Efficacy of the atypical antipsychotic aripiprazole in d-amphetamine-based preclinical models of mania.

The atypical antipsychotic aripiprazole has been demonstrated to reduce symptoms of bipolar mania. To further profile the antimanic-like properties of aripiprazole in relevant preclinical models, we examined its efficacy in d-amphetamine-based behavioural models of acute mania in rats. The effects of acute and repeated administration of aripiprazole were assessed in the facilitation of intracranial self-stimulation (ICSS) and hyperlocomotion after acute d-amphetamine, and in the sensitized facilitation of ICSS function and hyperlocomotion after repeated d-amphetamine. Acutely, aripiprazole (0.75, 1.5 and 2.5 mg/kg i.p.) increased ICSS thresholds, attenuated the reward-facilitating effects of d-amphetamine (0.5 mg/kg i.p.), decreased motor activity and prevented d-amphetamine-induced hyperlocomotion. Co-administration of aripiprazole and d-amphetamine for 7 d resulted in aripiprazole counteracting the d-amphetamine-induced sensitization in facilitation of brain reward function and hyperlocomotion. These results indicate the efficacy of aripiprazole in d-amphetamine-based preclinical models of acute mania that are characterized by increased motivational drive and/or hyperfunction of brain reward.

The effects of progesterone pretreatment on the response to oral d-amphetamine in Women.

Stimulant abuse continues to be a problem, particularly for women. There is increasing preclinical and clinical evidence showing that the hormone progesterone attenuates the behavioral effects of cocaine, and this effect is primarily observed in females. The purpose of the present study was to determine if progesterone would also alter the behavioral effects of another stimulant, oral d-amphetamine (AMPH) in women. Eighteen normal non-drug abusing women completed eight outpatient sessions over two menstrual cycles. During the follicular phase of each cycle, women were administered AMPH (0, 10, 20 mg); in one cycle they were pretreated with oral micronized progesterone (200 mg) and in another cycle they were pretreated with placebo progesterone. Each session, participants completed a range of tasks including subjective measures of abuse liability, cognitive performance tasks, and behavioral measures of impulsivity and risk-taking. AMPH produced dose-related increases in positive subjective effects and these effects were enhanced by progesterone pretreatment. AMPH alone, or in combination with progesterone, had little effect on performance or behavioral measures of impulsivity. These results are in contrast with previous studies showing that progesterone attenuates the subjective response to cocaine and nicotine. Additional studies are needed to explore the modulatory role of progesterone on the effects of AMPH to determine whether progesterone has any clinical utility for AMPH abuse.

Pimozide blocks establishment but not expression of amphetamine-produced environment-specific conditioning.

Animals with a history of receiving daily injections of +-amphetamine in a specific environment showed a placebo effect (enhanced activity) when injected with saline and placed there; control animals with similar but dissociated drug histories and experience with the test chamber failed to show the effect. The dopamine receptor blocker pimozide antagonized the establishment of conditioning. However, the same dose of pimozide, when given to previously conditioned animals on the placebo test day, failed to antagonize the expression of conditioned activity. Thus, during conditioning dopaminergic neurons mediated a change that subsequently influenced behavior even when dopaminergic systems were blocked. Although schizophrenia may be related to hyperfunctioning of dopamine, neuroleptic drugs, which block dopamine receptors on their first administration, do not have therapeutic effects for a number of days. The results of the pimozide experiments may resolve this paradox.

Route of administration affects the ability of naltrexone to reduce amphetamine-potentiated brain stimulation reward in rats.

