Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex.

BACKGROUND: The increase in glutamate efflux in the prefrontal cortex by the psychotomimetic drugs phencyclidine (PCP) and ketamine may produce the dopaminergic and some of the behavioral effects of these drugs. Here, we examined whether antipsychotic drugs influence this increase. METHODS: The effect of haloperidol, clozapine or the 5-HT(2A) antagonist, M100907, on PCP-induced increase in cortical glutamate efflux was examined by microdialysis. Because previous studies had suggested that M100907 attenuates some behavioral effects of PCP, we also examined the effect of M100907 on PCP-induced cortical and accumbal dopamine activation while making concomitant measures of locomotion and stereotypy. RESULTS: Haloperidol, clozapine or M100907 did not significantly block hyperglutamatergic effects of PCP. M100907 was ineffective in inhibiting the dopaminergic and motoric effects of PCP. CONCLUSIONS: These results contrast previous findings with glutamatergic drugs, such as AMPA antagonists or group II metabotropic glutamate agonists, that blocked glutamatergic and motoric effects of PCP. Thus, the PCP glutamate activation model lacks predictive validity for conventional antipsychotics; however, this model may be useful for design of novel classes of drugs that target those symptoms of schizophrenia that are not generally treated with monoamine-based antipsychotics.     

The effects of intraperitoneally administered phencyclidine on the central nervous system: behavioral and neurochemical studies

The effects of intraperitoneally (IP) injected phencyclidine (phencyclohexyl piperidine; PCP) on the metabolism of dopamine (DA) and cholecystokinin-like immunoreactivity (CCK-LI) in the rat brain were investigated in connection with PCP-induced behavioral changes. The predominant behavior change elicited by 2.5 mg/kg PCP was locomotion, while with higher doses (5 and 10 mg/kg) sniffing, swaying and falling were observed in addition to the enhanced locomotor activity. Backpedaling and rotation were observed in 10 mg/kg PCP-treated rats. IP injection of PCP caused a dose-related increase in the levels of DA and 3,4-dihydroxy-phenylacetic acid (DOPAC) in the medial frontal cortex (MFC) and anterior cingulate cortex (ant.CC) without any changes in the nucleus accumbens (NAc) or striatum. CCK-LI in the MFC, ant.CC and NAc was decreased in a dose-dependent manner following IP injection of PCP. These findings support the evidence that PCP selectively activates the mesocortical DA systems. Furthermore, our results indicate a functional relationship between the mesocortical DA neurons and intrinsic CCK containing cortical neurons, and the change in the activity of the intrinsic CCK-containing cortical neurons in these two areas, perhaps due to an alteration in DA transmission, might be involved in behavioral changes after PCP injection.     

Phencyclidine (PCP): effects of acute and chronic administration on EEG activities in the rhesus monkey

Effects of acute and chronic administration of phencyclidine (PCP) on EEG activities and gross behavior were studied in monkeys with electrodes implanted in the brain. Administration of PCP (2.0 or 4.0 mg/kg i.v.) in monkeys produced a biphasic pattern of inhibition and excitation of behavior during 6-8 h observation period. The inhibitory phase appeared 1-3 min after PCP injection, and was uniquely characterized by high-voltage slow waves with delta waves (0.6-0.8 c/sec) in the parietal lobe and by those with theta waves (4-5 c/sec) in the occipital lobe and hippocampus during behavioral stupor. This inhibitory phase lasted 1-1.5 h, and subsequently, high-voltage fast wave with enhancement of theta waves and nystagmus appeared during behavioral arousal. Upon chronic PCP administration, the intensity and duration of the inhibitory phase progressively decreased, while the effects of the excitatory phase increased. The results suggest that PCP administration in monkeys produces a biphasic pattern of inhibitory and excitatory effects and upon chronic administration a tolerance develops to the inhibitory effect while an augmentation of the excitatory effect develops.     

