ESMO expert consensus statements on the screening and management of financial toxicity in patients with cancer.

BACKGROUND: Financial toxicity, defined as both the objective financial burden and subjective financial distress from a cancer diagnosis and its treatment, is a topic of interest in the assessment of the quality of life of patients with cancer and their families. Current evidence implicates financial toxicity in psychosocial, economic and other harms, leading to suboptimal cancer outcomes along the entire trajectory of diagnosis, treatment, supportive care, survivorship and palliation. This paper presents the results of a virtual consensus, based on the evidence base to date, on the screening and management of financial toxicity in patients with and beyond cancer organized by the European Society for Medical Oncology (ESMO) in 2022. METHODS: A Delphi panel of 19 experts from 11 countries was convened taking into account multidisciplinarity, diversity in health system contexts and research relevance. The international panel of experts was divided into four working groups (WGs) to address questions relating to distinct thematic areas: patients with cancer at risk of financial toxicity; management of financial toxicity during the initial phase of treatment at the hospital/ambulatory settings; financial toxicity during the continuing phase and at end of life; and financial risk protection for survivors of cancer, and in cancer recurrence. After comprehensively reviewing the literature, statements were developed by the WGs and then presented to the entire panel for further discussion and amendment, and voting. RESULTS AND DISCUSSION: A total of 25 evidence-informed consensus statements were developed, which answer 13 questions on financial toxicity. They cover evidence summaries, practice recommendations/guiding statements and policy recommendations relevant across health systems. These consensus statements aim to provide a more comprehensive understanding of financial toxicity and guide clinicians globally in mitigating its impact, emphasizing the importance of further research, best practices and guidelines.

Are Italian-Polish veterinarians and breeders prepared to control an outbreak of Brucella canis infection in dogs?

Brucella canis infection is one of the most important causes of infertility in dogs and is a zoonosis for which no effective treatment or vaccines exist. It is not a mandatory notifiable disease. Following an increase of cases in Europe and worldwide, an investigation was performed to evaluate how much Italian and Polish veterinarians and breeders know about canine brucellosis and understand their perceptions of this infection. For this reason, two questionnaires were prepared, in Italian and Polish. Eighteen Italian and Polish veterinarians, specialists in canine reproduction, responded to the first survey and 44.4% of them affirmed having diagnosed canine brucellosis at least once in their clinical practice, and different perceptions emerged regarding the infection in the two countries. The second survey was completed by 145 Italian and Polish breeders; the disease was completely unknown to 22.8% of them, whereas 2.1% had diagnosed infection by B. canis in their kennels. In conclusion, knowledge of B. canis infection differs between these countries, with extremes ranging from diagnosed cases to complete underestimation of the presence of the problem. However, based on international data and reporting of a recent large outbreak in Italy, awareness of this contagious infectious disease and its management must be increased.

Cost-effectiveness of multifaceted evidence implementation programs for the prevention of glucocorticoid-induced osteoporosis.

SUMMARY: Using a computer simulation model, we determined that an intervention aimed at improving the management of glucocorticoid-induced osteoporosis is likely to be cost-effective to third-party health insurers only if it focuses on individuals with very high fracture risk and the proportion of prescriptions for generic bisphosphonates increases substantially. INTRODUCTION: The purpose of this study is to determine whether an evidence implementation program (intervention) focused on increasing appropriate management of glucocorticoid-induced osteoporosis (GIOP) might be cost-effective compared with current practice (no intervention) from the perspective of a third-party health insurer. METHODS: We developed a Markov microsimulation model to determine the cost-effectiveness of the intervention. The hypothetical patient cohort was of current chronic glucocorticoid users 50-65 years old and 70% female. Model parameters were derived from published literature, and sensitivity analyses were performed. RESULTS: The intervention resulted in incremental cost-effectiveness ratios (ICERs) of $298,000 per quality adjusted life year (QALY) and $206,000 per hip fracture averted. If the cohort's baseline risk of fracture was increased by 50% (10-year cumulative incidence of hip fracture of 14%), the ICERs improved significantly: $105,000 per QALY and $137,000 per hip fracture averted. The ICERs improved significantly if the proportion of prescriptions for generic bisphosphonates was increased to 75%, with $113,000 per QALY and $77,900 per hip fracture averted. CONCLUSIONS: Evidence implementation programs for the management of GIOP are likely to be cost-effective to third-party health insurers only if they are targeted at individuals with a very high risk of fracture and the proportion of prescriptions for less expensive generic bisphosphonates increases substantially.