Opioid receptor antagonism has been shown to attenuate behavioral and neurochemical effects of amphetamine in humans and rodents. The effects of acute (oral or subcutaneous) or extended-release naltrexone (XR-NTX) were tested on the reward-enhancing effects of amphetamine using the intracranial self-stimulation (ICSS) paradigm. Acute exposure to drugs of abuse reduces the locus of rise (LOR) in the ICSS procedure, reflecting enhanced brain stimulation reward (BSR). Rats were treated once a day with naltrexone orally (PO; 5.0 mg/kg) or subcutaneously (SC; 0.5 mg/kg) for four consecutive days and tested with D-amphetamine (0.5 mg/kg, intraperitoneal) in the ICSS paradigm 30 minutes later on days 1 and 4. Separate groups of rats received XR-NTX (50 mg/kg, SC) or placebo microspheres (similar mass to XR-NTX, SC) on day 0 and tested with D-amphetamine in the ICSS paradigm on days 4, 14, 21, 28 and 41 after administration. Naltrexone plasma concentrations were determined for each amphetamine testing session using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In rats pretreated with naltrexone acutely, amphetamine-potentiated BSR did not differ from vehicle-pretreated rats on either day 1 or day 4 (25-30% decrease in LOR). In XR-NTX-pretreated rats, amphetamine-potentiated BSR was reduced by 64 and 70% on days 4 and 14, respectively, compared to placebo microsphere-treated controls. This effect dissipated by day 21. Naltrexone plasma concentrations were comparable across all treatment groups (14-30 ng/ml) on days 1, 4 and 14. In summary, an extended-release formulation of naltrexone results in significant attenuation of psychostimulant-enhanced BSR that is not observed with acute naltrexone.

Atomoxetine attenuates dextroamphetamine effects in humans.

BACKGROUND: Although preclinical studies support the contribution of the noradrenergic system activation in mediating the acute effects of amphetamines, these findings have not been followed up in clinical studies. OBJECTIVES: To examine the effects of atomoxetine, a norepinephrine transporter inhibitor, on subjective, physiological, and plasma cortisol responses to dextroamphetamine in 10 healthy volunteers. METHODS: Subjects were randomly assigned to a sequence of atomoxetine (40 mg/day) or placebo treatments each lasting for 4 days. On Day 4 of each treatment period, responses to a single 20 mg/70 kg dose of dextroamphetamine were assessed. RESULTS: Atomoxetine treatment attenuated dextroamphetamine-induced increases in systolic and diastolic blood pressure and plasma cortisol as well as the self-report ratings of "stimulated," "high," and "good drug effects." CONCLUSIONS: These findings are consistent with previous preclinical studies supporting the role of the noradrenergic system in mediating acute amphetamine responses. SCIENTIFIC SIGNIFICANCE: Atomoxetine's capacity to attenuate some of the physiological and subjective responses to dextroamphetamine supports its potential use for stimulant addiction.

Naltrexone attenuates the subjective effects of amphetamine in patients with amphetamine dependence.

Amphetamine abuse and dependence is a global health concern with a collateral increase in medical and social problems. Although some of the neurobiological mechanisms underlying amphetamine dependence and its devastating effects in humans are known, the development of rational and evidence-based treatment is lagging. There is evidence from preclinical studies suggesting that the endogenous opioid system plays a role in mediating some of the behavioral and neurochemical effects of amphetamine in a variety of controlled settings. In the present study we assessed the effects of naltrexone, an opioid antagonist (50 mg) on the subjective physiological and biochemical response to dexamphetamine (30 mg) in 20 amphetamine-dependent patients. Patients received naltrexone/amphetamine followed by placebo/amphetamine, 1 week apart in a randomized double-blind placebo-controlled design. The primary objective of the study was to evaluate the effect of pretreatment with naltrexone on the subjective response to amphetamine, using a Visual Analog Scale. The secondary objective was to investigate the effects of naltrexone on physiological and biochemical responses to amphetamine, as measured by changes in blood pressure, heart rate, skin conductance, and cortisol. Naltrexone significantly attenuated the subjective effects produced by dexamphetamine in dependent patients (p<0.001). Pretreatment with naltrexone also significantly blocked the craving for dexamphetamine (p<0.001). There was no difference between the groups on the physiological measures. The results suggest that the subjective effects of amphetamine could be modulated via the endogenous opioid system. The potential of naltrexone as an adjunct pharmaceutical for amphetamine dependence is promising.