Subchronic treatment with phencyclidine in adolescence leads to impaired exploratory behavior in adult rats without altering social interaction or N‐methyl‐D‐aspartate receptor binding levels

Although both the onset of schizophrenia and human phencyclidine (PCP) abuse typically present within the interval from adolescence to early adulthood, the majority of preclinical research employing the PCP model of schizophrenia has been conducted on neonatal or adult animals. The present study was designed to evaluate the behavioral and neurochemical sequelae of subchronic exposure to PCP in adolescence. Male 35–42‐day‐old Sprague Dawley rats were subcutaneously administered either saline (10 ml · kg^?1) or PCP hydrochloride (10 mg · kg^?1) once daily for a period of 14 days (n = 6/group). The animals were allowed to withdraw from treatment for 2 weeks, and their social and exploratory behaviors were subsequently assessed in adulthood by using the social interaction test. To examine the effects of adolescent PCP administration on the regulation of N‐methyl‐D‐aspartate receptors (NMDARs), quantitative autoradiography was performed on brain sections of adult, control and PCP‐withdrawn rats by using 20 nM ³H‐MK‐801. Prior subchronic exposure to PCP in adolescence had no enduring effects on the reciprocal contact and noncontact social behavior of adult rats. Spontaneous rearing in response to the novel testing arena and time spent investigating its walls and floor were reduced in PCP‐withdrawn animals compared with control. The long‐term behavioral effects of PCP occurred in the absence of persistent deficits in spontaneous locomotion or self‐grooming activity and were not mediated by altered NMDAR density. Our results document differential effects of adolescent PCP administration on the social and exploratory behaviors of adult rats, suggesting that distinct neurobiological mechanisms are involved in mediating these behaviors. © 2014 Wiley Periodicals, Inc.     

Effect of repeated administration of prolactin releasing peptide on feeding behavior in rats

Prolactin releasing peptide (PrRP) has been reported to reduce food intake in rats. We tested the effect of i.c.v. administration of PrRP-31 on food intake in both food deprived and free-feeding rats. We did not find any effect of PrRP-31 on food intake after single injections of up to an 8-nmol dose, but observed a marked decrease in food intake and body weight in rats that received a repeated twice daily administration of 8 nmol of PrRP-31. This effect was associated with an adverse behavioral pattern, indicating that the repeated high doses of the peptide caused non-specific effects inducing anorexia. We also tested several other behavioral parameters like locomotion and exploratory time, grooming and resting time, using lower doses of PrRP that did not cause the adverse behavior. Moreover, we carried out locomotor and sensory motor activity tests at the doses that exerted the most pronounced effect on the food intake. None of these tests suggested any specific behavioral effect of PrRP. We conclude that the behavioral pattern induced by PrRP is likely to be different from those induced by many other neuropeptides affecting food intake in rats.     

A primate model of schizophrenia using chronic PCP treatment

To establish a primate animal model of schizophrenia with negative symptoms, the behavioral effects of chronic phencyclidine (PCP) and additional acute methamphetamine (MAP) administration were investigated in six monkeys. The results indicate that chronic PCP treatment induced a significant decrease in all categories of social behaviors, and that the chronic PCP monkeys also spent less time in proximity to other monkeys than the control monkeys. Acute MAP injection to the chronic PCP monkeys exacerbated the behavioral effects of PCP. The results suggest that these monkeys can be used as a primate model of schizophrenia with negative symptoms.     

