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Biomedical subjects

R H Lenox

Publications and source records attributed to R H Lenox.

At least 55 records · Page 3Linked to original sources
PubMed1994

Alprazolam withdrawal in patients with panic disorder and generalized anxiety disorder: vulnerability and effect of carbamazepine.

OBJECTIVE: This study was designed to examine the possibility that patients with panic disorder are especially vulnerable to alprazolam withdrawal, as well as to evaluate the efficacy of carbamazepine as adjunctive treatment during alprazolam discontinuation. METHOD: After a 2-month open trial of alprazolam, 36 patients with panic disorder and 35 with generalized anxiety disorder entered a controlled discontinuation phase. Carbamazepine or placebo was added in a randomized, double-blind fashion, followed after 1 week by single-blind dose reduction of alprazolam, approximately 25% every third day. RESULTS: Fifty-two percent of the patients were able to discontinue alprazolam, but only 37% completed the study, maintaining alprazolam-free status for 4 weeks. Survival analysis revealed that among the patients receiving placebo as adjunctive therapy, panic disorder patients had a significantly greater dropout rate than patients with generalized anxiety disorder. While carbamazepine exerted no beneficial effect for patients with generalized anxiety disorder, it appeared to improve outcome in the panic disorder group. CONCLUSIONS: Results of this study indicate that panic disorder patients are more vulnerable to alprazolam withdrawal than patients with generalized anxiety disorder, and this may reflect a general diathesis of panic disorder patients to encounter more difficulty during drug withdrawal. Carbamazepine may selectively assist with alprazolam withdrawal in panic disorder patients. However, these data do not support its widespread use during benzodiazepine discontinuation, especially given its potential toxicity. In light of a proposed greater vulnerability of panic disorder patients to withdrawal, future studies need to account for differential effects related to specific diagnosis.

Adult↗
PubMed1994

Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness.

Lithium, an effective treatment for mania and the prevention of recurrent episodes of both mania and depression in patients with manic depressive illness, exerts multiple biochemical effects. However, any clinically relevant site of action of lithium must occur at therapeutic concentrations attained in the brain of patients and must account for the lag period accompanying onset of action as well as effects persisting beyond discontinuation of treatment. This monovalent cation acts as a potent uncompetitive inhibitor in the receptor-coupled breakdown of inositol phospholipids, resulting in a relative depletion of inositol and an alteration in the generation of diacylglycerol, an endogenous activator of protein kinase C. In our laboratory, we are examining the action of chronically administered lithium on posttranslational modification of specific phosphoproteins involved in regulating signal transduction in the brain. We have found that chronic, but not acute, administration of lithium in rats markedly reduces a major phosphoprotein substrate of protein kinase C in the hippocampus, an effect that persists beyond the cessation of lithium treatment. This protein, myristoylated alanine-rich C kinase substrate ("MARCKS"), is implicated in synaptic neurotransmission, calcium regulation, and cytoskeletal restructuring. These findings have relevance for the long-term action of lithium in stabilizing an underlying dysregulation in the brain and may move us closer to formulating a molecular basis of manic depressive illness.

Bipolar Disorder↗
PubMed1992

Increased motor activity and recurrent manic episodes: predictors of rapid relapse in remitted bipolar disorder patients after lithium discontinuation.

Ten patients with remitted bipolar illness on lithium maintenance therapy underwent placebo-controlled lithium discontinuation. Clinical ratings and recording of sleep-wake activity using wrist-worn actigraphs were carried out before and after lithium discontinuation. Seven patients experienced relapse into mania or hypomania within the first 3 months after lithium discontinuation. Actigraphic recordings revealed that patients who relapsed had higher baseline levels of daytime motor activity than patients without relapse. This may suggest that motor activity can be a sensitive marker of subclinical manic tendencies and early relapse following lithium discontinuation.

Adult↗
PubMed1992

Chronic lithium administration alters a prominent PKC substrate in rat hippocampus.

