Self-change and therapy change of smoking behavior: A comparison of processes of change in cessation and maintenance

Cigarette smokers who quit on their own (n = 29) were compared with subjects from two commercial therapy programs: A version Group (n = 18) and Behavior Management Group (n = 16). Subjects were administered a Change-Process Questionnaire and a demographic and smoking-history questionnaire within seven weeks of successful cessation, then interviewed again in five months. Using a transtheoretical model of change developed by Prochaska (1979) six verbal and four behavioral processes of change and three stages of change (Decision to Change; Active Change; Maintenance) were analyzed. Subjects in each treatment group were middle class, heavy-smoking adults. The change-process analysis of cessation discriminated between the self-quitters and therapy quitters and between the two groups of therapy subjects on five variables. Stages of change interacted with the processes of change in the cessation of smoking behavior. Verbal processes were seen as important in making the decision to change while action processes were critical for breaking the actual smoking habit. Maintenance of cessation was related to, but not dependent on, how subjects actively changed smoking behavior.     

Conjugation kinetics of acetaminophen by the perfused rat liver preparation

Sulfate conjugation of acetaminophen was studied in the perfused rat liver preparation. Varying input concentrations of unlabeled acetaminophen (0.22 to 6.0 μg/ml or 1.5 to 40 μM) were added in a stepwise fashion once-through the liver preparation at a flow rate of 10 ml/min. For the concentration range tested, acetaminophen sulfate conjugate remained the only detectable metabolite in perfusate plasma. Other metabolites such as the glucuronide and the glutathione conjugates, however, were detected only in bile and, together with the sulfate conjugate and unconjugated acetaminophen, constituted 5 per cent of the total administered dose. Hepatic elimination of acetaminophen in the formation of sulfate conjugate was apparently maximal at input concentrations ? 1.0 μg/ml (6.7 μM) and could be viewed as mediated via a uni-enzyme system. Sulfate conjugation also decreased with preloading of the liver, especially with high concentrations of acetaminophen. A plot of the ratio of the steady-state output concentrations of drug to metabolite versus the reciprocal of drug extraction ratio, which might prove useful in the prediction of metabolite concentrations in the liver, was introduced.     

Role of type A and type B monoamine oxidase in the metabolism of released [3H]dopamine from rat striatal slices

The effects of selective inhibition of multiple forms of monoamine oxidase (MAO) on the in vitro release and metabolism of newly-synthesized [³H]dopamine (DA) were examined using rat brain slices. Striatal slices were preincubated in the presence of [³H]l-tyrosine (20 μM) followed by a short incubation period in the presence of the selective irreversible MAO-inhibitor agents clorgyline (type A) and deprenyl (type B). Tissue pretreated in this manner was then subjected to a release incubation, and DA release and metabolism were determined under spontaneous and depolarizing conditions. Pretreatment with clorgyline (10^?7 M) significantly reduced the spontaneous, as well as K⁺-evoked, formation of both 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Deprenyl (10^?7 M) pretreatment did not significantly affect these variables, but clorgyline + deprenyl pretreatment resulted in a reduction of both DOPAC and HVA that was greater than that produced by clorgyline alone. By contrast, deprenyl pretreatment significantly decreased both DOPAC and HVA under depolarizing conditions, but only in the presence of the DA uptake inhibitor nomifensine (10^?5 M). In the absence of MAO inhibition, nomifensine increased K⁺-evoked formation of DOPAC and HVA, while spontaneous formation was not affected. The results suggest that released DA is deaminated primarily by the type A form of MAO; however, in the absence of the type A MAO, or under conditions that promote exclusive postsynaptic deamination, minor but significant metabolism occurs via the type B enzyme. Data obtained are further discussed in relation to the mechanism of MAO-inhibitor drug action and pre- versus postsynaptic formation of DOPAC and HVA.     

