Acute and repeated cocaine induces alterations in FosB/DeltaFosB expression in the paraventricular nucleus of the hypothalamus.

Apart from activation of the brain reward system, cocaine administration influences the activity of the hypothalamo-pituitary-adrenal (HPA) axis by affecting CRH neurons in the paraventricular nucleus of the hypothalamus (PVN). In order to find a molecular mechanism of cocaine-evoked effects in the PVN, in the present study, we investigated the impact of cocaine on the expression of FosB/DeltaFosB transcription factors in the PVN. Using an immunohistochemical method, we found that acute cocaine treatment (25 mg/kg) induced a relatively long-lasting (at least 72 h) expression of FosB/DeltaFosB in the PVN, whereas repeated cocaine administration (25 mg/kg, once daily for 5 consecutive days) caused accumulation of FosB/DeltaFosB in the PVN. The latter observation was further confirmed by the Western blot technique which revealed that repeated exposure to cocaine specifically increased the expression of a stable isoform of DeltaFosB (35 kDa). Using a double-labeling immunofluorescent method, it was established that FosB/DeltaFosB proteins induced by repeated cocaine treatment were present in a small population of CRF-immunoreactive neurons of the PVN. Furthermore, it was found that pretreatment with the specific antagonist of dopamine D1-like receptors SCH 23390 (1 mg/kg) attenuated the expression and accumulation of FosB/DeltaFosB in the PVN, evoked by repeated cocaine administration. Although functional consequences of the above effects for the process of addiction remain to be established, the obtained results indicate that cocaine administration can produce relatively long-lasting changes in the expression of FosB/DeltaFosB transcription factors in PVN neurons (in some populations of CRF-immunoreactive neurons, among others) and that dopamine D1-like receptors are involved in the above effects. Finally, it is proposed that the long-lasting expression as well as the accumulation of DeltaFosB in the PVN may constitute a molecular basis underlying adaptive changes occurring in the HPA axis after relatively high doses of cocaine.

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).

Serotonin 5-HT1A receptors might control the output of cortical glutamatergic neurons in rat cingulate cortex.

The present study was designed to investigate the distribution of serotonin 5-HT1A receptor protein (5-HT1A-immunoreactivity) and its localization within cortical pyramidal neurons of the rat cingulate cortex. This experimental direction was inspired by recent data showing the role of 5-HT1A receptors in the pathology of schizophrenia, and in the mechanism of action of novel antipsychotic drugs as well as by the importance of the cingulate cortex in regulation of cognitive functions. It was found that 5-HT1A-immunoreactivity was densely distributed in neuronal eyelash-like elements, and their size, shape and spatial orientation may suggest concentration of 5-HT1A-immunopositive material in the proximal fragments of axons of cortical neurons. Moreover, it was observed that these 5-HT1A-immunopositive fragments were present predominately on proximal fragments of axons of pyramidal neurons, which was evidenced by double labeling experiments using glutamate and non-phosphorylated neurofilament H as markers of the cortical pyramidal cells. The 5-HT1A receptor immunoreactivity was localized distally to the inhibitory GABAergic terminals of chandelier and basket cells surrounding the pyramidal cell bodies and occasionally surrounding short initial segment of axonal hillock of pyramidal neurons. These anatomical data indicate that 5-HT1A receptors might control the excitability and propagation of information transmitted by the pyramidal cells. Moreover, our results indicate that drugs operating via 5-HT1A receptors in the cingulate cortex might control from this level the release of glutamate in the subcortical structures. Finally, the 5-HT1A receptors present in the cingulate cortex, as demonstrated in the present study, may constitute an important target for drugs used to repair dysfunction of glutamate neurotransmission, which is observed for example in schizophrenia.

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.

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.

A competitive antagonist of NMDA receptors CGP 40116 attenuates experimental symptoms of schizophrenia evoked by MK-801.

In the present study, the interaction between a noncompetitive [(+)-MK-801] and a competitive (CGP 40116) NMDA receptor antagonists was tested in two different behavioral paradigms: locomotor activity test and prepulse inhibition of the acoustic startle reflex. Additionally, their effects on working memory and selective attention were evaluated in the delayed alternation task. All above paradigms served to model the symptoms of schizophrenia. It was found that locomotor stimulatory effect of (+)-MK-801 (0.4 mg/kg) was antagonized by prior administration of CGP 40116 (5 mg/kg). Lower doses of CGP 40116 (1.25 and 2.5 mg/kg) were ineffective. CGP 40116 given alone did not influence locomotor activity in rats. It was also shown that CGP 40116 antagonized the disruption of the process of sensorimotor gating evoked by (+)-MK-801. On the contrary, both CGP 40116 and (+)-MK-801 increased a number of errors in the delayed alternation test revealing detrimental effect of CGP 40116 on spatial working memory and selective attention even at a lower dose than that required to antagonize the effects of (+)-MK-801. The presented results indicate that noncompetitive and competitive NMDA receptor antagonists, when used at relatively low doses, may produce qualitatively different behavioral effects, as evidenced by the experiments with locomotor activity and prepulse inhibition. Moreover, the competitive NMDA receptor antagonists may even inhibit some psychotomimetic effects related to the noncompetitive blockade of this receptor. However, therapeutic potential of CGP 40116, a competitive NMDA receptor antagonist, should be considered with caution since in the range of doses effective against the psychotomimetic effects of (+)-MK-801, it impairs rats' performance in the delayed alternation paradigm, i.e. it worsens efficacy of working memory.

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.

Inhibition of arachidonic acid cascade attenuates the induction of c-Fos proteins by DOI, 5-HT2A/2C receptor agonist, in the rat cortex.

Previous immunohistochemical studies have shown that c-Fos proteins induced by DOI, a 5-HT2A/2C agonist, are present in the population of cortical neurons, which are devoid of 5-HT2A receptors. A mechanism of the induction of c-Fos proteins expression by DOI is still unclear. However, the involvement of the 5-HT2A and AMPA, but not 5-HT2C receptors in this process has been reported. In the present study, we investigated whether arachidonic acid, a retrograde messenger, is involved in the above mechanism of c-Fos induction. Phospholipase A2 pathway, which leads to the subsequent generation of arachidonic acid and its metabolites, is known to be coupled to 5-HT2A receptor activation. The inhibition of arachidonic acid cascade both at the level of phospholipase A2 (by dexamethasone, 1.5 mg/kg) or at the level of cyclooxygenases that catalyze arachidonic acid biotransformation (by indomethacin, 3 mg/kg), decreased the number of c-Fos immunopositive cells after induction by DOI (8 mg/kg). Our results suggest that arachidonic acid cascade may be involved in the induction of c-Fos proteins by DOI in the rat parietal cortex.