The therapeutic effect of lithium in the treatment of bipolar disorder exhibits a significant delay in the onset of action and a persistence of efficacy beyond abrupt discontinuation of treatment. Lithium is known to alter receptor-coupled phosphoinositide second messenger pathway in brain, resulting in indirect changes in an endogenous activator of protein kinase C (PKC). Such evidence has suggested that PKC may be involved in the mechanism of action of lithium in the brain. PKC represents a site wherein long-term regulatory changes in cell function occur through the phosphorylation of specific phosphoproteins involved in processes including neurotransmitter release and receptor activation. In studies of rats exposed to lithium, however, we have found no significant effects of chronic administration on the relative activity, subcellular distribution, or activation of PKC in hippocampus. We did find a major reduction in the in vitro PKC mediated phosphorylation of two major substrates, 83 kDa and 45 kDa, in hippocampus of rats exposed to chronic lithium and maintaining clinically relevant therapeutic levels in brain. Using immunoblot analysis we have identified a known myristoylated alanine-rich C kinase substrate (MARCKS) at 83 kDa. In vivo levels of MARCKS in hippocampus were found to be significantly reduced after chronic lithium exposure. These findings persist in animals withdrawn from lithium, but are not apparent following acute treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Peripheral noradrenergic function during chronic lithium treatment in the rat.

Noradrenergic function was evaluated in the rat vas deferens following chronic treatment with lithium (30 mM in the diet for 2 weeks followed by 50 mM for 1 week). No alteration could be detected in: a) 3H-noradrenaline release evoked by electrical field stimulation, b) alpha 1-adrenoceptor function as assessed by contractile response to noradrenaline, c) active neuronal uptake of 3H-noradrenaline, d) alpha 2-adrenoceptor activity, as assessed by yohimbine-enhancement of evoked release of 3H-noradrenaline. The data argue against a primary action of lithium on the noradrenergic nerve. On the other hand, these findings do not rule out the possibility that the function of CNS noradrenergic neurons could be altered as a result of the known effects of lithium on the phosphatidyl-inositol system, and the greater sensitivity of CNS neurons to depletion of the neuronal membrane inositol pool.

Animals↗
PubMed1992

Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study.

BACKGROUND: While lithium is effective in treating the majority of bipolar patients during a manic episode, the addition of neuroleptic during the early phase of treatment has been common clinical practice in inpatient settings. In an earlier open study, we demonstrated the utility of the short-acting benzodiazepine lorazepam as an adjunct to lithium for the clinical management of manic agitation. METHOD: We now present data from a randomized, double-blind clinical study of lorazepam versus haloperidol in 20 hospitalized patients with a DSM-III-R diagnosis of bipolar disorder who were being treated concomitantly with lithium. Patients were rated using the Mania Rating Scale, Brief Psychiatric Rating Scale, Physician Global Impression Scale, and side effects scales. Data were analyzed using standard group comparisons and survival analysis. RESULTS: There was no evidence for a significant difference between the two treatment groups in the magnitude of or time to response (5.0 +/- .82 days for haloperidol; 6.5 +/- .93 days for lorazepam). Of the patients who were terminated from the protocol early, nonresponse was the primary reason in the lorazepam group while side effects were the reason in the haloperidol group. CONCLUSION: Lorazepam may offer an efficacious and safe alternative to haloperidol as an adjunctive treatment to lithium in the clinical management of the early phase of manic agitation in a subgroup of bipolar patients.

Adult↗
PubMed1991

Muscarinic receptor regulation and protein kinase C: sites for the action of chronic lithium in the hippocampus.

Regulation of muscarinic receptor activity in critical regions of the limbic system may represent a site for the therapeutic action of lithium. Muscarinic receptors in the hippocampus are coupled to phosphoinositide (PI) hydrolysis and the generation of the second messengers inositol (1,4,5) trisphosphate [Ins (1,4,5)P3] as well as diacylglycerol (DAG), which can directly activate protein kinase C (PKC). Since lithium may affect the regeneration of critical receptor-coupled pools of phosphatidylinositol 4,5-bisphosphate, studies in our laboratory have investigated the effects of chronic lithium on the regulation of the muscarinic receptor response. We have recently demonstrated that, following chronic administration of atropine in control and chronic lithium animals, there is an up-regulation of muscarinic receptor binding sites in the hippocampus; however, a concomitant sensitization of the carbachol-stimulated PI response is observed only in control animals. We have so far detected no effects of either in vitro or in vivo lithium on muscarinic receptor interactions with G proteins. However, we have observed a reduction in the in vitro phosphorylation of a major PKC phosphoprotein substrate in the rat hippocampus, following chronic lithium treatment. This effect may be related to long-lasting changes in regulation of receptor activity.

