Phencyclidine disturbs relational memory in the transitive inference task.

Transitive inference, that is, the ability to infer relationships among stimuli that are only indirectly associated, is impaired in schizophrenic patients and in rats with lesions of the prefrontal cortex. Symptoms of schizophrenia can be pharmacologically modeled by administration of the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP). Here, a subchronic administration of PCP (2.5 mg/kg for 5 days) to well-trained rats impaired the subsequent transitive inference judgment; the effect was observed 3 days, but not 10 days after the last dose. These results support the findings showing that PCP administration impairs cognitive domains specifically affected in schizophrenia in addition to mimicking the 'positive' and 'negative' symptoms of the disorder.

Detrimental effect of postnatal blockade of N-methyl-D-aspartate receptors on sensorimotor gating is reversed by neuroleptic drugs.

Postnatal hypofunction of N-methyl-D-aspartate (NMDA) receptors leads to several behavioral deficits in adult rats resembling deficits typical of schizophrenia-like deficits of sensorimotor gating. Thus far, it is not known whether the above disruptions are sensitive to neuroleptic drugs. In order to verify the above model in pharmacological terms, we investigated whether deficits in the sensorimotor gating evoked by administration of NMDA receptor antagonists in the postnatal period is sensitive to neuroleptic drugs. We also investigated whether such treatment evoked alterations in the expression of dopamine D(1), D(2) and D(3) receptors in the nucleus accumbens, a key structure for dopamine-dependent alterations in sensorimotor gating. CGP 40116, a competitive antagonist of NMDA receptors was given in doses of 1.25 mg/kg on days 1, 3, 6 and 9; 2.5 mg/kg on days 12, 15 and 18; and 5 mg/kg on day 21 (all injections were sc). The efficacy of sensorimotor gating was tested on rats at the age of 60 days using a prepulse-induced inhibition of the startle reflex. In order to measure the expression of dopamine D(1), D(2) and D(3) receptors, we used quantitative autoradiography and tritiated ligands i.e. [(3)H]-SCH 23390, [(3)H]-Spiperone and [(3)H]-7-OH-DPAT, respectively. Haloperidol (0.1 mg/kg, sc), risperidone (1.0 mg/kg, sc) and clozapine (2.5 mg/kg, sc) reversed deficits of sensorimotor gating observed in adult rats evoked by the postnatal administration of CGP 40116. We also observed enhanced density of dopamine D(3), but not D(1) and D(2) receptors in the nucleus accumbens of CGP40116 treated rats. It is concluded that models of cognitive dysfunction, typical for schizophrenia based on postnatal administration of NMDA receptor antagonists, are sensitive to neuroleptic drugs and possibly not dependent on alteration in the density of dopaminergic receptors.

Clinical/Therapeutic Approaches for Cannabinoid Ligands in Central and Peripheral Nervous System Diseases: Mini Review.

OBJECTIVE: Cannabinoids, the components of Cannabis sativa Linnaeus, interact with CB1 and CB2 receptors, which are located both in the central nervous system and in the periphery and thus may exert a widespread biological activity in the body. The main medicinal properties of cannabinoids include analgesic, anti-inflammatory, antitumor, appetite stimulation, antiemesis, and muscle relaxation effects. This mini review aims to explore existing clinical trials that investigated the use of cannabinoids in diseases affecting the nervous system. METHODS: We reviewed recent studies of cannabinoid-based therapy for disorders affecting central and peripheral nervous system in human subjects. RESULTS: There is evidence that cannabinoid-based drugs may effectively control some symptoms associated with nervous system dysfunction, especially various types of pain and neurologic disorders, although studies are limited. CONCLUSIONS: The efficacy of cannabinoid drugs in the treatment of nervous system diseases should be verified in future large-scale randomized clinical trials.

Alterations in the dendritic morphology of prefrontal pyramidal neurons in adult rats after blockade of NMDA receptors in the postnatal period.

