Biomedical subjects

Carol A Paronis

Publications and source records attributed to Carol A Paronis.

6 recordsLinked to original sources

PubMed2006

Modulating GABA modulators.

Benzodiazepines produce a broad spectrum of behavioral effects, which may be clinically desirable or undesirable, by positively or negatively modulating the effects of GABA at GABAA receptors. Over the past 20 years, much effort has been devoted towards identifying new compounds with limited undesirable effects. Most of this work has focused on developing drugs either with lower intrinsic activity than drugs such as diazepam, or with different binding profiles at subtypes of GABAA receptors. However, the benzodiazepine binding site is only one of multiple binding sites contained within the GABAA receptor complex, and other endogenous or exogenous compounds also may positively or negatively modulate the effects of GABA. Despite the availability of ligands for each of these distinct binding sites, very little research has examined the effects of GABA modulators given in combination. This may be due, in part, to the noncompelling results of those few studies which, depending on the particular drugs, have demonstrated site-selective antagonism or only additive effects, suggesting that each site modulates the effects of GABA independently. In this issue, McMahon and France challenge this view by showing that low-efficacy benzodiazepine ligands will effectively antagonize midazolam and, at the same doses, will enhance the effects of a neuroactive steroid. These studies raise interesting questions regarding the nature of the interaction between the benzodiazepine and neurosteroid binding sites on GABAA receptors.

Animals↗

PubMed2006

Measuring the reinforcing strength of abused drugs.

Animal models for human diseases are highly valued for their utility in developing new therapies. Animals have long provided suitable platforms for the development of innovative surgical procedures and for the study of disease states that are relatively easy to produce in otherwise healthy animals, such as diabetes or hypertension. Increasingly, new strains of animals susceptible to common human illnesses are being introduced into medical research, promising new inroads into the treatment of a variety of organic disorders. Despite these advances in model development, psychiatric disorders, by and large, remain among the hardest to induce experimentally, and the search for reasonable animal procedures to study diseases of the mind is an ongoing challenge for experimental biologists. An exception to this limitation, however, comes in the study of drug abuse. Major developments in this area of research over the last several decades have steadily advanced our ability to identify pharmacological, genetic, and environmental determinants that contribute to the development of drug dependence and addictive behavior.

Animals↗

PubMed2005

Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys.

Most medications prescribed for attention-deficit-hyperactivity disorder are psychomotor stimulants with reinforcing effects in laboratory animals (eg methylphenidate). The present studies were conducted to evaluate the reinforcing effects of the recently approved medication atomoxetine in monkeys trained to 'choose' between automated deliveries of either an i.v. injection or food. Rhesus monkeys were trained to lever-press under concurrent schedules of reinforcement; responses on one lever resulted in an injection of either saline or drug, and responses on the alternative lever resulted in food delivery. Data were collected on four measures: response rates, percentage of total responses occurring on the injection-lever (% ILR), number of injections earned, and number of food pellets earned. Dose-effect functions were determined for cocaine (0.003-0.3 mg/kg/inj), methylphenidate (0.003-0.1 mg/kg/inj), amphetamine (0.003-0.1 mg/kg/inj), atomoxetine (0.01-0.3 mg/kg/inj), and desipramine (0.03-1.0 mg/kg/inj) using a double alternation schedule of saline and drug availability. Results indicate that the distribution of behavior changed according to the drug and dose available for self-injection. Saline availability was typically associated with high rates of food-maintained responding. The % ILR increased from 3+/-1% when saline was available to >90% when >0.03 mg/kg/inj of cocaine, methylphenidate or d-amphetamine was available. However, no dose of atomoxetine or desipramine maintained self-administration behavior on the injection-lever. The number of food pellets earned per session decreased as the dose of each drug increased, indicative of behavioral activity with all five drugs. The reinforcing effects of cocaine, methylphenidate, and d-amphetamine in these studies are consistent with previous findings in nonhuman primates and with their documented abuse liability. The absence of reinforcing effects of atomoxetine support the view that, like desipramine, it has no evident abuse potential.

Adrenergic Uptake Inhibitors↗

PubMed2003

Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys.

