Nicotinic aspects of the discriminative stimulus effects of arecoline.

Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The goal of this work was to understand more about the mediation of discriminative stimulus effects of arecoline. Arecoline (1.

Nicotine-like discriminative and aversive effects of two α4β2-selective nicotine agonists, ispronicline and metanicotine.

An attempt to determine the receptor selective nature of some of nicotine's behavioral effects was undertaken through the evaluation of the ability of two nicotinic α4β2*-selective receptor agonists to produce nicotine-like effects and modify rates of responding in a discrimination assay and in an aversive stimulus assay. A group of eight rats was trained to discriminate the presence of 1 mg/kg nicotine base. Another group of 4-6 rats was trained to report the aversive effects of nicotine by selecting a lever that produced one food pellet over a second lever that produced two food pellets and an intravenous injection of nicotine.

Novel Antimuscarinic Antidepressant-like Compounds with Reduced Effects on Cognition.

The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage of the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggravate cognitive deficits that occur with depression itself. Thus, the identification of antimuscarinic drugs that are free of such detrimental effects may provide an important avenue for the development of novel therapeutics for the management of depression.

Comparison of the muscarinic antagonist effects of scopolamine and L-687,306.

This study aimed to use central and peripheral assays to compare the effects of the muscarinic antagonist scopolamine with those of a novel muscarinic antagonist, L-687,306 [(3R,4R)-3-(3-cyclopropyl-1,2,4,oxadiazol[5-yl]-1-azabicyclo[2.2.1]heptane.

Individual differences in the reinforcing and punishing effects of nicotine in rhesus monkeys.

Rationale: The relatively weak reinforcing effects of nicotine in experimental studies have been attributed to possible aversive effects or the need to space nicotine administrations over time to expose reinforcing effects.

Objective: This study was designed to determine if the response-maintaining effects of nicotine are increased when availability is spaced through time, and whether nicotine is an effective punisher of remifentanil-maintained responding.

Methods: Compared to a cocaine reference dose, nicotine dose and timeout (TO) value were varied in eight rhesus monkeys responding for intravenous (i.

Random-ratio schedules produce greater demand for i.v. drug administration than fixed-ratio schedules in rhesus monkeys.

Rationale: Organisms emit more responses when food is provided according to random as compared with fixed schedules of reinforcement. Similarly, many human behaviors deemed compulsive are maintained on variable schedules (e.g.

Self-administration of agonists selective for dopamine D2, D3, and D4 receptors by rhesus monkeys.

Dopamine receptor mechanisms are believed to play a role in the reinforcing effects of cocaine and other drugs of abuse. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D(3)-preferring agonists, a D(2)-preferring agonist, and a D(4) agonist.

Individual differences in rhesus monkeys' demand for drugs of abuse.

A relatively small percentage of humans who are exposed to drugs of abuse eventually become addicted to or dependent on those drugs. These individual differences in likelihood of developing drug addiction may reflect behavioral, neurobiological or genetic correlates of drug addiction and are therefore important to model. Behavioral economic measures of demand establish functions whose overall elasticity (rate of decrease in consumption as price increases) reflects the reinforcing effectiveness of various stimuli, including drugs.

Effects of daily morphine administration and deprivation on choice and demand for remifentanil and cocaine in rhesus monkeys.

Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or cocaine.

Naltrexone decreases D-amphetamine and ethanol self-administration in rhesus monkeys.

Amphetamines are the second most highly abused illicit drugs worldwide, yet there is no pharmacological treatment for amphetamine abuse and dependence. Preclinical studies and, more recently, human studies, suggest that the opioid receptor antagonist, naltrexone, might be useful in the treatment of amphetamine abuse. Naltrexone, an opioid receptor antagonist, is currently used for the treatment of alcohol dependence.

The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys.

Rationale: The synthetic nonpeptide NOP (nociceptin/orphanin FQ peptide) receptor agonist Ro 64-6198 produces antinociception in rhesus monkeys. In rodents, it has much more variable effects on pain responses, but has response rate-increasing effects on punished operant behavior and decreases drug reward.

Objectives: The aim of this study was to compare Ro 64-6198 with the benzodiazepine diazepam in tests of analgesia, drug self-administration, and response-increasing effects in rhesus monkeys.

A behavioral economic analysis of cocaine and remifentanil self-administration in rhesus monkeys.

Rationale: Behavioral economics can be used to evaluate the relative reinforcing effectiveness of drugs and the economic interaction between drugs, information which may help to explain patterns of polydrug abuse in humans.

Objectives: In phase 1, the reinforcing effectiveness of the opiate remifentanil and the stimulant cocaine was compared using a demand-curve analysis. In phase 2, the economic relation between these drugs was determined.

Modification of ethanol's reinforcing effectiveness in rhesus monkeys by cocaine, flunitrazepam, or gamma-hydroxybutyrate.

Background: Although ethanol is frequently used in combination with other psychoactive drugs, the behavioral and pharmacological reasons for this form of polydrug abuse have not been well described.

Materials And Methods: Rhesus monkeys with indwelling intravenous catheters produced intravenous injections of ethanol (50, 100, or 200 mg/kg/inj), flunitrazepam (0.001-0.

Fixed-ratio schedules of cocaine self-administration in rhesus monkeys: joint control of responding by past and upcoming doses.