Candidate mechanisms underlying phencyclidine-induced psychosis: an electrophysiological behavioral, and biochemical study

The central effects of phencyclidine (PCP) were investigated using electrophysiological, biochemical, and behavioral techniques. PCP produced depressions of neuronal firing of several brain regions when applied locally or parenterally. At the cerebellar locus coeruleus Purkinje neuron pathway PCP produced depressions of spontaneous firing. Use of lesion techniques and receptor antagonists revealed that at this synapse PCP acted as an agonist, i.e., an indirect sympathomimetic in that it caused release and or blocked reuptake of norepinephrine. PCP also produce alterations in behavioral measures such as stereotypy and rotarod performance. In addition PCP, like norepinephrine, produced increases in cyclic AMP levels in cerebellar slices. Inhibition of central neuron firing, and alterations in behavior were correlated with brain and blood levels of PCP. Many effects of PCP were antagonized by neuroleptics. It can be concluded that PCP has profound effects on several indices of central neuron function and such changes can be related to the psychosis and other effects of this drug.     

Phencyclidine and MK-801: a behavioral and neurochemical comparison of their interactions with dihydropyridine calcium antagonists

The impairment of rotarod ability and the convulsive activity of phencyclidine (PCP) and MK-801 were compared in male CD-1 mice. The putative interaction between nifedipine and PCP and MK-801 on these behavioral measurements was also quantitated and compared. MK-801 produced a dose dependent inhibition of rotarod ability with an ED50 of 0.5 mg/kg. Nifedipine potentiated the impairment of rotarod ability by MK-801. Both PCP and MK-801 produced convulsive behavior in mice which was characterized by jumping and wild running fits; the CD50 for MK-801 was 1.3 mg/kg. Nifedipine dose dependently inhibited the convulsions associated with MK-801 and PCP. PCP but not MK-801 increased [3H]nitrendipine binding to dihydropyridine (DHP) binding sites on mouse brain membranes. MK-801 blocked the effects of PCP on [3H]nitrendipine binding. These findings suggest that MK-801 is a potent PCP-like drug which interacts with nifedipine and neuronal DHP binding sites. Nifedipine's reduction of the hyperactivity and convulsions elicited by MK-801 may be of importance in the eventual development of MK-801 as an antiischaemic and anticonvulsant drug.     

Biochemical and behavioral effects of sigma and PCP ligands

The purpose of this study was to examine the binding and behavioral effects mediated by PCP and sigma receptors in the rat. From the radioreceptor assays, it was possible to characterize two binding sites that interact with PCP and sigma ligands. The two sites, a PCP and sigma receptor, could be differentiated based on drug selectivity and potency. In the behavioral assays, MK-801, which bound preferentially to the PCP receptor, and 1,3-di-0-tolylguanidine, which bound preferentially to the sigma receptor, induced sniffing, rearing, circling, backpedaling, and weaving behavior. These results indicate that there are distinct PCP and sigma receptors that are both involved in mediating stereotyped behavior and ataxia in the rat.     

The role of glucocorticoid receptor-dependent activity in the amygdala central nucleus and reversibility of early-life stress programmed behavior

Early-life stress (ELS) leads to sustained changes in gene expression and behavior, increasing the likelihood of developing a psychiatric disorder in adulthood. The neurobiological basis for the later-in-life psychopathology is relatively unknown. The current study used a mouse model of ELS, achieved by daily maternal separations during the first 2 weeks of postnatal life, to test the role of amygdalar glucocorticoid receptor (GR) function in mediating the persistent increase in risk-taking behaviors. ELS produced a decrease in GR mRNA in the brain, with a notable reduction in the amygdala that was associated with sustained alterations in anxiety, fear and sociability-like behaviors. Lentiviral-mediated restoration of the GR mRNA deficit, specifically within the adult central nucleus of the amygdala (CeA), reversed the enduring changes in anxiety and social behavior after ELS. These results provide evidence of lasting changes in CeA GR neural circuitry following ELS and suggest a mechanistic role for GR-regulated processes in the CeA in mediating the lifelong maladaptive behaviors of ELS. We demonstrate that the long-lasting behavioral effects of ELS are reversible later in life and implicate the involvement of CeA GR-dependent activity in the sustained dysregulation of emotion following ELS.     