Strain differences in lithium attenuation of d-amphetamine-induced hyperlocomotion: a mouse model for the genetics of clinical response to lithium.

Lithium attenuation of stimulant-induced hyperlocomotion is a rodent model that may be useful both to understand the mechanism of the therapeutic action of lithium and to develop novel lithium-mimetic compounds. To lay the foundation for future investigations into the neurobiology and genetics of lithium as a therapeutic agent, we studied the effect of lithium on d-amphetamine-induced hyperlocomotion in 12 (3 outbred) mouse strains. In our initial screening, mice received either (1) no drugs, (2) LiCl only, (3) d-amphetamine only, or (4) d-amphetamine and LiCl. Whereas there was no significant effect of LiCl alone on locomotion in any strain, there was a large degree of strain variation in the effects of LiCl combined with d-amphetamine. LiCl attenuated d-amphetamine-induced hyperlocomotion in C57BL/6J, C57BL/6Tac, Black Swiss, and CBA/J mice, whereas CD-1, FVB/NJ, SWR/J, and NIH Swiss mice, which were responsive to d-amphetamine, showed no significant effect of LiCl. d-Amphetamine-induced hyperlocomotion in the C3H/HeJ strain was increased by pretreatment with lithium. A subset of strains were treated for 4 weeks with lithium carbonate before the d-amphetamine challenge, and in each of these strains, lithium produced effects identical to those seen following acute administration. Strain responsiveness to lithium was not dependent upon the dose of either d-amphetamine or LiCl. Further, the results are not explained by brain lithium levels, which suggests that these behavioral responses to lithium are under the control of inherent genetic or other biological mechanisms specific to the effects of lithium on brain function.

Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity.

Currently available antipsychotic medications work primarily by antagonizing D2 dopamine receptors, thus raising intracellular cAMP levels. We hypothesized that intracellular stimulation of cAMP levels in the CNS would have similar effects to treatment with antipsychotic medication. To test this hypothesis, we studied the effect of an acute treatment of rolipram, an inhibitor of type 4 phosphodiesterases that degrade cAMP, on acoustic startle and prepulse inhibition (PPI) of the acoustic startle response in C57BL/6J mice known to exhibit poor PPI. PPI is disrupted in schizophrenia patients, and the ability of a drug to increase PPI in mice is predictive of antipsychotic efficacy. We show here that acute treatment with rolipram significantly increases PPI at doses that do not alter the acoustic startle response (lowest effective dose 0.66 mg/kg). In addition, rolipram (0.66 mg/kg) blocks the disruptive effects of amphetamine (10 mg/kg) on PPI. At a slightly higher dose (1.0 mg/kg), rolipram also induces catalepsy. Thus, phosphodiesterase-4 (PDE4) inhibition has many of the same behavioral effects as traditional antipsychotic medications. In contrast to traditional antipsychotics, these effects are achieved through alteration of an intracellular second messenger system rather than antagonism of neurotransmitter receptors. Given previous reports showing rolipram improves cognition, we conclude that PDE4 represents an important novel target for further antipsychotic drug development.

A gastrin-releasing peptide receptor antagonist blocks D-amphetamine-induced hyperlocomotion and increases hippocampal NGF and BDNF levels in rats.

The gastrin-releasing peptide receptor (GRPR) has emerged as a novel molecular target in neurological and psychiatric disorders, and previous animal studies suggest that GRPR antagonists might display cognitive-enhancing and antipsychotic properties. Hyperlocomotion produced by administration of D-amphetamine (D-AMPH) to rats has been put forward as a model of the manic phase of bipolar disorder (BD). In the present study, we examined the effects of a single systemic administration of the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095) on hyperlocomotion induced by a single systemic injection of D-AMPH in male rats. We also evaluated the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of rats treated with D-AMPH and RC-3095. Administration of RC-3095 at any of the doses used blocked D-AMPH-induced hyperlocomotion. Specific doses of RC-3095 increased the levels of NGF and BDNF in the dorsal hippocampus. Administration of D-AMPH did not affect NGF or BDNF levels by itself, but blocked the RC-3095 effects. The results suggest that GRPR antagonists might display anti-manic activity.