Low doses of prenatal ethanol exposure and maternal separation alter HPA axis function and ethanol consumption in adult male rats.

Adverse maternal behaviors during pregnancy and unfavorable postnatal experiences during development are associated with an increased risk of developing psychiatric disorders, as well as, a vulnerability to alcohol addiction in adulthood. Here, we examined the effects of combined ethanol exposure during late pregnancy and postnatal maternal separation (MS) on HPA responsiveness, anxiety behavior and preference for alcohol consumption in adult male rats. Animals exposed to both conditions revealed a decrease in blood levels of allopregnanolone accompanied by increased anxiety behavior. In addition, basal blood levels of corticosterone were markedly decreased in all experimental groups while increases in the foot-shock-induced corticosterone levels were more pronounced in MS animals. Finally, evaluating EtOH drinking behavior, MS animals exhibited a remarkable EtOH preference even at low doses (0.1-1%). Altogether, these data suggest that adverse conditions, alone or in combination, may alter anxiety-like states as well as modify behavior towards alcohol consumption.

Monoamine receptors and immature cerebellum cytoarchitecture after cisplatin injury.

The experimental model of cisplatin treatment provides the opportunity to identify the precise function of the neurotransmitters in some crucial events of brain development, and their interactions or modulatory roles. The serotonin and noradrenaline monoamines influence the formation of the cerebellar cortex circuitry. In this study we found changes in the expression of the serotonin and noradrenaline receptors after a single injection of cisplatin in 10-day-old rats. The growth of Pc dendrites was early altered in lobules VI-VIII of cerebellum vermis. In these lobules, at postnatal day (PD) 17, the cisplatin-induced increase of the serotoninergic receptor 5-HT2AR, a factor that inhibits Pc dendrite growth by acting post-synaptically, occurred in all cerebellar layers, suggesting also alteration of granule cell proliferation and migration. The decreased labelling of beta l adrenergic receptor (beta1AR) in the soma of some Pc at PD11 can be correlated with the altered expression of glutamate receptors and GAD65 (glutamic acid decarboxylase) of and on Pc we have previously described [Pisu, M.B., Guioli, S., Conforti, E., Bernocchi, G., 2003. Signal molecules and receptors in the differential development of cerebellum lobules. Acute effects of cisplatin on nitric oxide and glutamate system in Purkinje cell population. Dev. Brain Res. 145, 229-240; Pisu, M.B., Roda, E., Avella, D., Bernocchi, G., 2004. Developmental plasticity of rat cerebellar cortex after cisplatin injury: inhibitory synapses and differentiating Purkinje neurons. Neuroscience 129, 655-664]. Moreover, beta1AR seems to be the key factor in the cerebellar reorganization between PD17 and PD30. The expression of this receptor was maintained in the molecular layer (ML), in particular in the inhibitory interneurons, despite their different distributions. The labelling of 5-HT1AR in the ML areas lacking Pc dendrite branches could contribute to the recovery phase of the cerebellar cytoarchitecture in cisplatin-treated rats. In general these findings should be taken into consideration in therapeutic interventions for developmental CNS disorders with a morphological basis.

Mechanically induced self-propagating reactions: analysis of reactive substrates and degradation of aromatic sulfonic pollutants.

Mechanochemical reactions have been identified as a valuable alternative to conventional methodologies for the degradation of toxic pollutants as well as for their abatement in contaminated matrices. This paper discusses the application of the mechanochemical technique to the degradation of sulfonic acids in a contaminated matrix. The degradation of the pollutant compound was carried out by taking advantage of combustive reactions on a suitable reactive system ignited under mechanical treatment conditions. Two systems have been investigated as possible reactive substrates. The first one was a Mg-SiO2 powder mixture while the second system was a Ca-SiO2 powder mixture. Milling trials performed under different mechanical processing conditions allowed one to characterise the reactivity of these chemical systems, which basically undergo a reduction/oxidation reaction involving the formation of MgO and Si phases when the Mg-SiO2 system is considered and CaO and Si phases when the Ca-SiO2 system is employed, respectively. The systematic change of the stoichiometric ratios Mg:SiO2 and Ca:SiO2 permitted to identify the minimum Mg or Ca content necessary for the ignition of the combustive reactions. The experimental runs performed with such systems have shown a greater effectiveness of the Mg-SiO2 because of less energy inputs required to ignite a combustion. For this reason the Mg-SiO2 has been considered as a reactive substrate in the following trials. Since the SiO2 amount in stoichiometric excess may be regarded as inert phase, it was substituted with a different phase consisting of the matrix contaminated by sulfonic acids. This aspect permitted to ignite a combustive reaction with the minimum possible content of Mg-SiO2 reacting mixture. The chemical analyses performed after the combustive reaction proved the complete removal of the sulfonic acid from the contaminated matrix.

