonin (5-HT)) and acetylcholine (ACh) in the anterior cingulate subregion of the medial prefrontal cortex. The in vivo neurochemical profile of SB-277011-A (10 mg/kg, i.p.) in the anterior cingulate cortex was compared with both typical and atypical antipsychotics including clozapine (10 mg/kg, s.c.), olanzapine (10 mg/kg, s.c.), sulpiride (10 mg/kg, s.c.), and haloperidol (0.5 mg/kg, s.c.). The acute administration of SB-277011-A, clozapine, and olanzapine produced a significant increase in extracellular levels of DA, NE, and ACh without affecting levels of 5-HT. Sulpiride also significantly increased extracellular DA, but with a delayed onset over SB-277011-A, clozapine, and olanzapine. In contrast, haloperidol failed to alter any of the three monoamines and ACh in the anterior cingulate cortex. These findings add to a growing body of evidence suggesting a differentiation between typical and atypical antipsychotic drugs (APDs) in the anterior cingulate cortex and a role of DA D(3) receptors in desired antipsychotic drug profile. Similar to their effects on DA and NE, SB-277011-A, clozapine, and olanzapine increased extracellular levels of ACh, whereas haloperidol and sulpiride did not alter ACh. The results obtained in the present study provide evidence of the important role of DA D(3) receptors in the effect of pharmacotherapeutic agents that are used for the treatment of psychiatric disorders such as schizophrenia and drug dependence.     

Pharmacologic control of pemoline induced self-injurious behavior in rats

Administration of oral Pemoline produces long lasting amphetamine-type stereotyped behavior and persistent self-biting behavior in rats. The effects of haloperidol, pimozide, diazepam, and serotonin depletion by pretreatment with p-chlorophenylalanine (PCPA) or chronic pretreatment with p-chloroamphetamine (PCA) on abnormal behavior produced by pemoline were studied. Diazepam consistently increased the duration of stereotyped behavior. It also reduced licking/biting and self-biting but the latter effects were not consistent. Pretreatment with PCA had negligible effects on stereotyped behavior. Pretreatment with PCPA dramatically increased locomotion and rearing without affecting the other components of stereotypy--stereotyped head movements, licking/biting, and self-biting. Haloperidol (0.2 and 0.3 mg/kg) produced a dose related normalization of pemoline induced behaviors, including elimination of self-biting. Pimozide (0.5, 0.8 and 1.3 mg/kg) had little or no effect on behaviors such as locomotions, rears, licking/biting, or stereotyped head movements but eliminated self-biting at 1.3 mg/kg. These data suggest that pemoline, like amphetamine, produces stereotyped behavior through central dopaminergic mechanisms. Dopaminergic mechanisms also appear to be involved in pemoline induced self-biting. pemoline is apparently pharmacologically and behaviorally very similar to amphetamine. Pemoline may provide a useful animal model for syndromes characterized by self-injurious behavior and other repetitive behaviors.     

The effects of atypical antipsychotics and phencyclidine (PCP) on rotorod performance.

A series of six experiments were conducted to determine the effects of haloperidol, clozapine, olanzapine, and phencyclidine (PCP) on rotorod performance. Rodents were trained to walk on a rotorod to avoid a mild shock to a criterion of 20 rpm for 3 min. None of the vehicles of any of these drugs disrupted rotorod performance. Haloperidol disrupted rotorod performance at doses of 0.03, 0.1, and 0.3 mg/kg, and olanzapine disrupted rotorod performance at doses of 3.0 and 10.0 mg/kg. Clozapine produced a much milder disruption across all three doses (3.0, 10.0, and 30.0 mg/kg). PCP produced a consistent and severe disruption of rotorod performance at doses of 4.0 and 6.0 mg/kg, but not at a dose of 2.0 mg/kg. Twenty-four hours postinjection there were no residual PCP effects on rotorod performance. Coadministration of either haloperidol or olanzapine with PCP did not reverse PCP-induced disruption in rotorod performance, while clozapine produced a partial reversal at only one dose. These findings indicate that olanzapine functions similarly to classic antipsychotics with respect to their effects on locomotion and balance.