The present study assessed whether the blockade of NMDA receptors in the postnatal period, used to model the symptoms of schizophrenia altered morphology of pyramidal neurons in the medial prefrontal cortex of rats. CGP 40116, an antagonist of NMDA receptors, was given postnatally (days 1-21 after birth). The analysis of the morphology of pyramidal neurons visualized by the Golgi-Cox technique revealed that the exposure to an antagonist of NMDA receptors in the postnatal period diminished the length of basilar dendrites, while that of apical dendrites remained unchanged. The number of dendritic branches and the spine density remained unchanged. It is concluded that the blockade of NMDA receptors in the postnatal period only partially models morphological changes in pyramidal neurons of the medial prefrontal cortex, which are observed in some cases of schizophrenia.

The effect of 'binge' cocaine administration on the expression of cyclin-dependent kinase 5 and its activator p35 in various regions of rat brain.

The present study was aimed at determining whether the administration of cocaine in 'binge' pattern regimen that evoked tolerance to the locomotor stimulant effects of cocaine also influenced the expression of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in the amygdala, medial prefrontal cortex, nucleus accumbens septi and caudate-putamen. Western blot techniques revealed that acute and repeated 'binge' cocaine decreased expression of the Cdk5 protein in the amygdala. In the medial prefrontal cortex, only exposure to repeated 'binge' cocaine decreased the content of the Cdk5 protein. 'Binge' cocaine administration also altered the expression of Cdk5 activator p35 protein. In the amygdala, only repeated 'binge' cocaine decreased the expression of p35, while in the medial prefrontal cortex, a decrease was observed after acute and repeated 'binge' cocaine exposure. In neither the nucleus accumbens septi nor the caudate-putamen acute or repeated 'binge' cocaine modified the expression of Cdk5 and p35. The above data indicate that in contrast to sensitizing doses of cocaine, a single and repeated binge of cocaine, which evoked tolerance to its locomotor stimulant effects, decreases expression of Cdk5 and p35 and possibly decreases the efficacy of neurotransmission or induces brain plastic changes regulated by Cdk5 and its activator p35.

Acute and repeated administration of cocaine differentially regulates expression of PSA-NCAM-positive neurons in the rat hippocampus.

Recent data indicating that addictive substances are able to alter brain plasticity and its morphology inclined us to determine whether acute and chronic cocaine administration could modify the expression of a polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus of the rat hippocampus. Alterations in the PSA-NCAM expression are known to effect a variety of neuroanatomical rearrangements in the brain structure. Cocaine was administered acutely (15 mg/kg, i.p.) or repeatedly (15 mg/kg, i.p. once a day for five consecutive days). The number of PSA-NCAM immunopositive cells was determined at six time points after cocaine treatment: 6 h and 1, 2, 4, 6, and 10 days (both in acute and repeated treatment). It was found that a single injection of cocaine induced a time-dependent decrease in the number of PSA-NCAM cells in the dentate gyrus. The decrease was observed on day 1 after cocaine treatment and lasted for at least 6 days. In contrast, an increase in the number of PSA-NCAM-positive cells in the dentate gyrus was observed 2 and 4 days after the last dose of repeated cocaine. It is concluded that cocaine can evoke long-lasting changes in the PSA-NCAM protein expression in the dentate gyrus and that the direction of cocaine-induced PSA-NCAM changes depends on the regimen of cocaine administration. It is postulated that cocaine may have impact on hippocampal plasticity and subsequent processes that are controlled by plastic changes in the hippocampal structure.

Working memory deficits and alterations of ERK and CREB phosphorylation following withdrawal from cocaine self-administration.

BACKGROUND: The mechanisms underlying memory functions during withdrawal from the chronic drug use are poorly understood. METHODS: We assessed learning and spatial working memory using the delayed alternation assay (T-maze) in rats, previously subjected to cocaine self-administration. The T-maze training was conducted 1-5 weeks after cocaine cessation; working memory efficacy was assessed at 5-8 weeks of drug withdrawal. After behavioral training and testing, the rats were sacrificed and the levels of p-CREB/CREB and p-ERK2/ERK2 in several brain areas were measured. The same molecular assessment was performed in rats with cocaine injections, but forced to drug abstinence in home cages. RESULTS: After 5 weeks of cocaine withdrawal from self-administration, a significant impairment of working memory under increased working memory load (inter-trial delay extended to 30s), with no changes at baseline conditions (inter-trial delay 10s), was noticed. Neither acquisition phase nor working memory performance measured 6-8 weeks after the last drug intake differed between cocaine or saline pretreated rats. Upon T-maze training and 8-week withdrawal, cocaine-pretreated rats had higher levels of p-CREB/CREB in prefrontal cortex and dorsal striatum and lower in hippocampus compared to saline rats. Increased levels of p-ERK2/ERK2 were observed in dorsal striatum, hippocampus and decreased in nucleus accumbens. In cocaine-pretreated caged rats no changes in p-CREB/CREB levels were observed, while ERK2 levels either decreased (frontal cortex) or increased (nucleus accumbens). CONCLUSION: Our results suggest that cocaine self-administration results in cognitive impairments and alterations in ERK/CREB signaling pathway long after discontinuation of drug use.

