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.

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Non-competitive antagonists of NMDA receptors such as phencyclidine (PCP) or ketamine are known for their strong, frequently neuroleptic-resistant psychotomimetic effects in humans (Javitt and Zukin 1991). These clinical effects, as well as evidence suggesting the involvement of NMDA receptors in the pathophysiology of schizophrenia (Carlsson et al. 1999;Harrison 1999;Wachtel and Turski 1990), support the experimental modeling of psychoses by administration of non-competitive NMDA receptor antagonists (Jentsch and Roth 1999). In this respect, MK-801 seems to be of special interest in experimental pharmacology. It belongs to a class of non-competitive NMDA receptor antagonists (Seeburg 1993;Lodge and Johnson 1990; Willetts et al. 1990) and MK-801 seems to be highly specific to the PCP binding site located in the ion channel of the NMDA receptor complex (Lodge and Johnson 1990;Seeburg 1993 (Carlsson 1993;Maj et al. 1991), impairment of sensorimotor gating (Mansbach and Geyer 1989; W dzony et al. 1994), and detrimental effects on spatial working memory (Verma and Moghaddam 1996). Although it is generally agreed that the psychostimulant and psychotomimetic effects of PCP, ketamine, and MK-801 are initiated by blockade of the NMDA receptor ion channel complex, the neuronal pathways or neurotransmitter systems involved in the propagation of the psychotomimetic effects are not precisely known (Bakshi and Geyer 1998). Moreover, the apparent lack of chemical compounds which might directly abolish the pharmacological blockade of these NMDA receptors (Lodge and Johnson 1990; Willetts et al. 1990), and prevent impairments of their function during the course of schizophrenia (Harrison 1999) justifies attempts to define neuroanatomical/neurochemical systems responsible for the propagation of the effects of non-competitive NMDA receptors.Apart from the dopaminergic system (Jentsch and Roth 1999), traditionally linked with psychotomimetic effects of non-competitive antagonists of NMDA receptors, and the noradrenergic system [currently under investigation (Bakshi and Geyer 1998, 1999;Jentsch et al. 1998)], considerable interest has been focused on serotonin and its receptors (Geyer 1998). It has been shown, for example, that MK-801 increases serotonin release (Whitton et al. 1992) and influences serotonin turnover (Loscher et al. 1991;W dzony et al. 1997). Moreover, the psychostimulant and psychotomimetic effects of MK-801 and PCP are attenuated by specific antagonists of 5-HT2A receptors (Schmidt and Fadayel 1996;Varty et al. 1999;Varty and Higgins 1995).Apart from 5-HT2A receptors, a growing number of studies indicate that MK-801 may also influence other serotonin receptors; for example, it increases mRNA of 5-HT6 and 5-HT7 receptors (Healy and Meador-Woodruff 1999). Moreover, the increased density of 5-HT1A receptors after a single administration of MK-801 has been reported in one of our recent studies (W dzony et al. 1997). The possible involvement of 5-HT1A receptors in the psychotomimetic effects of NMDA receptor antagon...

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).

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