The effects of serotonergic stimulation on hippocampal and neocortical slow waves and behavior

The effect of central serotonergic stimulation on hippocampal and neocortical electrical activity and behavior was studied in freely moving rats by administering: (a) tranylcypromine followed by tryptophan, (b) fluoxtine followed by 5-hydroxytryptophan, or (c) p-chloroamphetamine alone. In all rats, scopolamine-resistant hippocampal thytmical slow activity (RSA), thought to be dependent on brain serotonin, maintained its normal relation to behavior, occuring in close correlation with Type 1 behaviors (postular changes, turning of the head, walking). This RSA was generally absent during stereotyped behavior (head weaving, forepaw treading, hindlimb splaying and tremor). Scopolamine-resistant neocortical low-voltage fast activity (LVFA), also thought to be dependent on brain serotonin, was present during Type 1 behaviors and also during stereotyped behavior.Most rats developed a full stereotyped behavior syndrome had behavioral and electrocortical seizures which were associated with a reduction in the amplitude of hippocampal activity. These seizures were suppressed by methylsergide or benserazide. Metergoline (and methylsergide to a lesser extent) suppressed the stereotypic behaviors of the serotonin syndrome, resulting in a striking increase in the locomotion caused by central serotonergic stimulation. Such locomotion was accompanied by RSA and LVFA. It was concluded that increased serotonergic activity in the CNS causes an increase in motor activity and a correlated increase in scopolamine-resistant hippocampal RSA and scopolamine-resistant neocortical LVFA and suggested that metergoline blocks serotonin receptors mediating stereotyped behaviors, thereby permitting the expression of serotonin-mediated locomotion.     

Alterations in striatal dopamine overflow during rotational behavior induced by amphetamine,phencyclidine, and MK-801

Rats lesioned unilaterally in the medial forebrain bundle with 6-OHDA rotated ipsilateral to the lesion following injections of amphetamine, phencyclidine (PCP), and MK-801. Concurrent measurement of striatal dopamine (DA) in the intact striatum with in vivo microdialysis revealed a dissociation between rotational behavior and alterations in DA overflow induced by the three drugs. Amphetamine produced robust ipsilateral rotational behavior and a substantial elevation in striatal DA (∼130% increase at asymptote). PCP produced comparable increases in rotational behavior, but only ∼30% increase in striatal DA. MK-801 also had a comparable behavioral effect but failed to alter DA overflow in the intact striatum. Since MK-801, a noncompetitive NMDA antagonist which does not enhance extracellular dopamine in the striatum, is able to produce ipsilateral rotational behavior in rats with unilateral nigrostriatal lesions, it is likely that the effects of PCP may also be determined predominantly through NMDA blockade in this model. Synapse 26:218–224, 1997. © 1997 Wiley-Liss Inc.     

Increase in spontaneous motor activity following infusion of neurotensin into the ventral tegmental area

Microinjection of neurotensin (NT) into the ventral tegmental area (VTA) of the rat produced a dose-dependent increase in spontaneous motor activity. The NT-induced hyperactivity consisted of an increase in exploratory behaviors, such as locomotion, rearing and sniffing, and a decrease in sleep or resting. The structural specificity of this response was demonstrated by microinjecting NT analogues and endogenous neuropeptides into the VTA. The fact that high levels of immunoreactive NT have been demonstrated in the VTA indicates that the observed behavioral effects may reflect an underlying physiological action by endogenous NT.     