Effect of chlordecone on pH and temperature dependent substrate activation kinetics of rat brain synaptosomal ATPases

Chlordecone, a polycyclic chlorinated insecticide known as Kepone, inhibited the activities of (Na+-K+)ATPase and Mg2+-ATPase in rat brain synaptosomes. Altered pH and specific activity curves for both enzymes demonstrated significant inhibition by chlordecone in buffered acidic, neutral and alkaline pH ranges. Noncompetitive inhibition with respect to activation by ATP in the case of (Na+-K+)ATPase was indicated by altered Vmax values with no significant change in Km values at any pH studied, except at pH 9.5. Mg2+-ATPase was inhibited uncompetitively as evidenced by altered Vmax and Km values. The activities of both ATPase were decreased in the presence of chlordecone at higher temperatures. Activation energy (delta E) values were found to be decreased significantly in the presence of chlordecone at 37 degrees. Arrhenius plots of both ATPases preincubated with chlordecone were found to be nonlinear. In the presence of chlordecone, Vmax was decreased without significant change in Km values for (Na+-K+)ATPase at all temperatures, suggesting a noncompetitive type of inhibition. In the case of Mg2+-ATPase, similar noncompetitive type inhibition was obtained at 27 degrees but not at 32 and 37 degrees. The kinetic data in general suggest that the chlordecone inhibited (Na+-K+)ATPase noncompetitively and Mg2+-ATPase uncompetitively at all pHs and temperatures studied. The present data suggest that inhibition of (Na+-K+)ATPase and Mg2+-ATPase, the two membrane-bound enzymes in synaptosomes, by chlordecone is temperature dependent and pH independent.     

The influence of guanyl-5′-yl imidodiphosphate and sodium chloride on the binding of the muscarinic agonist, [3H] cis methyldioxolane

[³H]Quinuclydinyl benzylate([³H]QNB) binding was carried out on crude synaptosomal membranes isolated from cat cerebral cortex. The specific binding showed a single type of site with K_D 0.25 nM, Hill number 0.89 and B_max 114 pmol/g protein. The local anesthetics procaine, tetracaine, and the adrenergic antagonists phentolamine and propranolol, in concentrations between 1 nM and 500 μM, inhibited [³H]QNB binding with K_i varying between 9 μM for procaine and 80 μM for propranolol. The Hill coefficients obtained from logit/log plots suggested that there was no cooperativity between the binding sites for local anesthetics. At various concentrations the inhibition by procaine and propranolol may appear as competitive or non-competitive. The Hill numbers obtained from the saturation curves suggest that there was no cooperativity between anesthetics and [³H]QNB binding sites. Neither 1 mM Ca²⁺ nor Mg²⁺ affected [³H]QNB binding or the action of the drugs. The effect of local anesthetics and adrenergic antagonists was reversible and these drugs did not protect the muscarinic receptor from the deleterious effect of Triton X-100 as was the case with muscarinic agents. Our findings suggest that local anesthetics inhibit [³H]QNB binding to the muscarinic receptor by acting at some accessory site but not on the true receptor site. The possible mechanism of action of local anesthetics on synaptic transmission is discussed.     

Disposition and metabolism of [3H] cocaine in acutely and chronically treated monkeys