Sex differences in the outcome of juvenile social isolation on HPA axis function in rats.

Women are more likely than men to suffer from anxiety disorders and major depression. These disorders share hyperresponsiveness to stress as an etiological factor. Thus, sex differences in brain arousal systems and their regulation by chronic stress may account for the increased vulnerability to these disorders in women. Social isolation is a model of early life stress that results in neurobiological alterations leading to increased anxiety-like and depressive-like behaviors. Here we investigated the sex difference in the effects of post-weaning social isolation on acute stress sensitivity and behavior in rats. In both sexes, social isolation at weaning reduced basal levels of the neuroactive steroid allopregnanolone in the brain and of corticosterone in plasma. Moreover, acute stress increased plasma corticosterone levels in both group-housed and socially isolated male and female rats; however this effect was greater in male than female rats subjected to social isolation. Intriguingly, group-housed female rats showed no change in plasma and brain levels of allopregnanolone after acute foot-shock stress. The absence of stress-induced effects on allopregnanolone synthesis might be due to the physiologically higher levels of this hormone in females vs. males. Accordingly, increasing allopregnanolone levels in male rats blunted the response to foot-shock stress in these animals. Socially isolated male, but not female, rats also display depressive-like behavior and increased hippocampal brain-derived neurotrophic factor (BDNF). The ovarian steroids could "buffer" the effect of this adverse experience in females on these parameters. Finally, the dexamethasone (DEX) suppression test indicated that the chronic stress associated with social isolation impairs feedback inhibition in both sexes in which an increase in the abundance of glucocorticoid receptors (GRs) in the hippocampus was found. Altogether, these results demonstrate that social isolation affects neuroendocrine reactivity to stress, plasticity and emotionality in a sexually dimorphic manner.

Ret, GFRalpha-1, GFRalpha-2 and GFRalpha-3 receptors in the human hippocampus and fascia dentata.

The immunohistochemical occurrence and localization of the receptor components of the glial cell line-derived neurotrophic factor (GDNF) family ligands, the Ret receptor tyrosine kinase and GDNF family receptor (GFR) alpha-1 to -3, is described in the human post-mortem hippocampal formation at pre- and full-term newborn, and adult age. Two different antibodies for each of the four-receptor molecules were used. Western blot analysis indicates that the availability of GFRalpha receptor proteins may vary with age and post-mortem delay. The immunohistochemical detectability of GFRalpha-1, GFRalpha-2, GFRalpha-3 and Ret receptor molecules is shown in the rat up to 72 h post-mortem. In the human specimens, labelled neuronal perikarya were detectable for each receptor protein at all examined ages, with prevalent localization in the pyramidal layer of the Ammon's horn and hilus and granular layer of the fascia dentata. In the adult subjects, abundant punctate-like structures were also present. Labelled glial elements were identifiable. Comparison of the pattern of immunoreactive elements among young and adult subjects suggests that the intracellular distribution of the GDNF family ligands may vary between pre- and perinatal life and adult age. The results obtained suggest the involvement of the Ret and GFRalpha receptors signalling in processes subserving both the organization of this cortical region during development and the functional activity and maintenance of the mature hippocampal neurons.

NPY-Y1 coexpressed with NPY-Y5 receptors modulate anxiety but not mild social stress response in mice.

The Y1 and Y5 receptors for neuropeptide Y have overlapping functions in regulating anxiety. We previously demonstrated that conditional removal of the Y1 receptor in the Y5 receptor expressing neurons in juvenile Npy1r(Y5R-/-) mice leads to higher anxiety but no changes in hypothalamus-pituitary-adrenocortical axis activity, under basal conditions or after acute restraint stress. In the present study, we used the same conditional system to analyze the specific contribution of limbic neurons coexpressing Y1 and Y5 receptors on the emotional and neuroendocrine responses to social chronic stress, using different housing conditions (isolation vs. group-housing) as a model. We demonstrated that control Npy1r(2lox) male mice housed in groups show increased anxiety and hypothalamus-pituitary-adrenocortical axis activity compared with Npy1r(2lox) mice isolated for six weeks immediately after weaning. Conversely, Npy1r(Y5R-/-) conditional mutants display an anxious-like behavior but no changes in hypothalamus-pituitary-adrenocortical axis activity as compared with their control littermates, independently of housing conditions. These results suggest that group housing constitutes a mild social stress for our B6129S mouse strain and they confirm that the conditional inactivation of Y1 receptors specifically in Y5 receptor containing neurons increases stress-related anxiety without affecting endocrine stress responses.