Cholinergically mediated reduction of locomotor activity from the basal forebrain of the rat

Carbachol when injected into the basal forebrain alters spontaneous motor behavior and usually decreases locomotion. However, the extent of the brain area producing this effect has not yet been determined. The goal of the present study was to use quantitative mapping of injection sites to further localize the effect of carbachol on spontaneous locomotion of rats. The distance travelled by an animal and the time spent moving were simultaneously measured before and after injection of carbachol or saline into 96 sites in the basal forebrain. Each site was injected with 1.0 microgram (5.47 nmol) of carbachol, a dose close to ED50, in a volume of 0.2 microliter. A decrease in spontaneous locomotion was obtained as a result of injections of carbachol into the preoptic and anterior hypothalamic areas, particularly into the medial preoptic nucleus and the latero-anterior hypothalamic nucleus. The area from which a consistent decrease in spontaneous locomotion was obtained was surrounded by an area producing an increase in locomotion with a narrow zone of overlap. This decrease in locomotion was dose dependent and reversed by atropine. The results indicate that both the decreasing and increasing effects of carbachol on locomotion are anatomically specific and that the decreasing effects can be elicited from a limited forebrain area. It is suggested that muscarinic cholinergic mechanisms in the basal forebrain may be involved in the pathogenesis of neural dysfunction associated with locomotor activity in man.     

A comparison of CNS stimulants with phencyclidine on dopamine release using in vivo voltammetry

Phencyclidine (PCP) produces some neurochemical and behavioral effects in rats similar to those produced by the indirectly acting dopamine (DA) agonists amphetamine and amfonelic acid. In view of these findings, the effects of PCP, d-amphetamine and amfonelic acid on the release of DA in the rat striatum were examined by in vivo voltammetry. Drug effects on DA release were determined using newly developed electrodes selective for catecholamines. PCP (5 and 10 mg/kg IP) produced a dose-dependent decrease in the electrochemical signal that lasted for approximately 4 hr. In contrast, d-amphetamine (2.5 mg/kg, IP) and amfonelic acid (5.0 mg/kg, IP) both caused marked increases in electrochemical signals. The data provide evidence that PCP at the doses tested alters dopaminergic neurotransmission in a manner different from that of amphetamine and the non-amphetamine central nervous system stimulants by decreasing DA release from dopaminergic nerve terminals.     

Contents of volume 111

The effects of sex differences and hormonal factors on the locomotor alterations following intrastriatal injections of quinolinic acid (QA) and the ability of fetal striatal transplants to reverse those effects were examined. Male, female, or ovariectomized female rats received bilateral injections of 150 nmol QA or vehicle into the striatum. Using a multidimensional analysis of spontaneous nocturnal locomotor behavior, a significant increase in locomotion was observed in female but not male or ovariectomized female rats. The increases in activity observed in the lesioned females were attenuated at 6 and 10 weeks following transplantation of rat fetal (E17) striatal tissue into the lesioned striata. Transplanted striatal tissue had no effect on locomotion in male or ovariectomized female rats. Cytochrome oxidase histochemistry revealed that QA produced a marked loss of metabolic activity in regions exhibiting cell loss. Within these areas there was a marked loss of striatal neurons including those reactive for NADPH diaphorase. Despite the sex-related differences in QA-induced locomotion, there were no apparent differences in the extent of striatal pathology or survival of the grafts in any of the groups receiving QA. These experiments demonstrate a sex-dependent dissociation between the behavioral and neurobiological consequences of QA and suggest that sex and hormonal variables play an important role in the locomotor changes following excitotoxic-induced striatal damage.     

Chronic phencyclidine increases NMDA receptor NR1 subunit mRNA in rat forebrain

The present study was designed to determine whether the sensitization of locomotor activity that results from chronic phencyclidine (PCP) administration is associated with altered NMDA receptor function or mRNA in rat brain. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once daily for 5 days. After withdrawal for 72 hr, challenge with 3.2 mg/kg PCP (i.p.) revealed a significant sensitization to the locomotor activating effect of PCP. In situ hybridization analysis with an oligonucleotide probe complementary to the mRNA encoding the NR1 subunit of the NMDA receptor demonstrated that chronic PCP treatment resulted in a marked increase in NR1 subunit mRNA in the forebrain. Quantitative image analysis revealed a significant increase in the labeling of NR1 mRNA in the olfactory tubercle, piriform cortex, frontal cortex, and anterior striatum. However, no significant difference between PCP and saline-treated rats was found in the hippocampus or cerebellum. In a parallel study, possible functional alterations in the NMDA receptor were assessed by measuring NMDA-stimulated release of [3H]DA from slices of the olfactory tubercle and piriform cortex. NMDA-stimulated release was not affected by chronic PCP treatment, but the inhibition of this release by PCP, 7-chlorokynurenic acid (7-CK), and DL-2-amino-5-phosphovaleric acid (AP-5) was significantly diminished by chronic PCP. This suggests that the behavioral plasticity associated with chronic PCP may be related to an altered subunit stoichiometry of NMDA receptors in selective forebrain regions.     