Monkeys were chronically treated with cocaine, 1 mg/kg subcutaneously twice daily for the first week and four times daily for the subsequent 21 weeks, followed by the same dose of [³H] cocaine injected intravenously. The $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ values of cocaine in the plasma, cerebrospinal fluid, liver, kidney and heart of acutely and chronically treated monkeys were 1.32, 0.85; 0.91, 0.75; 1.60, 1.29; 0.90, 0.91; and 1.02, 0.91 h, respectively. In areas of the central nervous system (CNS) the values for the acute and chronic group ranged between 0.75 – 0.90 and 0.62 – 0.84 h, respectively. With the exception of the temporal cortex, cerebellum and caudate nucleus, the $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ were not significantly different in the two groups. Norcocaine, benzoylnorecgonine, benzoylecgonine, and minor amounts of ecgonine were the metabolites of cocaine in the brain of monkeys. Significant amounts of total radioactivity due to benoylnorecgonine and benzoylecgonine persisted in the CNS of chronically treated monkeys. Norcocaine constituted approximately 3, 21, 8, and 6% of the values of cocaine in the CNS areas in the acutely treated monkeys, and 14, 13, 14, and 16% in the chronically treated ones, 0.25, 0.5, 1 and 2 h after cocaine injection. A biphasic pattern of peak levels in the plasma and bile of chronically treated monkeys indicated enterohepatic circulation of cocaine. Brain to plasma and CSF to plasma ratios of cocaine were higher in the chronic than in the acute group. The amounts of cocaine excreted in urine and feces as a percentage of dose were 0.23 – 5.1 and 0.1 – 0.23 in the acute group, 0.54 – 7.0 and 0.1 – 0.14 in the chronic group. Major excretion of radioactivity occurred in urine within 24 h and the mean values of the total radioactivity in urine and feces (96 h) in the acute and chronic groups were 60.4 and 63.2% of the dose, respectively. Norcocaine, benzoylnorecgonine, benzoylecgonine, ecgonine methyl ester, ecgonine, and unidentified compounds were the urinary metabolites of cocaine in the two groups. The percentage of benzoylecgonine was higher, that of benzoylnorecgonine lower, in the chronic than in the acute group and the values of other metabolites were not markedly different in the two groups. Data support the postulate that chronic treatment of monkeys with cocaine does not produce dispositional tolerance.     

Effects of various 2-amino-6-alkyldithiopurines on brain specific [3H]diazepam binding

Various derivatives of 2-amino-6-methylthiopurine with substituents at the 6-position of purine were tested for their abilities to displace [³H]diazepam binding to rat brain membranes. The potency was dependent on the carbon chain-length in the 6-position of purine. Among the derivatives tested, 2-amino-6-n-pentyldithiopurine had the highest potency, with a K_i value of 0.92, μM.     

Effects of pentachlorophenol on hepatic drug-metabolizing enzymes and porphyria related to contamination with chlorinated dibenzo-p-dioxins and dibenzofurans

The hepatic effects of technical and pure grade pentachlorophenol were investigated in female rats fed 20, 100 and 500 ppm of each for 8 months. Technical pentachlorophenol was contaminated with 8 ppm hexa-, 520 ppm hepta-, and 1380 ppm octachlorodibenzodioxtns and with 4 ppm tetra-, 42 ppm penta-, 90 ppm hexa-, 1500 ppm hepta- and 200 ppm octachlorodibenzofurans; pure pentachlorophenol contained less than 0.1 ppm of each of these contaminants. Technical pentachlorophenol produced hepatic porphyria and increased hepatic aryl hydrocarbon hydroxylase activity, glucuronyl transferase activity, liver weight, cytochrome P-450 and microsomal heme, but not N-demethylase activity. The peak of the CO-difference spectrum of cytochrome P-450 was shifted to 448 nm, and there was a dramatic increase in the 455-430 ratios of the ethyl isocyanide difference spectrum. The enzyme changes were observed at 20 ppm of technical pentachlorophenol. Porphyria occurred at 100 and 500 ppm. Pure pentachlorophenol had no significant effect on aryl hydrocarbon hydroxylase activity, liver weight, cytochrome P-450, microsomal heme, the ethyl isocyanide difference spectrum or N-demethylase activity at any dose level, but did increase glucuronyl transferase at 500 ppm. In contrast, both pure and technical pentachlorophenol decreased body weight gain comparably at 500 ppm. It is concluded that technical pentachlorophenol produces a number of liver changes which cannot be attributed to pentachlorophenol itself, but are consistent with the effects of biologically active chlorinated dibenzo-p-dioxins and dibenzofurans.     

Effects of neurohumoral and adrenergic agents on cyclic amp levels in various areas of the rat brain in vitro