A low dose of aripiprazole attenuates the subject-rated effects of d-amphetamine.

Despite increased reports of amphetamine abuse and dependence, a putative pharmacotherapy has yet to be identified. In a previous study from our laboratory, 20 mg aripiprazole, an atypical antipsychotic that has partial agonist activity at D(2) receptors, attenuated many of the behavioral effects of d-amphetamine. Aripiprazole (20 mg) also impaired performance on a computerized version of the DSST when administered alone, indicating that the attenuation observed may have been functional as opposed to receptor mediated. The present experiment was conducted to determine whether a lower dose of aripiprazole (10 mg) could acutely attenuate the discriminative-stimulus, subject-rated, and physiological effects of d-amphetamine (2.5-15 mg) without impairing performance as measured with a computerized version of the DSST. The results of the present experiment indicate that 10 mg aripiprazole attenuated some abuse-related behavioral effects of d-amphetamine and was generally devoid of effects, including significant performance impairment, when administered alone. These findings suggest that 10 mg aripiprazole would be a reasonable starting dose for the treatment of stimulant abuse and dependence. Future research should examine the effects of chronic aripiprazole administration in combination with methamphetamine or cocaine.

Effects of the cannabinoid CB1 receptor agonist CP55,940 and antagonist SR141716A on d-amphetamine-induced behaviours in Cebus monkeys.

Several clinical studies have shown that alterations in the cannabinoid system in the brain may be associated with schizophrenia. Although evidence points towards an antipsychotic potential for cannabinoid antagonists, experimental studies have shown inconsistent behavioural effects of cannabinoid ligands within and across species. The aim of the present study was to explore these contradictory findings in a non-human primate model, predictive of antipsychotic efficacy in humans. The effects of the cannabinoid CB1 receptor antagonist SR141716A and the CB1 receptor agonist CP55,940 were explored in an d-amphetamine-based Cebus monkey model of psychosis. The monkeys were sensitive to extrapyramidal side effects (EPS), and the side-effect profiles of the drugs were explored as well. SR141716A (0.1, 0.25, 0.375, 0.5 and 0.75 mg/kg) and CP55,940 (0.0025, 0.005 and 0.01 mg/kg) were administered by subcutaneous injection alone and in combination with d-amphetamine (0.25mg/kg). SR141716A (0.1-0.5mg/kg) reduced d-amphetamine-induced arousal, while CP55,940 had no significant effect upon d-amphetamine-induced behaviours. No EPS were observed with either of these compounds. These data suggest that cannabinoid CB1 antagonists such as SR141716A may have limited antipsychotic potential in man as to positive symptoms. SR141716A administered alone induced anxiolytic-like behaviour, whereas administration of CP55,940 alone showed anxiogenic properties.

Design, synthesis, and evaluation of the antipsychotic potential of orally bioavailable neurotensin (8-13) analogues containing non-natural arginine and lysine residues.