Effect of MS-153 on the development of behavioral sensitization to stereotypy-inducing effect of phencyclidine

The present study examined the effects of a novel compound, MS-153 [(R)-(-)-5-methyl-1-nicotinyl-2-pyrazoline], which has an ability to enhance glutamate uptake and inhibit glutamate release, on the development of behavioral sensitization to phencyclidine (PCP). MS-153 (10 and 100 mg/kg) enhanced stereotypy induced by a single injection of PCP (7.5 mg/kg). Repeated administration of PCP (20 mg/kg, once every day for 5 days) enhanced stereotypy-inducing effects of PCP (7.5 mg/kg) when tested 4 days after the withdrawal from the repeated PCP treatment, indicating the development of behavioral sensitization. MS-153 given 60 and 120 min after the PCP treatments blocked the development of behavioral sensitization to stereotypy-inducing effects of PCP. These results suggest that the attenuation of glutamatergic neural transmission enhances acute effect of PCP, but in contrast, blocks the behavioral sensitization to PCP.     

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

In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist, would cause a long-lasting behavioral sensitization associated with neuronal toxicity. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP. Following assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microscopy or terminal dUTP nick-end labeling (TUNEL). In study I, PCP challenge produced a much more robust and long-lasting increase in locomotor activity in rats chronically treated with PCP than in those chronically treated with saline. In study II, clozapine pretreatment blunted the degree of sensitization caused by PCP. In study I, a marked increase in TUNEL-positive neurons was found in layer II of the olfactory tubercle and piriform cortex of rats chronically treated with PCP. Many of these neurons had crescent-shaped nuclei consistent with apoptotic condensation and margination of nuclear chromatin under the nuclear membrane. Acute PCP had no effect. Electron microscopy revealed that PCP caused nuclear condensation and neuronal degeneration consistent with apoptosis. Cell counts in layer II of the piriform cortex revealed that chronic PCP treatment resulted in the loss of almost 25% of the cells in this region. However, an increase in glial fibrillary acidic protein (GFAP)-positive cells in the molecular layer suggests that this neurotoxicity also may involve necrosis. In study II, the PCP-induced neuronal degeneration was essentially completely abolished by clozapine pretreatment. This pattern of degeneration was found to coincide with the distribution of the mRNA of the NR1 subunit of the NMDA receptor. The relevance of these data to a PCP model of chronic NMDA receptor hypofunction is discussed. J. Neurosci. Res. 52:709–722, 1998. © 1998 Wiley-Liss, Inc.     

Behavior characteristics of children during the first year of kindergarten attendance

The field research reported in this paper was intended to detect changes occurring in the early behavioral repertoire of children during their first exposure to the classroom environment. Fourteen kindergarten children were observed during structured classroom activities in their first and seventh month of school attendance. Behaviors were videotaped and analysed according to a behavior catalogue which covered six broad areasvisual, facial, head, upper limbs, postures and locomotion. The analysis showed that school experience is related to an increase in peer-oriented and work behavior, while teacheroriented behaviors tend to decrease, along with a reduction in periods of inactivity and aimless movements. These results and some detected sex and age differences are discussed in terms of environmental effects and developmental tendencies.