Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon.

We previously reported that treatment and withdrawal from cocaine increases: (1) 5-HT2A receptor-mediated neuroendocrine responses, and (2) Galphaq and Galpha11 G-protein levels in the hypothalamic paraventricular nucleus (PVN) at 48 h post-treatment. This study investigates changes in the initial 24 h of withdrawal to discern whether 5-HT2A receptor supersensitivity is due to cocaine treatment or is induced during the withdrawal period. We report here increases in 5-HT2A receptor-mediated neuroendocrine responses only 12 or 24 h post-treatment, but not during the initial 4 h withdrawal period. Levels of membrane- or cytosol-associated Galphaq or Galpha11 proteins in PVN are not altered during the first 24 h of withdrawal. However, the density of 125I-(-)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI)-labeled high-affinity 5-HT2A receptors in PVN increased 35% in rats withdrawn from cocaine for 24 h. These findings demonstrate that cocaine-induced increases in 5-HT2A receptor function in PVN represents a withdrawal-induced phenomena that: (1) is likely attributed to increased G-protein coupled/high-affinity conformational state of the 5-HT2A receptor, and (2) occurs in the absence of changes in the levels of associated G proteins during the first 24 h.

Effect of valproic acid on serotonin-2A receptor signaling in C6 glioma cells.

Valproic acid (VPA), which has demonstrated efficacy in the treatment of bipolar disorder, has been shown to alter components of the phosphoinositide (PI) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 (AP-1). Central serotonin-2A (5-HT2A) receptors, which have been implicated in the pathophysiology of manic-depressive illness, are coupled to PI hydrolysis. The promoter region of the 5-HT2A receptor gene contains AP-1 binding sites. We examined in C6 glioma cells the effect of VPA on 5-HT2A receptor signaling. Treatment of cells with VPA (100 microg/mL) for 20 h, but not 1.5 h, resulted in an enhancement of 5-HT2A receptor-stimulated PI hydrolysis. This effect of 20-h VPA exposure appeared not to be at the level of G protein or effector (i.e. phospholipase C: PLC) as inositol phosphate accumulation stimulated by aluminum fluoride or the PLC activator 2,4,6-trimethyl-N-(m-3-trifluromethylphenyl) benzenesulfonamide was not increased. The number of 5-HT2A receptors, as determined in saturation binding experiments using [3H]ketanserin, was increased by 20-h VPA treatment, with no change in affinity (KD). Taken together, our data suggest that the increase in 5-HT2A receptor-mediated PI hydrolysis following 20-h VPA exposure is not due to a general effect of VPA on this signaling cascade, but due to the up-regulation of 5-HT2A receptor number.

Estrogen treatment increases the levels of regulator of G protein signaling-Z1 in the hypothalamic paraventricular nucleus: possible role in desensitization of 5-hydroxytryptamine1A receptors.

Desensitization of post-synaptic serotonin1A (5-HT1A) receptors may underlie the clinical improvement of neuropsychiatric disorders. In the hypothalamic paraventricular nucleus, Galphaz proteins mediate the 5-HT1A receptor-stimulated increases in hormone release. Regulator of G protein signaling-Z1 (RGSZ1) is a GTPase-activating protein selective for Galphaz proteins. RGSZ1 regulates the duration of interaction between Galphaz proteins and effector systems. The present investigation determined the levels of RGSZ1 in the hypothalamic paraventricular nucleus of rats subjected to four different treatment protocols that produce desensitization of 5-HT1A receptors. These protocols include: daily administration of beta estradiol 3-benzoate (estradiol) for 2 days; daily administration of fluoxetine for 3 and 14 days; daily administration of cocaine for 7 or 14 days; and acute administration of (+/-)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI; a 5-HT2A/2C receptor agonist). Estradiol treatment was the only protocol that increased the levels of RGSZ1 protein in the hypothalamic paraventricular nucleus in a dose-dependent manner (46%-132% over control). Interestingly, previous experiments indicate that only estradiol produces a decreased Emax of 5-HT1A receptor-stimulation of hormone release, whereas fluoxetine, cocaine and DOI produce a shift to the right (increased ED50). Thus, the desensitization of 5-HT1A receptors by estradiol might be attributable to increased levels of RGSZ1 protein. These findings may provide insight into the adaptation of 5-HT1A receptor signaling during pharmacotherapies of mood disorders in women and the well-established gender differences in the vulnerability to depression.

The prevalence of methicillin-resistant staphylococcus aureus among the residents of six nursing homes for the elderly.

Admissions to Irish hospitals from nursing homes are recognized as a high-risk category for methicillin-resistant Staphylococcus aureus (MRSA) colonization. This study was conducted between August 1994 and May 1995 to determine the prevalence of MRSA within six Eastern Health Board elderly care nursing homes. A point prevalence survey was conducted in each home on two separate occasions at an interval of five to six months. An MRSA prevalence rate of 8.6% (65 of 754 residents) was recorded for the first survey, and an increased prevalence rate 10.1% (75 of 743 residents) for the second. The prevalence rates within individual homes varied from 1-27%. The body site most commonly colonized was the nares (83%), as anticipated. The main unexpected finding was a low wound colonization rate of 12%, which increased to only 20%, among MRSA positive residents. The dynamic state of MRSA colonization within nursing homes was documented among the 587 residents screened in both surveys. The MRSA positive status of 19 residents remained unchanged, but 32 who were initially positive became negative, while 34 residents acquired the organism. Twenty-six of the 56 (46%) residents identified as MRSA positive in the second survey had acquired the organism within the nursing home over the preceding five to six months. These findings suggest that 'infection control' interventions could have a significant impact on MRSA prevalence within nursing homes.

Importance of models for recovery from alcoholism: another view.

Models of alcoholism abound providing unicausal explanations of this complex problem and leading to narrow perspectives on treatment of alcoholics. All models contain elements of truth and there is a trend toward considering the role of various factors in alcoholism. Some effort has been made to incorporate more than one model into a treatment approach. This paper is another effort at synthesis and integration of various models into a comprehensive treatment plan. It recommends the addition of the sociological and familial interaction models to medical, psychogenic and moral ones, and suggests that focus of treatment should be shifted from an individual alcoholic to the alcoholic-in-his-social-situation.