When norepinephrine (NE) at 10^?5 M was added to slices of various areas of the rat brain in vitro there was a 2–5 fold increase in the level of adenosine 3',5'-monophosphate (cyclic AMP) within 6 min in all areas except the cerebellum. The basal level of cyclic AMP in the cerebellum was higher than in other areas of the rat brain, and the response to NE was smaller. Histamine and serotonin (5-HT) at 10^?5 M had no effect on cyclic AMP in any brain area. However, 5-HT when added simultaneously with NE, prevented the rise in cyclic AMP elicited by NE in the hypothalamus, midbrain and brainstem. Pargyline elevated the basal levels of cyclic AMP in all brain areas but did not potentiate the action of NE. Chronic reserpine pretreatment in the rat caused an enhanced cyclic AMP response to NE. No effect on cyclic AMP in any brain area was observed following dopamine, amphetamine, or prostaglandins E₁ and E₂. Theophylline slightly reduced cyclic AMP levels. In slices of rat hypogthalamus NE, epinephrine, isoproterenol and α-methyl NE, significantly elevated cyclic AMP levels. Phenylephrine and several “false” transmitters were without effect. Further studies in the hypothalamus revealed that both α and β adrenergic blocking agents effectively antagonized the cyclic AMP response to NE. These results are somewhat difficult to interpret because the precise cellular location of the observed changes are unknown.     

Effect of a single oral dose of malathion on D-glucose and glycine uptake and on brush border enzymes in rat intestine

The effect of a single oral dose of malathion (1 g/kg body wt.) on the digestive and absorptive functions of the intestinal epithelium has been investigated in rats. The absorption of glucose and glycine was considerably reduced (35%) in pesticide fed animals compared to controls. The activities of brush border sucrase, lactase, alkaline phosphatase, Mg²⁺-ATPase and lactate dehydrogenase were also significantly depressed in malathion exposed rats, but there was no change in the leucine aminopeptidase levels under these conditions. Mucosal DNA, RNA and protein contents remained unaltered in pesticide toxicity. These results suggest that malathion toxicity induces functional derangements of the intestine.     

Clofibrate-induced alterations in serum protein patterns

Clofibrate when added to the diet at 0.05 to 1.25% (w/w) not only causes an apparently dose-dependent decrease in serum cholesterol of rats but also markedly affects the plasma protein pattern. An increase in albumin is detectable by cellulose acetate strip electrophoresis, acrylamide gel electrophoresis, and by extraction of albumin from plasma. Cellulose acetate strip electrophoresis reveals a decrease in the α₂-globulin fraction, while acrylamide gel electrophoresis indicates that there are manifold changes. Extractable seromucoid concentration declined from 440 mg/100 ml to 150 mg/ml as the dose of clofibrate increased. A concentration decrease in plasma glucose was also observed. Part of the decrement in seromucoid at low drug levels may be related to lessened haptoglobin concentration. The trypsin inhibitory capacity of the plasma was significantly decreased in what appeared to be a dose-dependent fashion. The decrease in seromucoid is consistent with the reduction in bound fraction of ribosomal RNA. Another explanation would appear to be required to explain the rise in albumin.     

Genetic differences in the induction of aryl hydrocarbon hydroxylase and its components by 3-methylcholanthrene in liver and lung microsomes among four strains of guinea pigs

Four strains of guinea pigs (Hartley, No. 2, No. 13 and JY-1) were examined for the effects of intraperitoneal treatment with 3-methylcholanthrene on aryl hydrocarbon hydroxylase activity, total cytochrome P-450 content in liver and lung microsomes, and NADPH-cytochrome c reductase activity in liver microsomes. Following treatment with 3-methylcholanthrene at a dose of 50 mg/kg body weight, aryl hydrocarbon hydroxylase activity and cytochrome P-450 content in liver were both increased in all the strains used, and the activity of NADPH-cytochrome c reductase in liver was also increased in all strains except No. 13. While the cytochrome P-450 content in lung was increased in all the strains except No. 13, there was no increase in the aryl hydrocarbon hydroxylase activity in lung from any strain of guinea pig examined. When the dose of 3-methylcholanthrene was increased to 250 mg/kg body weight, an apparent induction of aryl hydrocarbon hydroxylase was detected in the lung from the Hartley strain of guinea pigs, but not in the other three strains. In summary, marked differences were seen in sensitivity to 3-methylcholanthrene between liver and lung, and apparent strain differences were observed among the guinea pigs used in this experiment.     