Animals↗
PubMed1991

Referral and screening patterns at a clinic for anxiety disorders; implications for the planning of clinical studies.

During a two year period (1988-1990), 302 patients who were referred to our anxiety disorder clinic were evaluated and diagnosed according to a screening procedure which will be described. Of these initial referrals, 171 met a DSM-3-R diagnosis of panic disorder (with or without agorophobia) or generalized anxiety disorder; 81 patients (27% of the initial referrals) participated in a double blind placebo controlled clinical trial with a dropout rate of 12%. The implications for the planning and design of referral and screening strategies at research oriented specialized clinics are discussed.

Adult↗
PubMed1990

Chronic lithium treatment prevents atropine-induced supersensitivity of the muscarinic phosphoinositide response in rat hippocampus.

Rats were placed on a lithium diet for 3 weeks or an identical diet without lithium for the same period. During the third week, atropine sulfate (10 mg/kg/day) or saline was infused via subcutaneously implanted osmotic pumps. Twenty-four hours following the removal of the pumps, brain slices and membranes were prepared from the cortex and hippocampus for determination of muscarinic stimulation of phosphoinositide turnover and for receptor-binding studies. Treatment with lithium alone did not significantly affect any of the binding or response parameters measured. Administration of atropine led to (1) an upregulation of muscarinic binding sites in both cortex and hippocampus without significant alteration in the proportion of muscarinic receptor subtypes; and (2) an enhancement of the muscarinic phosphoinositide response in hippocampal slices. However, atropine did not induce supersensitivity of the hippocampal response in rats undergoing lithium administration. These results are consistent with recent suggestions that lithium's efficacy in affective disorders may be related to a dampening of muscarinic supersensitivity.

Animals↗
PubMed1990

Criterion for learned helplessness in the rat: a redefinition.

Numerous investigators have reported difficulty obtaining reliable learned helplessness. Various laboratories have used differing test environments and criteria, making comparisons among experiments difficult. Some use an escape deficit criterion, in which escape is slowed down in a shuttle box, while others have used an escape failure criterion, in which rats do not escape at all on most test trials. Little work has been done to test the validity of LH, i.e., the prediction of persistence of escape failure after exposure to uncontrollable shock. The present studies demonstrate that the reliability and validity of learned helplessness can be improved by 1) modifying the shuttle box to increase task difficulty and decrease random escape behavior and 2) adopting a new escape failure criterion for helpless behavior which is based on statistical prediction of the persistence of escape deficits.

Animals↗
PubMed1989

Translocation and activation of protein kinase C in striatal neurons in primary culture: relationship to phorbol dibutyrate actions on the inositol phosphate generating system and neurotransmitter release.

The actions of the tumor-promoting phorbol ester phorbol dibutyrate were examined, under identical physiological conditions, on three distinct cellular processes in striatal neurons: the distribution of protein kinase C, the carbachol-stimulated generation of [3H]inositol monophosphate, and the KCl-evoked release of gamma-[3H]aminobutyric acid ([3H]GABA). Phorbol dibutyrate induced a rapid (complete in 5 min), dose-dependent, entirely reversible (t0.5 = 15 min) translocation of protein kinase C from cytosol to membrane. On longer exposure to phorbol dibutyrate, membrane-associated protein kinase C returned toward the control level, and total cellular enzyme activity declined markedly. Phorbol dibutyrate also induced the dose-dependent attenuation of carbachol-stimulated [3H]inositol monophosphate production and potentiation of KCl-evoked release of [3H]GABA. The translocation of protein kinase C and the potentiation of KCl-evoked [3H]GABA release were both rapidly reversed following washout of phorbol dibutyrate. In addition, for both processes, the effect of a 1-h exposure to phorbol dibutyrate was markedly less than that observed following a 5-min exposure to the agent. In direct contrast, inhibition of carbachol-stimulated [3H]inositol monophosphate production was not rapidly reversed following washout of phorbol dibutyrate and was actually more pronounced following a 1-h exposure, compared with a 5-min exposure. These findings indicate that some, but not all, of the actions of phorbol dibutyrate are closely associated with the translocation of protein kinase C in striatal neurons in primary culture.

