Biomedical subjects

E McCance-Katz

Publications and source records attributed to E McCance-Katz.

6 recordsLinked to original sources

PubMed2003

Clonidine and yohimbine in opioid-dependent humans responding under a naloxone novel-response discrimination procedure.

Opioid-maintained volunteers were trained to distinguish between a low dose of the opioid antagonist naloxone (0.15 mg/70 kg, i.m.; i.e. Drug A) and placebo (i.e. Drug B), under an instructed novel-response drug discrimination procedure in which subjects identify the drug condition as 'A', 'B', or 'N' (neither A nor B - 'novel'). Once the discrimination was acquired, doses of naloxone, the alpha2-adrenergic antagonist yohimbine, the alpha2-adrenergic agonist clonidine, and the training dose of naloxone in combination with clonidine were tested. Naloxone and yohimbine each produced a dose-related increase and decrease in naloxone- and 'novel'-appropriate responding, respectively, with the naloxone stimulus partially generalizing to yohimbine. Clonidine produced primarily placebo-appropriate responding. Naloxone produced expected changes in self-reports, but effects of yohimbine and clonidine were unremarkable, and yohimbine was never identified as an opioid antagonist. Clonidine partially attenuated naloxone-occasioned responding in a non-dose-related manner, and attenuated some, but not all, naloxone-induced changes in self-report measures. Naloxone attenuated or enhanced several clonidine-induced changes in self-report and physiological measures. These findings indicate that adrenergic mechanisms are involved in the expression of opioid withdrawal, but the involvement is indirect.

Adrenergic alpha-Agonists↗

PubMed2000

A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia.

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.

Alleles↗

PubMed1999

Pharmacotherapy of stimulant dependence: one of Japan's greatest public health challenges.

Stimulant dependence has become a major public health problem in the world over the last 15 years, and pharmacotherapies have been evolved based on our understanding of the neurobiological alterations induced by these drugs. Among the stimulants cocaine and amphetamine are the most common dependencies, and they share several common pathophysiologies in producing disease and in guiding medication approaches to treatment--neurotransmitter re-normalization, reversal of cerebral perfusion abnormalities and peripheral cocaine blockers. First is neurotransmitter re-normalization. A relative catecholamine deficiency occurs following prolonged abuse of cocaine and amphetamine due to transporter upregulation and receptor downregulation. This abnormality in dopamine and serotonin neurotransmission appears to be associated with depression and has supported antidepressant treatments to re-normalize neurotransmission. Dopaminergic and serotonergic agonists have also been given to re-normalize neurotransmission, but in contrast to substitution therapies such as methadone, LAAM or buprenorphine for opioids, these approaches have had limited success in unselected cocaine dependent patients. As a correlary approach to substitution, however, aspects of dopamine function can be augmented by dopamine beta hydroxylase inhibitors such as disulfiram to increase the aversive properties of stimulants and decrease their abuse. The second medication approach relates to cerebral perfusion defects and associated cognitive deficits due to vasoconstriction and abnormalities in platelets, which can respond to antiplatelet therapies as well as excitatory amino acid (EAA) antagonists. These EAA antagonists can prevent neuronal damage that is due to the release of EAA during cerebral ischemia induced by stimulant use. Finally, peripheral blockade treatment for cocaine may be possible using a newly developed active vaccine that blocks the uptake of cocaine from the bloodstream into the brain. Its potential efficacy has been shown in rodents that decrease their self-administration of cocaine when immunized with this vaccine, and preliminary human studies support its safety and immunogenicity. In summary, stimulant pharmacotherapy has made great progress in developing treatments based on understanding the neurobiology of these abused drugs, but these pharmacotherapies must be delivered in the context of appropriate behavioral and cognitive psychotherapies, which are also rapidly evolving.

Animals↗

PubMed1998

Effects of d-amphetamine and caffeine in humans under a cocaine discrimination procedure.

This study examined further the pharmacological specificity of an oral cocaine discriminative stimulus in humans. Five male cocaine-abusing volunteers (two African-American/three Caucasian) were trained to discriminate between a low dose of cocaine hydrochloride (80 mg/70 kg, p.o.) and placebo. Once the criterion for discrimination was met (i.e. > or = 80% correct responding for four consecutive sessions), dose-effect curves were determined for the dopamine reuptake inhibitor cocaine (20, 40, 80, 120 mg/70 kg, p.o.), the indirect dopamine agonist d-amphetamine (5, 10, 20 mg/70 kg, p.o.) and the adenosine antagonist caffeine (150, 300, 600 mg/70 kg, p.o.). Cocaine, d-amphetamine and caffeine each produced dose-related increases in cocaine-appropriate responding. Each compound produced at least a trend towards increases in a few stimulant-like self-reports and vital signs. When the relationship between cocaine-appropriate responding and self-reports were examined, cocaine and d-amphetamine, but not caffeine, had a similar profile of significant associations between discriminative performance and stimulant-like self-reports. These results suggest that, although the cocaine discriminative stimulus (80 mg/70 kg) is not specific only to stimulants with primarily dopaminergic actions, its pharmacological specificity may be more clearly defined when the relationship between discrimination and self-reports is examined.

Adult↗

PubMed1993

Limited therapeutic effect of addition of buspirone in fluvoxamine-refractory obsessive-compulsive disorder.

The authors found that buspirone added to the treatment of 33 patients with obsessive-compulsive disorder who were refractory to the serotonin reuptake inhibitor fluvoxamine was no better than placebo in reducing obsessive-compulsive, depressive, or anxiety symptoms. This finding suggests that addition of buspirone to ongoing fluvoxamine therapy is not an effective treatment strategy for most patients with obsessive-compulsive disorder.

Adult↗

PubMed1992

Serotonergic function during lithium augmentation of refractory depression.

Serotonergic mechanisms have been implicated in the pathophysiology of depression and in the neuropharmacology of antidepressant treatment. One measure of central serotonergic function is the prolactin (PRL) response to IV L-tryptophan (L-TRP). We used the L-TRP test to assess the role of serotonin in the mechanism of action of lithium augmentation in refractory major depression. Twenty-six patients with antidepressant-refractory major depression each received three L-TRP tests (after 2 weeks of placebo, after 4 weeks of active primary antidepressant, and after 1 week of lithium augmentation). Primary antidepressant treatment did not increase the PRL response, but lithium augmentation resulted in a statistically significant increase in PRL response as compared to both placebo pretreatment (P less than 0.04) and antidepressant treatment alone (P less than 0.025). This study supports a role for serotonergic mechanisms in the action of lithium augmentation.

Adult↗