8-OHDPAT-induced disruption of prepulse inhibition in rats is attenuated by prolonged corticosterone treatment.

The present study investigated the impact of acute and repeated administrations of corticosterone (10 mg/kg, twice daily, for 7 days) on serotonin (5-HT)(1A) receptor function, density and expression. The effect on 5-HT(1A) receptor function was assayed in rats by assessing the corticosterone-induced modulation of disruption of prepulse inhibition (PPI) of acoustic startle response induced by 8-OHDPAT, a 5-HT(1A) receptor agonist. Our experiments revealed that repeated but not acute treatment with corticosterone attenuated the 8-OHDPAT-evoked disruption of PPI without having any effect on PPI or startle amplitude alone. Chronic corticosterone treatment modulated also the neuronal activity of serotonergic pathways in the brain decreasing the level of 5-HIAA in the raphe nuclei and increasing both 5-HT and 5-HIAA levels in the hippocampus. Nevertheless, the effects of 8-OHDPAT on 5-HT metabolism were not changed by corticosterone. However, 5-HT(1A) receptor binding in the ventral hippocampus and entorhinal cortex but not in the raphe nuclei was decreased after chronic corticosterone treatment. It is concluded that chronically elevated corticosterone level is capable of inducing functional desensitization of 5-HT(1A) receptors which is paralleled by decreases in the 5-HT(1A) receptor binding in the ventral hippocampus and entorhinal cortex, the brain structures shown to be engaged in the regulation of PPI. Alterations in 5-HT(1A) receptors may be one of important mechanisms by which glucocorticoids/stress influence various psychiatric conditions.

Prolonged corticosterone treatment alters the responsiveness of 5-HT1A receptors to 8-OH-DPAT in rat CA1 hippocampal neurons.

Hippocampal 5-HT(1A) receptors have been shown to be suppressed by glucocorticoids in a variety of animal studies, however the molecular mechanism and the functional meaning of this effect are still not well understood. The present study was designed to investigate the impact of repeated administration of corticosterone (10 mg/kg s.c. twice daily for 7 days) on the functional consequences of 5-HT(1A) receptor stimulation measured electrophysiologically in hippocampal slices. Additionally, the effects of corticosterone on 5-HT(1A) receptor binding and on receptor mRNA levels in the hippocampus were studied. Prolonged, but not acute treatment with corticosterone attenuated (+/-)-8-hydroxy-2-di- N-propylamino)tetralin hydrobromide (8-OH-DPAT)-induced inhibition of population spikes, and 8-OH-DPAT-induced hyperpolarization in rat CA1 hippocampal neurons. Chronic, but not acute treatment with corticosterone also decreased 5-HT(1A) receptor binding in the CA1 region (in the ventral part only) and the dentate gyrus. A single dose of corticosterone increased [(3)H]8-OHDPAT binding in the dentate gyrus and in the CA3 and CA4 hippocampal regions. Only acute, but not prolonged treatment with corticosterone decreased the level of 5-HT(1A) receptor mRNA in the CA1 region and dentate gyrus of the hippocampus. 5-HT turnover in the hippocampus was not influenced by chronic corticosterone. It is concluded that a chronically elevated level of corticosterone can induce functional desensitization of 5-HT(1A) receptors in the CA1 area of the hippocampus, although this effect is not always followed consequently by decreases in 5-HT(1A) receptor synthesis in this or other areas of the hippocampus.