Animals↗
PubMed1989

Do volunteer subjects bias clinical trials?

The availability of volunteers for research on antidepressant medications raises questions about similarities between symptomatic volunteers and clinic patients. Volunteers accepted for a depression study and patients with major depressive disorder have been shown to have some similarities with regard to depressive symptoms and responses to treatment. However, it is unknown whether the population from which volunteers are drawn differs from the patient population in other ways that affect the generalizability of research findings. Respondents to newspaper advertisements for symptomatic volunteers and new clinic patients at a university-based, outpatient psychiatric facility received the Beck Depression Inventory, the Millon Behavioral Health Inventory and a questionnaire developed for the study. The first 30 respondents in each group with a Beck Depression Inventory score of at least 10 constituted the sample. No significant differences (p less than 0.05) between the groups were found on demographics, coping styles with help givers, perceptions of psychosocial stress, or overall depression severity. However, volunteers were sadder, more discouraged, and less interested in others than clinic patients. Symptomatic volunteers also more frequently reported financial concerns as an important factor in the decision about seeking help. However, they reported the desire to find effective treatment as the primary factor in the decision. Clinic patients, on the other hand, cited being referred as primary in the seeking help decision, with the desire for effective treatment being secondary. Results of this study suggest that volunteers for drug research are similar in important ways to persons who seek treatment for similar symptomatology. They also suggest that perception of need for treatment may be affected by the strength of specific depressive symptoms.

Adaptation, Psychological↗
PubMed1988

Alpha-2 adrenergic receptor binding in platelets and brains of nervous and normal pointer dogs.

Nervous pointer dogs have been suggested as an animal model for certain human pathological anxiety states. Work done in humans and in animals suggests a role for noradrenergic overactivity in the manifestations of anxiety. We studied alpha 2 adrenergic receptor binding as determined by [3H]-yohimbine in platelets and brains of the nervous and normal dogs in our colony. Our findings indicate that alpha 2 adrenergic receptor density and affinity are similar in platelets and frontal cortex, but we did not observe significant differences in binding between the two groups of dogs.

Animals↗
PubMed1988

Desensitization of muscarinic receptor-coupled phosphoinositide hydrolysis in rat hippocampus: comparisons with the alpha 1-adrenergic response.

In the presence of lithium, carbamylcholine chloride (carbachol) and epinephrine increase the accumulation of inositol monophosphate severalfold in hippocampal slices from the rat. The stimulation by carbachol (EC50, 31 microM) is mediated by muscarinic receptors, whereas the effects of epinephrine (EC50, 2 microM) are due to activation of alpha 1-adrenergic receptors. The responses of epinephrine and carbachol are additive, even under conditions that significantly reduce the levels of phosphoinositides and free inositol, suggesting that the muscarinic and adrenergic receptors may be located on separate cells. At concentrations that saturate their respective receptors, epinephrine induces an increase in inositol monophosphate that is linear with time to at least 60 min, whereas the response to carbachol begins to reach a plateau by 20-40 min. When hippocampal slices are preincubated with saturating concentrations of carbachol, the subsequent response to carbachol is reduced by 42%. However, preincubation with carbachol or epinephrine has no effect on the subsequent response to epinephrine. Despite the lack of adrenergic desensitization by this paradigm, preexposure of hippocampal slices to the tumor-promoting phorbol ester, phorbol 12,13-dibutyrate, reduces the response to epinephrine to a significantly greater degree (57%) than it reduces the muscarinic response (25%). These studies indicate that, although they utilize the same second messenger, the muscarinic and alpha 1-adrenergic receptors of hippocampal slices have different characteristics and regulatory mechanisms.

Animals↗
PubMed1988

Modulation of neuronal signal transduction systems by extracellular ATP.