Nitric oxide-containing neurons in the nervous ganglia of Helix aspersa during rest and activity: immunocytochemical and enzyme histochemical detection.

Nitric oxide synthase (NOS) immunoreactivity and staining for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-diaphorase) activity are two cytochemical markers for nitric oxide (NO)-containing neurons. The authors examined the changes in the distribution of NOS immunolabeling and NADPH-diaphorase reactivity in the cerebral and buccal ganglia of the terrestrial snail Helix aspersa during resting and active phases. During inactivity and after 1 day of activity, in the mesocerebrum and metacerebrum of the snails, there were several reactive neurons for both markers; after 7 days of activity, the number of reactive neurons was lower. Opposite results were obtained in the buccal ganglia, in which increased staining and numbers of reactive neurons were present in the active snails (after 1 day and 7 days of activity). Although the staining patterns for the two reactions were similar, colocalization was not always observed. The comparison between inactive and active animals provided a more precise survey of NOS-containing neurons in the snail cerebral ganglia than previously described. Moreover, it suggested that not only is NO involved in distinct nervous circuits, but, as a ubiquitous molecule, it also plays a role in neuroprotection and neuropeptide release.

Steroidogenesis in rat brain induced by short- and long-term administration of carbamazepine.

Although carbamazepine (CBZ) is used therapeutically in the treatment of various neurological and psychiatric conditions, its mechanism of action remains largely unknown. CBZ has now been shown to inhibit the binding of [(3)H]PK 11195 to peripheral benzodiazepine receptors (PBRs) in rat brain and ovary membranes in vitro with a potency (IC(50), approximately 60 microM) much lower than that of unlabeled PK 11195 (IC(50), approximately 2.0 nM). Administration of CBZ to rats induced dose (25 to 100 mg/kg, i.p.) and time (15 to 60 min) dependent increases in the concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone in both the cerebral cortex and plasma. CBZ also induced steroidogenesis in the brain of adrenalectomized-orchiectomized rats, suggesting that this effect is mediated in a manner independent of peripheral PBRs. The increase in brain concentrations of neuroactive steroids induced by a single injection of CBZ was associated with a marked protective effect against isoniazid-induced convulsions. In contrast, long-term administration of CBZ (50 mg/kg, twice a day for 30 days) induced tolerance to the anticonvulsant action of the drug. This same treatment, however, did not prevent the ability of a challenge dose of CBZ to stimulate steroidogenesis. These results indicate that CBZ-induced steroidogenesis might not be responsible for the anticonvulsant activity of this drug.

Long-term treatment with antidepressant drugs reduces the sensitivity of cortical cholinergic neurons to the activating actions of stress and the anxiogenic drug FG 7142.

Certain antidepressant drugs exert an anxiolytic action in both humans and rodents. The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical cholinergic neurons to foot-shock stress or to the anxiogenic drug FG 7142 were investigated in freely moving rats. Chronic treatment with imipramine or mirtazapine reduced the increase in cortical acetylcholine output induced by foot-shock stress by approximately 50%. The same treatment also reduced the sensitivity of cortical cholinergic neurons to the stimulatory effect of acute administration of FG 7142. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock or FG 7142 injection failed to increase the threshold of excitability of cortical cholinergic neurons. These results demonstrate that long-term treatment with either imipramine or mirtazapine reduces the sensitivity of cortical cholinergic neurons to stress or to an anxiogenic drug with an efficacy similar to that of acute administration of benzodiazepines. The neurochemical mechanism responsible for regulation of cholinergic neuron sensitivity might contribute to the modulation of cognitive function associated with emotional and affective disorders.

Developmental plasticity of rat cerebellar cortex after cisplatin injury: inhibitory synapses and differentiating Purkinje neurons.