Different pattern of brain c-Fos expression following re-exposure to ethanol or sucrose self-administration environment.

Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behavior and lead to relapse to heavy drinking. The aim of the present study was to identify brain regions activated by alcohol (ethanol)-related stimuli in Wistar rats trained to lever press for 8% ethanol solution in operant self-administration cages. Ethanol self-administration was stabilized in a maintenance phase, which lasted for 30 days. c-Fos protein expression was used as a marker of neuronal activation.Re-exposure to ethanol self-administration environment after 30-day but not after 24-h abstinence increased the number of Fos-positive nuclei in the thalamic paraventricular nucleus, granular insular cortex and medial prefrontal cortex. In general, no differences were found in c-Fos protein expression between the rats allowed to self-administer alcohol and the subjects exposed only to alcohol-related stimuli. In contrast, no increase in c-Fos immunoreactivity was observed in rats trained to lever press for sucrose solution and exposed to sucrose-related environmental stimuli after 30-day abstinence. Taken together, these results suggest that at least some thalamo-cortical circuits become more responsive to ethanol-paired stimuli after prolonged abstinence and that ethanol- and sucrose-seeking behavior may be regulated by partially different neural mechanism(s).

Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats.

RATIONALE: Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits. OBJECTIVE: We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test. RESULTS: MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25-1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit. CONCLUSION: The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs.

The 5-hydroxytryptamine (serotonin) receptor 6 agonist EMD 386088 ameliorates ketamine-induced deficits in attentional set shifting and novel object recognition, but not in the prepulse inhibition in rats.

Preclinical data suggest that the 5-hydroxytryptamine (serotonin) 6 (5-HT6) receptor may be a potential target for the development of new therapies for treating cognitive dysfunctions in schizophrenia and other central nervous system disorders. Recent evidence indicates that not only blockade but also activation of 5-HT6 receptors exerts procognitive effects. Nevertheless, little is known about the potential efficacy of 5-HT6 receptor agonists in models of schizophrenia-like cognitive deficits. The aim of the present study was to evaluate the effects of the 5-HT6 receptor agonist, EMD 386088, on the ketamine-induced deficits in the attentional set-shifting task (ASST), novel object recognition (NOR) task and prepulse inhibition (PPI) task in rats. Acute administration of EMD 386088 (2.5 and 5 mg/kg, intraperitoneally) to Sprague-Dawley rats reversed the deficit in the ASST induced by repeated ketamine administration. Moreover, the ketamine-induced deficit in the NOR task was ameliorated by EMD 386088 at a dose of 5 mg/kg. However, in contrast to the antipsychotic drug clozapine, the 5-HT6 agonist did not affect PPI disrupted by ketamine. The present study demonstrated the beneficial effects of the 5-HT6 agonist in ameliorating some of the ketamine-induced deficits relevant to schizophrenia. It thus seems likely that the 5-HT6 receptor activation may represent a useful pharmacological approach to the treatment of cognitive disturbances observed in this disorder.

Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats.

A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg) or amisulpride (3 mg/kg) ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia.

Hyperactivity of the hypothalamus-pituitary-adrenal axis in lipopolysaccharide-induced neurodevelopmental model of schizophrenia in rats: effects of antipsychotic drugs.

Recent data indicate that a significant number of schizophrenic patients are hypercortisolemic and that glucocorticoids are involved in the pathogenesis of schizophrenia. The aim of the present study was to evaluate whether behavioural schizophrenia-like changes in the lipopolysaccharide (LPS)-induced neurodevelopmental model of this brain disorder are associated with alterations in the level of plasma corticosterone, the concentration of glucocorticoid receptors and the amount of the immunophilin FKBP51, the glucocorticoid receptor co-chaperone, in the hippocampus and frontal cortex. We found that the adult offspring of prenatally LPS-treated rats showed a deficit in prepulse inhibition (PPI), an enhancement of amphetamine-induced locomotor activity, an elevated plasma level of corticosterone and a decrease in both the glucocorticoid receptor level in the hippocampus and the FKBP51 concentration in the frontal cortex. Most of these changes were reversed by the atypical antipsychotic drug clozapine, whereas chlorpromazine had no effect on PPI but attenuated the amphetamine-induced hyperactivity and normalised the hippocampal level of glucocorticoid receptors. The changes in the level of plasma corticosterone and cortical FKBP51 were attenuated by chlorpromazine in female offspring only. This study supports the hypothesis of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in schizophrenia and suggests that this hyperactivity results from a decrease in the hippocampal glucocorticoid receptor level and a decrease in FKBP51 in the frontal cortex.

