Effects of chronic treatment with corticosterone and imipramine on fos immunoreactivity and adult hippocampal neurogenesis.

In a previous study we showed that rats chronically treated with corticosterone (CORT) display anxiogenic behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. Treatment with the tricyclic antidepressant imipramine significantly reversed the anxiogenic effects of CORT, while inhibiting ETM escape, a response related to panic disorder. To better understand the neurobiological mechanisms underlying these behavioral effects, analysis of c-fos protein immunoreactivity (fos-ir) was used here to map areas activated by chronic CORT (200 mg pellets, 21-day release) and imipramine (15 mg/kg, IP) administration. We also evaluated the number of cells expressing the neurogenesis marker doublecortin (DCX) in the hippocampus and measured plasma CORT levels on the 21st day of treatment. Results showed that CORT increased fos-ir in the ventrolateral septum, medial amygdala and paraventricular hypothalamic nucleus and decreased fos-ir in the lateral periaqueductal gray. Imipramine, on the other hand, increased fos-ir in the medial amygdala and decreased fos-ir in the anterior hypothalamus. CORT also decreased the number of DCX-positive cells in the ventral and dorsal hippocampus, an effect antagonized by imipramine. CORT levels were significantly higher after treatment. These data suggest that the behavioral effects of CORT and imipramine are mediated through specific, at times overlapping, neuronal circuits, which might be of relevance to a better understanding of the physiopathology of generalized anxiety and panic disorder.

Phenylpiperazinylalkylamino substituted pyridazinones as potent alpha(1) adrenoceptor antagonists.

QSAR models have been used for designing a series of compounds characterized by a N-phenylpiperazinylalkylamino moiety linked to substituted pyridazinones, which have been synthesized. Measurements of the binding affinities of the new compounds toward the alpha(1a)-, alpha(1b)-, and alpha(1d)-AR cloned subtypes as well as the 5-HT(1A) receptor have been done validating, at least in part, the estimations of the theoretical models. This study provides insight into the structure activity relationships of the alpha(1)-ARs ligands and their alpha(1)-AR/5-HT(1A) selectivity.

Novel adrenoceptor antagonists with a tricyclic pyrrolodipyridazine skeleton.

A still unknown tricyclic heterocyclic system (5) was synthesized from 6-hydroxy-2-methylpyridazin-3-one and its structure identified as 2,8-dichloro-6-methylpyrrolo[1,2-b:3,4-d']dipyridazin-5(6H)- one by spectroscopic investigations. Selective condensation of 5 with 2-[4-(2-substituted-phenyl)piperazin-1-yl]ethylamine gave the 2-arylpiperazinylethylamino-8-chloro derivatives 6a-c, which were investigated in binding studies toward the three alpha1-adrenergic and 5-HT1A-serotonergic receptor subtypes. They displayed high potency on all the assays and some selectivity for alpha1a and alpha1d subtypes.

Isoxazolo-[3,4-d]-pyridazin-7-(6H)-ones and their corresponding 4,5-disubstituted-3-(2H)-pyridazinone analogues as new substrates for alpha1-adrenoceptor selective antagonists: synthesis, modeling, and binding studies.

A series of phenylpiperazinylalkyl moieties were attached to monocyclic or bicyclic substituted pyridazinones and the new compounds tested for their affinity towards alpha1-adrenoceptor and its alpha1a, alpha1b and alpha1d subtypes, as well as serotonin 5-HT1A receptor. Several analogues (5, 6, 9, and 10) showed remarkable potency and selectivity towards alpha1a, and alpha1d with respect to alpha1b subtype. None of the test compounds exhibited significant affinity for 5-HT1A receptor. Finally, on the basis of the alpha1-AR subtypes 3D models recently proposed, we have elaborated theoretical interaction models for the new compounds. The theoretical study allowed us to predict the affinity of the new compounds as well as to infer the structural/dynamics determinants of their interaction with the three alpha1-AR subtypes.

Relevance of intravenous cocaine use in relation to prevalence of HIV, hepatitis B and C virus markers among intravenous drug abusers in southern Italy.

The purpose of this study was to analyze the relationship between intravenous (i.v) drug use practices and the prevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) in 146 heterosexual male i.v. drug users (IVDUs) attending a methadone-maintainance treatment program in Catanzaro, Southern Italy. One hundred and forty-six heterosexual male IVDUs attending a methadone-maintainance treatment program in Catanzaro were interviewed in order to obtain the following information: age, number of drug injections (calculated by multiplying the mean number of daily injections by 365 and then by the number of years of injections), number of injection equipment-sharing partners in the last year, number of sexual partners in the last year and possible IV cocaine use. Their sera were studied for the presence of antibodies to HIV, HBV and HCV by commercial enzyme-linked-immuno-sorbent assays run in duplicate. HIV positive samples were confirmed by Western Blot assay. Sixteen per cent of IVDUs were anti-HIV positive, 40% were anti-HBc positive and 68% were anti-HCV positive. Twenty-three per cent were seronegative and 12% were seropositive for all 3 viral markers. Multiple logistic analysis of HIV, HBV and HCV seropositivities in relation to age, number of drug injections, i.v. cocaine use and presence of injection equipment-sharing partners in the last year, showed that: a) older age (more than 27 years) was significantly associated with all 3 viral infections (mainly with HIV); b) i.v. cocaine use was associated with HBV, but even more with HIV; c) injection equipment-sharing partners in the last year was directly associated with HCV and inversely with HIV. No significant association was observed with the number of drug injections and the number of sexual partners. In conclusion, this study: a) demonstrates a difference of prevalence for HIV, HBV and HCV serum markers in this group of IVDUs from Catanzaro, Southern Italy; b) underlines the importance of i.v. cocaine use in the spreading of HIV; c) emphasizes the need of preventive strategies.

Anti-hepatitis C antibody prevalence among intravenous drug addicts in the Catanzaro area.

A higher seroprevalence of anti-HCV antibodies (63.4%) was found in 41 intravenous drug addicts (IVDA) when compared to 220 controls (1.8%). Life style is an important risk factor for HCV transmission among IVDA.