Neurotensin (NT) and its active fragment NT(8-13) elicit behavioral responses typical of clinically used antipsychotic drugs when administered directly to the brain. However, limited peptide stability and oral bioavailability have prevented these compounds from being developed as relevant pharmaceuticals. Recently, our laboratory designed and studied a first-generation NT(8-13) derivative, KK13, that elicited key pharmacokinetic and behavioral responses typical of clinically used antipsychotic drugs when administered to rats parenterally. This compound was the basis for the rational design of a series of second-generation NT(8-13) analogues (KH1-KH30) studied in this paper. Initial screening of these analogues for CNS activity by monitoring hypothermia induction after peripheral administration defined several compounds (KH11, KH24, KH26, and KH28-KH30) that warranted further investigation. Each compound maintained binding affinity for NTR(1), however, only KH24, KH26, and KH28 (as well as KK13) elicited significant hypothermic responses after oral administration. Of these, KH28 demonstrated an oral activity 3-fold greater than any other analogue; hence it was further characterized in a series of rat behavioral assays. KH28 attenuated d-amphetamine induced hyperlocomotion, a hallmark of current clinically effective antipsychotic drugs, after both IP and oral administration. In addition, tolerance to the compound did not develop after repeated daily dosing, as measured by hypothermic induction as well as attenuation of d-amphetamine induced hyperlocomotion. Finally, KH28 did not produce catalepsy, a deleterious side-effect elicited by classical antipsychotic drugs. KH28 is considered to be an ideal compound for further development as a potential novel antipsychotic.

Atypical antipsychotic profile of flunarizine in animal models.

RATIONALE: Flunarizine is known as a calcium channel blocker commonly used in many countries to treat migraine and vertigo. Parkinsonism has been described as one of its side-effects in the elderly, which is in agreement with its recently characterized moderate D2 receptor antagonism. OBJECTIVES: To perform a pre-clinical evaluation of flunarizine as a potential antipsychotic. METHODS: We evaluated the action of orally administered flunarizine in mice against hyperlocomotion induced by amphetamine and dizocilpine (MK-801) as pharmacological models of schizophrenia, induction of catalepsy as a measure for extrapyramidal symptoms and impairment induced by dizocilpine on the delayed alternation task for working memory. RESULTS: Flunarizine robustly inhibited hyperlocomotion induced by both amphetamine and dizocilpine at doses that do not reduce spontaneous locomotion (3-30 mg/kg). Mild catalepsy was observed at 30 mg/kg, being more pronounced at 50 mg/kg and 100 mg/kg. Flunarizine (30 mg/kg) improved dizocilpine-induced impairment on the delayed alternation test. CONCLUSIONS: These results suggest a profile comparable to atypical antipsychotics. The low cost, good tolerability and long half-life (over 2 weeks) of flunarizine are possible advantages for its use as an atypical antipsychotic. These results warrant clinical trials with flunarizine for the treatment of schizophrenia.

Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat.

RATIONALE: Phencyclidine (PCP), a glutamate/N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to induce a range of symptoms similar to those of patients with schizophrenia, while D-amphetamine induces predominantly positive symptoms. Previous studies in our laboratory have shown that PCP can selectively impair the performance of an operant reversal-learning task in the rat. Furthermore, we found that the novel antipsychotic ziprasidone, but not the classical antipsychotic haloperidol, could prevent the PCP-induced deficit. OBJECTIVES: The aim of the present study was to validate the model further using the atypical antipsychotic clozapine and then to investigate the effects of lamotrigine, a broad-spectrum anticonvulsant that is known to reduce glutamate release in vitro and is able to prevent ketamine-induced psychotic symptoms in healthy human volunteers. A further aim was to compare effects of PCP and D-amphetamine in the test and investigate the effects of the typical antipsychotic haloperidol against the latter. METHODS: Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm. RESULTS: PCP at 1.5 mg/kg and 2.0 mg/kg and D-amphetamine at 0.5 mg/kg significantly and selectively impaired performance in the reversal phase of the task. The cognitive deficit induced by 1.5 mg/kg PCP was attenuated by prior administration of lamotrigine (20 mg/kg and 30 mg/kg) or clozapine (5 mg/kg), but not haloperidol (0.05 mg/kg). In direct contrast, haloperidol (0.05 mg/kg), but not lamotrigine (25 mg/kg) or clozapine (5 mg/kg), prevented a similar cognitive impairment produced by D-amphetamine (0.5 mg/kg). CONCLUSIONS: Our findings provide further data to support the use of PCP-induced disruption of reversal learning in rodents to investigate novel antipsychotic drugs. The results also provide evidence for different mechanisms of PCP and D-amphetamine-induced disruption of performance in the test, and their different sensitivities to typical and atypical antipsychotic drugs.