The secretion of ATP by stimulated nerves is well documented. Following repetitive stimulation, extracellular ATP at the synapse can accumulate to levels estimated to be well over 100 microM. The present study examined the effects of extracellular ATP in the concentration range of 0.1-1.0 mM on second-messenger-generating systems in cultured neural cells of the clones NG108-15 and N1E-115. Cells in a medium mimicking the physiological extracellular environment were used to measure 45Ca2+ uptake, changes in free intracellular Ca2+ levels by the probes aequorin and Quin-2, de novo generation of cyclic GMP and cyclic AMP from intracellular GTP and ATP pools prelabeled with [3H]guanosine and [3H]adenine, respectively, and phosphoinositide metabolism in cells preloaded with [3H]inositol and assayed in the presence of LiCl. Extracellular ATP induced a concentration-dependent increase of 45Ca2+ uptake by intact cells, which was additive with the uptake induced by K+ depolarization. The increased uptake involved elevation of intracellular free Ca2+ ions, evidenced by measuring aequorin and Quin-2 signals. At the same concentration range (0.1-1.0 mM), extracellular ATP induced an increase in [3H]cyclic GMP formation, and a decrease in prostaglandin E1-stimulated [3H]cyclic AMP generation. In addition, extracellular ATP (1 mM) caused a large (15-fold) increase in [3H]inositol phosphates accumulation, and this effect was blocked by including La3+ ions in the assay medium. In parallel experiments, we found in NG108-15 cells surface protein phosphorylation activity that had an apparent Km for extracellular ATP at the same concentration required to produce half-maximal effects on Ca2+ uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1987

Alpha 2-adrenergic receptors mediate inhibition of cyclic AMP production in neurons in primary culture.

The actions of adrenergic agents on the intracellular production of cyclic adenosine monophosphate (AMP) was examined in intact cortical and striatal neurons in primary culture, generated from the fetal mouse brain. Exposure of striatal neurons to the beta-adrenergic agonist isoproterenol (10 microM) resulted in a 5-fold increase in intraneuronal cyclic AMP; norepinephrine (100 microM), alone or in combination with isoproterenol, produced only a 3-fold increase in cyclic AMP levels. However, in the presence of yohimbine (10 microM), cyclic AMP productions due to norepinephrine or isoproterenol plus norepinephrine were identical to isoproterenol alone. When striatal or cortical neurons were exposed to pertussis toxin (100 ng/ml) overnight, there was no detectable difference between isoproterenol- and norepinephrine-stimulated cyclic AMP production. These data suggest that alpha 2-adrenergic receptors mediate the attenuation of cyclic AMP production in neurons and do so via the inhibitory guanine nucleotide regulatory protein of adenylate cyclase.

Adenylate Cyclase Toxin↗
PubMed1987

Interactions of the alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines.

PAF-acether, a naturally occurring phospholipid, is a potent activator of various biological processes, including platelet aggregation. The mechanisms of action of PAF are largely unknown. We have found that the psychotropic triazolobenzodiazepine drugs, alprazolam and triazolam, potently (IC50 less than 1 microM) inhibit PAF-induced shape change, aggregation and secretion of human platelets. These effects are specific for PAF-activation, since the responses of human platelets to other agonists (ADP, thrombin, epinephrine, collagen, arachidonate and the Ca++ ionophore, A23187) are not inhibited by these triazolobenzodiazepines. The action of triazolobenzodiazepines on PAF-induced platelet function has clinical relevance, especially in diseases where enhanced platelet aggregability may lead to thrombosis and atherosclerosis. In addition, the ability of triazolobenzodiazepines to inhibit other PAF-mediated cellular-responses, such as anaphylactic shock or bronchoconstriction, suggests that these drugs may be useful in preventing several known pathophysiological effects of PAF. The specific antagonism of PAF action by psychotropic drugs also suggests that PAF or PAF-like phospholipids may play a role in neuronal function. This possibility was tested by examining the effects of PAF on neural cells of the clonal line NG108-15, grown in culture in a chemically defined, serum-free medium. Low concentrations of PAF (0.5-2.5 microM) induced neurite extension in NG108-15 cells, whereas higher concentrations (greater than 3 microM) were cytotoxic. Using NG108-15 cells preloaded with aequorin, it was found that PAF causes an increase in intracellular ionized calcium concentration, which is dependent on the presence of extracellular calcium. These results suggest that PAF-induced Ca++ uptake may play a role in neuronal development, and that circulating PAF may contribute to the neuronal degeneration caused by the exposure of neural tissues to blood in situations such as spinal cord injury, trauma, or stroke.

Animals↗