Release of endogenous catecholamines from isolated rat brain tissue by fenfluramine and N-ethylamphetamine—effects of pargyline

The influence of the monoamine oxidase inhibitor, pargyline. upon the release of endogenous norepinephrine from chopped rat cerebral cortex and endogenous dopamine from chopped rat corpus striatum by fenfluramine and N-ethylamphetamine was examined. Endogenous norepinephrine and dopamine were measured using an enzymatic-isotopic assay. Both fenfluramine and N-ethylamphetamine released significant amounts of each catecholamine. Fenfluramine-induced catecholamine release was associated with the decrease in the total content (i.e. catecholamine in media + catecholamine in tissue) of both cortical norepinephrine and striatal dopamine; N-elhylamphetamine decreased only total striatal dopamine content. In brain tissue obtained from rats pretreated with pargyline HCl (100 mg/kg, 12 hr prior to sacrifice), total cortical norepinephrine content was approximately twice that in the absence of pargyline: striatal dopamine was unchanged. Pargyline pretreatment also resulted in a marked potentiation of the amounts of both catecholamines released by each drug. and in an antagonism of the above drug-induced reductions in catecholamine content. Additionally, after pargyline pretreatment. N-ethylamphetamine reduced total cortical norepinephrine content. When pargyline (2.56 × 10^?1 M) was added to the media containing chopped cortical tissue from unpretreated animals, control content was slightly increased. Only fenfluramine-induced norepinephrine release was potentiated and the degree of potentiation was less than that observed after pargyline pretreatment. As with pargyline in vivo, pargyline in vitro also resulted in an antagonism of the fenfluramine-induced decrease in total norepinephrine and was associated with an N-ethylamphetamine-induced decrease in norepinephrine content. Since the locomotor stimulant effects of both fenfluramine and N-ethylamphetamine are potentiated after pargyline. the data are consistent with the importance of catecholamines to these effects. The data also suggest that pargyline potentiates the behavioral effects of fenfluramine and N-ethylamphetamine in part by increasing the pool of norepinephrine available for release by these drugs and in part by inhibiting the deamination of the released norepinephrine and dopamine by monoamine oxidase. Decreases in total norepinephrine produced by N-ethylamphetamine may reflect alterations in the formation of O-methylated amines.     

Isoproterenol and nucleotide induced stimulation of Ca2+ uptake by microsomal fractions from kidney and isolated glomeruli.

Renal cortical microsomal vesicles possess an ATP-dependent Ca²⁺ uptake system which is two to three times more active in accumulating Ca²⁺ than are the microsomes prepared from the outer medulla or papilla of the cat kidney. The microsomal Ca²⁺ uptake system was unaffected by sodium azide, and electron microscopy confirmed the absence of intact mitochondria. Ca²⁺ accumulating activity was significantly increased by 13 per cent in cortical microsomes prepared from kidneys which had been perfused with isoproterenol (2 × 10^?7 M), whereas medullary or papillary microsomal Ca²⁺ accumulation was unaffected. Perfusate containing a higher isoproterenol concentration (2 × 10^?6 M) stimulated cortical as well as papillary microsomal Ca²⁺ uptake by 13 and 31 per cent respectively, but had no effect on medullary microsomal Ca²⁺ accumulation. A lower isoproterenol concentration (2 × 10^?8 M) did not change the Ca²⁺ uptake activity of microsomes isolated from either region of the cat kidney. The isoproterenol concentrations (2 × 10^?7 and 2 × 10^?6 M) which activated Ca²⁺ uptake in microsomes produced graded increases in renin secretion, whereas 2 × 10^?8 M isoproterenol was relatively inactive in eliciting renin secretion. Renal cortical tissue exposed to cyclic AMP (cAMP) and 5'-AMP during subcellular fractionation showed significant increases in microsomal Ca²⁺ uptake. However, microsomes exposed to cAMP or 5'-AMP in the Ca²⁺ uptake medium were not stimulated. Isoproterenol also activated Ca²⁺ uptake by microsomes prepared from isolated glomeruli, and this stimulation was blocked by propranolol. We conclude that the cat renal cortex possesses specific receptors for isoproterenol which activate Ca²⁺ transport through a nucleotide mediated mechanism.