Attenuation of d-amphetamine-induced disruption of conditional discrimination performance by alpha-flupenthixol.

RATIONALE: Previous evidence suggests that manipulation of forebrain dopamine (DA) systems may impair the use of conditional information to inform goal-directed performance, and this may be related to impairments in the ability to use task-setting cues in schizophrenia. OBJECTIVE: To investigate, using the indirect DA agonist d-amphetamine and the D1/D2 receptor antagonist alpha-flupenthixol, the influence of DAergic manipulation on discrimination performance that requires the use of conditional information to inform goal-directed performance. METHODS: Both instrumental and Pavlovian conditional discriminations were employed in which rats learned to respond appropriately according to the presence of auditory conditional stimuli, and results from these experiments were contrasted with a control Pavlovian-instrumental transfer task. RESULTS: Experiment 1 showed a disruption of instrumental conditional discrimination performance by d-amphetamine at 1.5 mg/kg and attenuation of correct responding following 1.0 mg/kg. Disruption with both doses was observed in experiment 2 using a conditional discrimination based on Pavlovian, conditioned responding. Results from a control Pavlovian-instrumental transfer task (experiment 3) revealed that d-amphetamine (0.5, 1.0 and 1.5 mg/kg) did not have any detrimental effect on subjects' basic sensory, motor or motivational processes. Experiment 4 showed that d-amphetamine disruption of instrumental conditional discrimination was attenuated by pre-treatment with the D1/D2 receptor antagonist alpha-flupenthixol. CONCLUSION: These results demonstrate that tasks dependent on conditional relationships are highly sensitive to manipulation of DAergic systems.

Valproate attenuates dextroamphetamine-induced subjective changes more than lithium.

Dextroamphetamine administration in healthy controls produces a range of subjective and physiological effects, which have been likened to those occurring during mania. However, it is uncertain if these can be attenuated by lithium since conflicting results have been reported. To date there have been no previous studies examining the effects of valproate on dextroamphetamine-induced mood and physiological changes. The current study was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n=12), 900 mg lithium (n=9), or placebo (n=12) pre-treatment for 14 days. Subjective and physiological measures were then obtained prior to administration of a 25 mg dose of dextroamphetamine, and at two time points after administration. Differences in the response to dextroamphetamine were assessed between the three treatment groups. The results of this study show that pre-treatment with lithium only significantly attenuated dextroamphetamine-induced change in happiness, while valproate pre-treatment significantly attenuated the effects of dextroamphetamine on happiness, energy, alertness and on the diastolic blood pressure. These results suggest that lithium and valproate do not have the same mechanism of action on dextroamphetamine-induced changes, and this finding may relate to differences in their mechanism of action in mood disorders.

Dietary cadmium exposure attenuates D-amphetamine-evoked [3H]dopamine release from striatal slices and methamphetamine-induced hyperactivity.

Prolonged exposure to environmentally relevant amounts of CdCl2 results in cadmium accumulation in dopamine-rich brain regions, such as striatum. Exposure to these low levels of cadmium also diminishes cocaine-induced hyperactivity and conditioned reinforcement. The goal of the present study was to assess the effect of cadmium on amphetamine pharmacology. Direct application of cadmium (0.1-100 microM), within the concentrations reported in brain after chronic exposure, to preloaded rat striatal slices did not alter D-amphetamine-evoked [3H]dopamine release. To determine the effect of dietary cadmium exposure on amphetamines, rats received ad libitum access to diet containing CdCl2 (10 or 100 ppm) or to control diet for 30 days and then D-amphetamine-evoked [3H]dopamine release and methamphetamine-induced hyperactivity were measured. Dietary CdCl2 exposure produced a marked increase in cadmium blood and brain levels, approximate to environmental metal exposure. Dietary cadmium exposure was associated with decreased potency of D-amphetamine to evoke [3H]dopamine release. Cadmium-exposed rats were also less sensitive to the locomotor-activating effect of acute methamphetamine (0.3 or 1.0 mg/kg) injection. The present findings demonstrate that the presence of cadmium in brain is not sufficient for the inhibition of D-amphetamine-evoked dopamine release. This suggests that cadmium does not directly interfere with the mechanism of action for amphetamine pharmacology; rather, it suggests that long-term cadmium exposure induces a change in the number and/or function of striatal neurons.