By manipulating a signaled upcoming cocaine dose, we investigated how the dose just received and the upcoming dose jointly controlled cocaine self-administration. Three rhesus monkeys self-administered cocaine according to a multiple schedule differing in dose following completion of a fixed-ratio response requirement. The larger dose (0.

Aspartame demand in rhesus monkeys: effects of volume and concentration manipulations.

Three rhesus monkeys' lever presses produced aspartame-sweetened water according to a fixed-ratio schedule. The response requirement was increased across sessions and a demand-function analysis was used to assess the reinforcing effectiveness of different magnitudes of aspartame by manipulating reinforcer duration (1 and 3s) in Phase 1 and concentration (0.3, 0.

Assessing unit-price related remifentanil choice in rhesus monkeys.

Given a commodity available at different prices, a unit-price account of choice predicts preference for the cheaper alternative. This experiment determined if rhesus monkeys preferred remifentanil (an ultra-short-acting micro-opioid agonist) delivered at a lower unit price over a higher-priced remifentanil alternative (Phases 1 and 3). Choice between equal-priced alternatives also was assessed (Phase 2).

LARGE SCALE PURIFICATION OF BUTYRYLCHOLINESTERASE FROM HUMAN PLASMA SUITABLE FOR INJECTION INTO MONKEYS; A POTENTIAL NEW THERAPEUTIC FOR PROTECTION AGAINST COCAINE AND NERVE AGENT TOXICITY.

Pretreatment of animals with butyrylcholinesterase (EC 3.1.1.

Behavioral perspectives on the neuroscience of drug addiction.

Neuroscientific approaches to drug addiction traditionally have been based on the premise that addiction is a process that results from brain changes that in turn result from chronic administration of drugs of abuse. An alternative approach views drug addiction as a behavioral disorder in which drugs function as preeminent reinforcers. Although there is a fundamental discrepancy between these two approaches, the emerging neuroscience of reinforcement and choice behavior eventually may shed light on the brain mechanisms involved in excessive drug use.

Relative reinforcing effects of cocaine, remifentanil, and their combination in rhesus monkeys.

Human polydrug abusers often take combinations of opioids and stimulants, but it is not clear why. Behavioral economics with demand curve analysis is uniquely able to separate two of the possibilities: that the drug combination increases the reinforcing potency of the component drugs or that the drug combination is a more effective reinforcer than either drug alone. Rhesus monkeys self-administered a range of doses of cocaine, remifentanil, and combinations of the drugs through indwelling intravenous catheters; the number of responses required for each drug infusion increased across drug-availability sessions.

The economics of drug abuse: a quantitative assessment of drug demand.

Behavioral economic concepts have proven useful for an overall understanding of the regulation of behavior by environmental commodities and complements a pharmacological perspective on drug abuse in several ways. First, a quantitative assessment of drug demand, equated in terms of drug potency, allows meaningful comparisons to be made among drug reinforcers within and across pharmacological classes. Second, behavioral economics provides a conceptual framework for understanding key factors, both pharmacological and environmental, that contribute to reductions in consumption of illicit drugs.

Reinforcing and discriminative stimulus effects of 1-benzylpiperazine and trifluoromethylphenylpiperazine in rhesus monkeys.

1-Benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) are two designer drugs that are often sold in combination tablets via the internet. The discriminative stimulus properties and reinforcing effects of these compounds have not previously been assessed in laboratory primates. In this regard, the reinforcing effects of BZP and TFMPP (alone, and in combination) were assessed via intravenous self-administration in rhesus monkeys previously trained to self-administer cocaine, while the discriminative stimulus effects of these compounds were determined in rhesus monkeys trained to discriminate amphetamine (AMPH) from saline.

Self-administration of methohexital, midazolam and ethanol: effects on the pituitary-adrenal axis in rhesus monkeys.

Rationale: There is disagreement in the literature with respect to how drugs of abuse affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, and whether these changes in endocrine function may be related to the rewarding effects of these drugs.

Objectives: To determine whether reinforcing drugs with different mechanisms of action affect HPA axis function at doses at which they serve as reinforcers.

Methods: Seven monkeys (6 male) were randomly assigned to self-administer methohexital-a barbiturate (n=4), midazolam-a benzodiazepine (n=3), or ethanol (n=5).

Self-administration of fentanyl, cocaine and ketamine: effects on the pituitary-adrenal axis in rhesus monkeys.

Rationale: Drugs of abuse can affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Acute administration of drugs that serve as reinforcers have been observed to stimulate the rat HPA axis, leading to the suggestion that these stimulatory effects may contribute to the development of drug-maintained behaviors.

Objectives: To determine whether reinforcing drugs that are dissimilar with respect to their mechanisms of action have similar effects on HPA axis activity at doses that are self-administered.

Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys.

Relatively few studies have assessed the reinforcing effects of hallucinogenic compounds, and no such studies have attempted to engender contingent responding for these compounds in animals with behavioral histories that include experience with serotonergically mediated reinforcing effects. The objectives of the present study were to investigate the capacity of several hallucinogenic compounds to maintain self-administration behavior in rhesus monkeys with a previous history of 3,4-methylenedioxymethamphetamine (MDMA) self-administration, and to compare these effects across a range of doses of drugs from two structural classes (indolealkylamines and phenylisopropylamines). The results indicate that no compound generated reliable responding and that no subject ever self-administered 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI) at rates above those engendered by contingent saline.

Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys.

The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose-effect curves were generated for each MDMA compound repeatedly over the duration of the study.