A single injection of cisplatin, a cytostatic agent, (5 microg/g body weight) in 10-day old rats leads later to the reorganization of the cerebellar cortex in lobules VI-VIII of the vermis. Double immunofluorescence reaction for glutamate receptor (GluR)2/3, a ionotropic glutamate receptor that labels postsynaptically Purkinje neurons, and glutamic acid decarboxylase (GAD)65, an isoform of the GABA synthesis enzyme that labels presynaptically inhibitory terminals in the molecular layer, were employed. Less-differentiated Purkinje cells were present in rats treated on postnatal day (PD)11 at the top of lobule VI and in lobules VII-VIII, in comparison with the deep zones of the same lobules and lobule III. The changes were interpreted as due to loss of trophic factors of Purkinje cell growth, e.g. signaling molecules and granule cells. However, we have shown that a remodelling of Purkinje cell dendrites occurred on PD30 (20 days after cisplatin). In fact, despite of the GluR2/3 labeling of the entire Purkinje cell dendrites, the GAD65 immunofluorescent terminals were adjacent to the proximal parts of the dendrite, while they were scarce in the distal dendritic branchlets. The findings were discussed in relation to the changed cytoarchitecture of the cerebellar cortex, which from PD17 to PD30 includes regeneration of the external germinal layer, reorientation of the main dendritic branches and of the Purkinje cell branchlets, and the presence of ectopic cells.

Neuroactive steroid-serotonergic interaction: responses to an intravenous L-tryptophan challenge in women with premenstrual syndrome.

OBJECTIVE: To evaluate the circulating concentrations of the neuroactive steroids in response to an i.v. L-tryptophan (L-TP) challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and in controls. METHOD: An i.v. L-TP challenge was administered eight times during 1 month to five women with prospectively documented PMS and five age- and body mass-matched controls. Progesterone, allopregnanolone pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone were assessed 15 and 0 min before, and at 30, 60 and 90 min after the challenge, across the menstrual cycle. RESULTS: In response to L-TP challenge, only allopregnanolone concentrations were significantly increased across the cycle and this increase was of a greater magnitude in women with PMS. Pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone concentrations were not affected in women with PMS or controls after L-TP challenge. CONCLUSIONS: The data provide evidence for possible interaction between the serotonergic system and the neuroactive steroid, allopregnanolone. Women with PMS demonstrated a more significant increase in allopregnanolone concentrations in response to L-TP challenge, which could be due to an initial low basal serotonergic tone in the luteal phase in the PMS group.

Immunocytochemical changes of cytoskeleton components and calmodulin in the frog cerebellum and optic tectum during hibernation.

During hibernation, variation in the metabolism of nerve cells occurs. Since the cytoskeleton plays an important role in nerve cell function, we have analyzed the immunocytochemical expression of two cytoskeleton components, i.e. phosphorylated 200 kDa neurofilament protein, and microtubule-associated protein 2 in the cerebellum and optic tectum of hibernating frogs (Rana esculenta) in comparison with active animals. In addition, we have considered the immunocytochemical expression of calmodulin, which is known to be involved in neurofilament phosphorylation. In hibernating animals, there was a decrease in the immunoreactivity for phosphorylated 200 kDa neurofilament protein and microtubule-associated protein 2 of fibers in both the cerebellum and in the optic tectum. In contrast, in the large neurons of the cerebellum, i.e. Purkinje neurons, there was an increase in the immunoreactivity for microtubule-associated protein 2. The changes in the cytoskeleton components were accompanied by a decrease in calmodulin immunoreactivity in the cytoplasm of nerve cells of the cerebellum. All the changes observed are consistent with a low neuronal activity during hibernation, as also indicated by previous microdensitometric and microfluorometric data. This shows a higher degree of chromatin condensation in hibernating animals and suggests that hibernation represents a simple form of neuronal plasticity.

Distribution of calretinin-like immunoreactivity in the brain of Rana esculenta.

The distribution of calretinin-like immunoreactivity has been analyzed in the brain of Rana esculenta. Several neurons of nuclei belonging to sensory pathways, subhabenular area and left habenula were immunopositive. Immunoreactivity was present in fibers of motor and sensory pathways, thalamus, tegmentum and isthmus. The immunolabeling pattern partially overlapped that previously described in the rat. However, in comparison with the rat, fewer cells and fibers were immunoreactive and there were less positive brain nuclei. especially in the pallium, septum and striatum, that were totally negative. Taking into consideration that these regions are rather simple in the frog, the presence of calretinin seems to be consistent with the degree of complexity of brain areas and segregation of different nuclei.

Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain.

RATIONALE: Recent preclinical and clinical studies have shown that selective serotonin re-uptake inhibitors modulate neurosteroid synthesis in an opposite manner. OBJECTIVES: The action of long-term administration of fluoxetine was investigated on the peripheral and central concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-TH PROG) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (of 3alpha,5alpha-TH DOC), progesterone, and pregnenolone in rats. We also investigated the effect of chronic treatment with fluoxetine on the foot-shock stress-induced increase in the plasma and brain concentrations of these steroids. METHODS: Fluoxetine was administered acutely (20 mg/kg) or chronically (10 mg/kg, once daily for 15 days). Steroids were extracted from plasma and brain, separated and purified by means of high-performance liquid chromatography, and quantified by means of radioimmunoassay. RESULTS: A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after the last drug injection, in both brain and plasma. A challenge injection of fluoxetine (20 mg/kg, i.p.), however, was still able to increase the concentrations of steroids in both the brain and plasma of rats chronically treated with this drug. Acute foot-shock stress increased the cortical and plasma concentrations of steroids in rats chronically treated with fluoxetine to extents similar to those apparent in control rats. CONCLUSIONS: A repetitive increase in the brain concentrations of neuroactive steroids may contribute to the therapeutic action of fluoxetine.

Social isolation increases the response of peripheral benzodiazepine receptors in the rat.

Social isolation of rats for 30 days immediately after weaning reduces the cerebrocortical and plasma concentrations of progesterone, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG), and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC). The percentage increases in the brain and plasma concentrations of these neuroactive steroids apparent 30 min after intraperitoneal injection of the peripheral benzodiazepine receptor (PBR) ligand CB 34 (25 mg/kg) have now been shown to be markedly greater in isolated rats than in group-housed controls. The CB 34-induced increase in the abundance of 3alpha,5alpha-TH PROG was more pronounced in the brain than in the plasma of isolated rats. Analysis of [3H]PK 11195 binding to membranes prepared from the cerebral cortex, adrenals, or testis revealed no significant difference in either the maximal number of binding sites for this PBR ligand or its dissociation constant between isolated and group-housed animals. Social isolation also induced a small but significant decrease in the plasma concentration of adrenocorticotropic hormone. Moreover, CB 34 increased the plasma concentration of this hormone to a greater extent in isolated rats than in group-housed animals. The persistent decrease in the concentrations of neuroactive steroids induced by social isolation might thus be due to an adaptive decrease in the activity either of the hypothalamic-pituitary-adrenal axis or of PBRs during the prolonged stress, reflecting a defense mechanism to limit glucocorticoid production. The larger increase in neuroactive steroid concentrations induced by CB 34 and the enhanced pituitary response to this compound in isolated rats indicate that this mild stressor increases the response of PBRs.

Reversal of a selective decrease in hippocampal acetylcholine release, but not of the persistence of kindling, after discontinuation of long-term pentylenetetrazol administration in rats.

The time course of the effect of pentylenetetrazol (PTZ)-induced kindling on acetylcholine release in the hippocampus of freely moving rats was investigated with the transversal microdialysis technique. The basal extracellular concentration of acetylcholine in the hippocampus was reduced significantly (-29%, P < 0.05) after 3 weeks, and the effect was maximal (-52%, P < 0.01) after 4 weeks and remained essentially unchanged during the remaining 4 weeks of PTZ treatment (30 mg/kg, i.p., 3 times/week), relative to vehicle-treated rats. The basal release of acetylcholine in the prefrontal cortex and in the striatum of kindled rats was unchanged compared with that of vehicle-treated rats. The specific binding of [3H]quinuclidinyl benzilate, a non-selective ligand of muscarinic receptors, was significantly increased (+29%, P < 0.01) in hippocampal membrane, but not in membranes prepared from the prefrontal cortex or striatum, of PTZ-kindled rats. Thirty days after discontinuation of PTZ treatment, both hippocampal acetylcholine output and the density of muscarinic receptors had returned to values characteristic of vehicle-treated rats, whereas seizure susceptibility did not differ significantly from that apparent 4 days after PTZ administration. These results suggest that the selective and transient decrease in acetylcholine output and the parallel increase in the density of postsynaptic muscarinic receptors in the hippocampus may play a role in facilitating the development of kindling rather than in the maintenance of the kindled state.