The allocation of "choice" behavior provides a measure that may be useful in developing experimental models of clinical relapse. In the present experiments, indirect monoaminergic agonists [cocaine, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909), desipramine, and citalopram], and dopaminergic D1 family agonists [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 82958), R-(+)-6-bromo-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (R-(+)-6-BrAPB), and 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 83959)] and D2 family agonists [quinelorane, R-(-)-10,11-dihydroxy-N-n-propylnorapomorphine (R-NPA), (+)-N-propyl-hydroxynaphoxazine [(+)-PHNO], and S-(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol (PD 128907)] were evaluated for their capacity to alter the distribution of choice behavior in cocaine-experienced monkeys. Rhesus monkeys responded on two levers (injection-lever and food-lever) under concurrent fixed ratio 30; fixed ratio 30 schedules of i.v. cocaine and food delivery. Under training conditions, the distribution of behavior was related to the unit dose of i.v. cocaine: when saline was available, responding occurred predominantly on the food-lever and when reinforcing doses of cocaine were available, responding occurred predominantly on the injection-lever. Drugs were studied by administering i.m. pretreatment doses before components in sessions of i.v. saline availability. Cocaine produced dose-related increases in injection-lever responding in all monkeys, whereas desipramine failed to alter the distribution of behavior in any monkey. The dopamine transport blocker GBR 12909 and each dopamine D1 family agonist markedly increased injection-lever responding in three of four monkeys; the serotonin transport blocker citalopram and D2 family agonists were comparably effective in only one or two monkeys. These results agree with previous findings of similarity in the behavioral effects of cocaine and indirect or direct dopamine agonists and suggest, furthermore, that i.v. self-administration behavior engendered by priming doses of cocaine may involve actions mediated through both D1 and D2 families of dopamine receptors.

Animals↗

PubMed2003

Smoking, stress, and negative affect: correlation, causation, and context across stages of smoking.

This transdisciplinary review of the literature addresses the questions, Do stress and negative affect (NA) promote smoking? and Does smoking genuinely relieve stress and NA? Drawing on both human and animal literatures, the authors examine these questions across three developmental stages of smoking--initiation, maintenance, and relapse. Methodological and conceptual distinctions relating to within- and between-subjects levels of analyses are emphasized throughout the review. Potential mechanisms underlying links between stress and NA and smoking are also reviewed. Relative to direct-effect explanations, the authors argue that contextual mediator-moderator approaches hold greater potential for elucidating complex associations between NA and stress and smoking. The authors conclude with recommendations for research initiatives that draw on more sophisticated theories and methodologies.

Animals↗

PubMed2002

Effects of cocaine under concurrent fixed ratio schedules of food and IV drug availability: a novel choice procedure in monkeys.

RATIONALE: The relative reinforcing strength of cocaine can be characterized by the distribution of operant behavior during the availability of other reinforcing stimuli. OBJECTIVE: To develop a procedure to rapidly evaluate the relative reinforcing strength of cocaine in monkeys. METHODS: Monkeys were trained to respond on two levers under concurrent fixed-ratio 30 (FR30) schedules of reinforcement. Responding on one lever resulted in food delivery, responding on the alternative lever resulted in delivery of IV saline or cocaine (0.032 or 0.1 mg/kg per injection). Daily sessions consisted of three 30-min components separated by 10-min timeout periods. The availability of saline, 0.032, or 0.1 mg/kg per injection cocaine varied across components, and only in an ascending order. The relative reinforcing strength of 0.0032-0.32 mg/kg per injection cocaine was examined by substituting different unit doses for the training doses of cocaine. Effects of cocaine pretreatment on response distribution were determined by giving IM injections of 0.1-1.8 mg/kg cocaine 10 min prior to sessions of saline availability. RESULTS: Increasing unit doses of cocaine monotonically increased the distribution of responding on the injection-lever and monotonically deceased response rates. Responding occurred predominantly on the food-lever during availability of saline or 0.0032 mg/kg per injection cocaine, whereas availability of 0.032-0.32 mg/kg per injection produced >90% of responding on the injection-lever. Availability of 0.01 mg/kg per injection cocaine resulted in approximately equal levels of responding on the food- and injection-levers. Presession IM cocaine injections dose-dependently increased responding on the injection-lever. CONCLUSIONS: Stable behavior can be maintained under concurrent FR schedules of food and cocaine presentation in monkeys, and the distribution of behavior on food- and injection-levers is dependent on the available dose of cocaine.

Animals↗