Effects of serotonin (5-HT)6 receptor ligands on responding for cocaine reward and seeking in rats.

The endogenous brain serotonin (5-HT) system is believed to have an important modulatory influence in mediating drug reward and seeking mechanisms. Data from preclinical behavioral studies have provided emerging evidence that 5-HT(6) receptors, among other 5-HT receptors, may play a significant role in the mechanisms of action of psychostimulant addicted drugs. The aim of the present study was to investigate whether the selective pharmacological blockade or activation of 5-HT(6) receptors altered the maintenance of cocaine self-administration, reinstatement of cocaine-seeking behavior following an extinction of cocaine self-administration or cocaine-evoked conditioned place preference in rats. We also evaluated the effects of 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl)-2-benzothiophene-sulfonamide (SB 271046, a 5-HT(6) receptor antagonist) or N-1-(6-chloroimidazo-[2,1-b]-[1,3]thiazole-5-sulfonyl)tryptamine (WAY 181187, a potent 5-HT(6) receptor agonist) on locomotor activity in rats. Our results indicate that SB 271046 (1-10 mg/kg) altered cocaine-maintained self-administration as well as cocaine-evoked reinstatement of cocaine seeking and expression of cocaine place preference in rats.We also demonstrate that pharmacological stimulation of 5-HT(6) receptors by WAY 181187 (3-30 mg/kg) attenuated the expression of cocaine conditioned place preference but not cocaine self-administration and reinstatement of cocaine seeking. WAY 181187 at the highest dose used (30 mg/kg) reduced basal locomotor activity. Despite current results, the precise function and therapeutic relevance of 5-HT(6) receptors need further clarification.

Impact of postnatal dexamethasone on psychotomimetic effects of MK-801 measured on adult rats.

The present study investigates the impact of dexamethasone (DEX) given in tapering doses in the postnatal period on MK-801-induced locomotor activity and MK-801-evoked deficits of sensorimotor gating of adult rats (60 days old). It has been found that DEX given on postnatal day 1 (0.5 microg/g), day 2 (0.3 microg/g) and day 3 (0.1 microg/g) has no effects on spontaneous locomotor activity and does not influence locomotion observed after MK-801 given in a dose of 0.2 and 0.4 mg/kg. Postnatal DEX treatment did not alter the efficacy of sensorimotor gating and its deficits evoked by MK-801 at a dose of 0.2 and 0.4 mg/kg. However, a slight increase in the amplitude of startle reaction has been noted in DEX-treated animals. In conclusion, the results of the present study indicate that DEX given postnatally in tapering doses, although pharmacologically effective (decrease in a gain of body and brain weight), has no potential pro-psychotic effects and does not influence pharmacologically induced psychoses by MK-801. The above data indicate that apart from other side effects, the therapeutic application of DEX in the postnatal period is possibly safe in terms of the risk for developing schizophrenia.

Role of glucocorticoids in the regulation of dopaminergic neurotransmission.

Several lines of evidence indicate that exposure to various types of stressors, or stress hormones may increase or induce sensitization to psychostimulants or enhance susceptibility of experimental animals to the effects of abusing substances. In order to find out what is a biological substrate of the above phenomenon, we investigate the impact of stress hormones on the dopaminergic neurotransmission. It is postulated, first, that corticosterone, an important stress hormone, regulates the dopaminergic neurotransmission at the level of dopamine D-1 receptors. Secondly, corticosterone may enhance the dopaminergic tone by the alterations in the synthesis of tyrosine hydroxylase, however, it is also conceivable that, alternatively, corticosterone may evoke translocation of that enzyme from the cell bodies of dopaminergic neurons to their terminals. Finally, arguments that dopamine D-1 receptors might regulate the release of corticosterone by activation of neurons in the paraventricular nucleus of hypothalamus are discussed.