Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic deficits and reduces dendritic branching and spine density of neocortical pyramidal neurons

The role of basal forebrain-derived cholinergic afferents in the development of neocortex was studied in postnatal rats. Newborn rat pups received intraventricular injections of 192 IgG-saporin. Following survival periods ranging from 2 days to 6 months, the brains were processed to document the cholinergic lesion and to examine morphological consequences. Immunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the cholinergic neurons in the medial septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a marked reduction of the cholinergic axons in neocortex. Cholinergic axons are reduced throughout the cortical layers; this reduction is more marked in medial than in lateral cortical areas. The thickness of neocortex is reduced by approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal cells reveals a reduction in cell body size and also a reduction in numbers of branches of apical dendrites. Spine densities on apical dendrites are reduced by approximately 20-25% in 192 IgG- saporin-treated cases; no change was detected in number of spines on basal dendrites. These results indicate a developmental or maintenance role for cholinergic afferents to cerebral cortical neurons.      

ACUTE BUT NOT CHRONIC ANGIOTENSIN-CONVERTING ENZYME INHIBITION INDUCES ENZYME SYNTHESIS IN THE GLOMERULUS OF THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Treatment with angiotensin-converting enzyme (ACE) inhibitors slows the rate of progression of nephropathy in the spontaneously hypertensive rat (SHR) with streptozotocin-induced diabetes. Paradoxically, however, chronic ACE inhibitor therapy has been reported to be associated with induction of ACE in the plasma. We sought to determine whether induction also occurred in the glomerulus. 2. Seven days after induction of diabetes rats were randomized to receive perindopril (4mg/kg per day) in the drinking water or water alone. Blood glucoses were maintained 6–10 mmol/L by daily ultralente insulin. Rats were killed after 1 and 12 weeks of ACE inhibitor therapy and the kidneys were harvested. Angiotensin-converting enzyme activity was determined in isolated glomeruli before and after removal of perindopril and reconstitution with zinc sulphate. 3. After 1 week of ACE inhibitor therapy, glomerular ACE was significantly greater after removal of perindopril than either before its removal (P < 0.025) or in the untreated controls (P < 0.025). After 12 weeks of therapy, ACE activity was significantly lower in the perindopril-treated group than in the untreated controls (P < 0.025). There was no increase in ACE activity following removal of perindopril. 4. These studies suggest that short-term ACE inhibition is associated with induction of ACE in the glomerulus. However, there was no increase in ACE activity after removal of perindopril, suggesting that induction of synthesis of this enzyme in the glomerulus does not occur during chronic ACE inhibition.     

EVIDENCE FOR DIRECT INTERACTION OF KETAMINE WITH α- AND β2-ADRENOCEPTORS

1. Ketamine has a number of effects that suggest that it may interact with α- and β-adrenoceptors. To date, the experimental evidence for this has been indirect and has been based on physiological studies using competitive blocking agents. In the present study we sought to determine from receptor binding studies whether ketamine binds directly to α- and β-adrenoceptors. 2. Membrane preparations o. α₁- and β₂-adrenergic binding sites were obtained from urinary bladder and urethrae of sheep. These binding sites were characterized by saturation analyses using [³H]-prazosin for α₁-adrenoceptor binding sites and [¹²⁵I]-cyanopindolol (CYP) for the β₂-adrenoceptor binding sites. The receptors were further characterized by displacement studies using selective and non-selective antagonists. 3. Studies in which ketamine was used to displac. [³H]-prazosin revealed a K_d of 3.40±1.23× 10^?3 mol/L for ketamine binding to ai-adrenoceptors. Displacement studies of [¹²⁵I]-CYP by ketamine showed a K_d of 0.35±0.03× 10^?3 mol/L for ketamine binding to β₂-adrenoceptors. 4. We conclude that ketamine interacts directly with both ai- an. β₂-adrenoceptors and that such interactions probably explain the reported effects of this agent on the vasculature and the bronchial tree.     

The substance specificity of psychosocial correlates of alcohol, tobacco, coffee and drug use by Czech women

The paper reports results of an analysis based on face-to-face interviews with two samples of Prague women aged 20-49: (1) a probabilistic sample (h = 718) of the Prague female population; and (2) a sample of 152 inpatients treated for substance dependence/abuse. Of the inpatients, 79% were diagnosed as alcohol dependent only, 15% as both alcohol dependent and drug dependent/abusers, 6% as drug dependent only. With very few exceptions, those with drug problems among the inpatients abused analgesics, hypnotics, or anxiolytics. With data obtained from the general population sample, two-stage hierarchical logistic regression was run with each of the eleven differently defined substance uses as dependent variables. Four demographic variables were entered as predictors into the regression equations in the first stage. From the seven potential risk factors of substance use statistically significant predictors were entered stepwise in stage two. The major result of the study is the specificity of the pattern of predictors related to each of the eleven considered substance uses. It is also found that in the general population the use of a particular substance is generally uncorrelated with the use of other substances. Alcohol use (even heavy alcohol use) has no relation to smoking, to the use of analgesics, hypnotics, anxiolytics-and is connected with a specific pattern of predictors.