Variable attenuation of amphetamine effects by lithium.

In an open study of 8 subjects, approximately half showed some attenuation of CNS stimulant effects of amphetamine after pretreatment with lithium. Two showed specific blockade of euphoria, with persistence of some CNS stimulant effects. In 3 subjects lithium did not appear to affect the response to amphetamine. Lithium caused significant attenuation of the amphetamine-induced increase in systolic blood pressure for the group as a whole.

Chronic blockade of neurotensin receptors strongly reduces sensitized, but not acute, behavioral response to D-amphetamine.

This study investigated the effect of a chronic blockade of neurotensin (NT) receptors on the sensitized behavioral response to amphetamine using a nonpeptide NT receptor antagonist, SR 48692. Rats received four injections of D-amphetamine (0.5 or 1 mg/kg, IP) every other day (day 1, 3, 5 and 7) and were then challenged with the same dose of amphetamine after a 6-day withdrawal (day 14) to establish the presence of locomotor sensitization. Daily administration of SR 48692 (1 mg/kg, IP) throughout the amphetamine regimen (day 1 to day 14) almost completely blocked the sensitized locomotor response to amphetamine without affecting stereotyped behaviors (experiment 1). The decreased amphetamine-induced sensitization in chronically SR 48692-treated rats did not appear to result from an influence on basal locomotor activity, as chronic SR 48692 treatment did not modify the spontaneous locomotor activity developed in response to mild stresses (experiment 2). Moreover, we showed that chronic pretreatment with SR 48692 (1 mg/kg, 14 daily IP injections) had no effect on the locomotor activation induced by a single IP administration of amphetamine (experiment 3). These data suggest that a sustained blockade of NT receptors considerably reduces the sensitized behavioral response to amphetamine without altering the acute effect of this psychostimulant or the locomotor activation induced by a mild stress. This ability of SR 48692 to specifically reduce the behavioral sensitization to amphetamine suggests that NT receptor antagonists could have potential clinical utility in the treatment of some psychiatric disorders.

A test of the predictive validity of animal models of schizophrenia based on phencyclidine and D-amphetamine.

Antipsychotic drugs can inhibit the effects of phencyclidine (PCP) and d-amphetamine (AMPH) in many rodent tests, but the effects are usually seen at doses that also affect vehicle-treated control rats, suggesting that the inhibition may be nonspecific. This study will attempt to test the predictive validity of these models based on the clinical observations that antipsychotics are not fully effective until after 2-3 weeks of administration in patients and that patients do not relapse immediately following abrupt withdrawal of medication. Haloperidol and clozapine were tested in rats after daily administration for 3 and 21 days in combination with vehicle or PCP (2.0 mg/kg) in the social interaction test, and with vehicle or AMPH (0.5 mg/kg) in standard activity cages. To separate acute from more long-lasting effects on the central nervous system (CNS) haloperidol and clozapine were tested with a short (45 or 30 min depending upon test) and a long (22-24 h) pretreatment time. The results demonstrated that haloperidol and clozapine following both 3 and 21 days of administration at the short pretreatment time inhibited the activity of vehicle-, PCP-, and AMPH-treated rats, whereas neither drug had consistent effects in any group at the long pre-treatment time. The data suggest that antipsychotics only inhibit PCP- and AMPH-induced behaviors in rodents by an acute drug-drug interaction, whereas any long-term effects of antipsychotic drug administration on the CNS cannot be revealed by PCP and AMPH in rodents.