Evidence acquisition and evaluation for evidence summit on population-level behavior change to enhance child survival and development in low- and middle-income countries.

Recognizing the need for evidence to inform public health officials and health care workers in the U.S. government and low- and middle-income country governments on efficient, effective behavior change policies, strategies, and programs for child health and development, the U.S. government convened the Evidence Summit on Enhancing Child Survival and Development in Lower- and Middle-Income Countries by Achieving Population-Level Behavior Change. This article summarizes the background and methods for the acquisition and evaluation of the evidence used to the achieve the goals of the summit that is reviewed in other articles in this special issue of the Journal of Health Communication. The process began by identifying focal questions intended to inform the U.S. and low- and middle-income governments about behavior change interventions that accelerate reductions in under-5 mortality and optimize healthy and protective child development to 5 years of age. Experts were selected representing the research and program communities, academia, relevant nongovernmental organizations, and government agencies and assembled into evidence review teams. This was followed by the systematic gathering of relevant peer-reviewed literature that would inform the focal questions. Members of the evidence review teams were invited to add relevant articles not identified in the initial literature review to complete the bibliographies. Details of the search processes and methods used for screening and quality reviews are described. The evidence review teams were asked to comply with a specific evaluation framework for recommendations on practice and policy on the basis of both expert opinion and the quality of the data reviewed.

Evidence acquisition and evaluation for evidence summit on enhancing provision and use of maternal health services through financial incentives.

Recognizing the need for evidence to inform US Government and governments of the low- and middle-income countries on efficient, effective maternal health policies, strategies, and programmes, the US Government convened the Evidence Summit on Enhancing Provision and Use of Maternal Health Services through Financial Incentives in April 2012 in Washington, DC, USA. This paper summarizes the background and methods for the acquisition and evaluation of the evidence used for achieving the goals of the Summit. The goal of the Summit was to obtain multidisciplinary expert review of literature to inform both US Government and governments of the low- and middle-income countries on evidence-informed practice, policies, and strategies for financial incentives. Several steps were undertaken to define the tasks for the Summit and identify the appropriate evidence for review. The process began by identifying focal questions intended to inform governments of the low-and middle-income countries and the US Government about the efficacy of supply- and demand-side financial incentives for enhanced provision and use of quality maternal health services. Experts were selected representing the research and programme communities, academia, relevant non-governmental organizations, and government agencies and were assembled into Evidence Review Teams. This was followed by a systematic process to gather relevant peer-reviewed literature that would inform the focal questions. Members of the Evidence Review Teams were invited to add relevant papers not identified in the initial literature review to complete the bibliography. The Evidence Review Teams were asked to comply with a specific evaluation framework for recommendations on practice and policy based on both expert opinion and the quality of the data. Details of the search processes and methods used for screening and quality reviews are described.

Financial incentives and maternal health: where do we go from here?

Health financing strategies that incorporate financial incentives are being applied in many low- and middle-income countries, and improving maternal and neonatal health is often a central goal. As yet, there have been few reviews of such programmes and their impact on maternal health. The US Government Evidence Summit on Enhancing Provision and use of Maternal Health Services through Financial Incentives was convened on 24-25 April 2012 to address this gap. This article, the final in a series assessing the effects of financial incentives--performance-based incentives (PBIs), insurance, user fee exemption programmes, conditional cash transfers, and vouchers--summarizes the evidence and discusses issues of context, programme design and implementation, cost-effectiveness, and sustainability. We suggest key areas to consider when designing and implementing financial incentive programmes for enhancing maternal health and highlight gaps in evidence that could benefit from additional research. Although the methodological rigor of studies varies, the evidence, overall, suggests that financial incentives can enhance demand for and improve the supply of maternal health services. Definitive evidence demonstrating a link between incentives and improved health outcomes is lacking; however, the evidence suggests that financial incentives can increase the quantity and quality of maternal health services and address health systems and financial barriers that prevent women from accessing and providers from delivering quality, lifesaving maternal healthcare.

Preclinical evaluation of the abuse potential of the analgesic bicifadine.

The abuse liability of the analgesic bicifadine was investigated in animal models used to predict the abuse potential of psychostimulants in humans. Bicifadine, cocaine, d-amphetamine, bupropion, and desipramine were evaluated for the production of cocaine-like discriminative stimulus effects in rats. Cocaine, d-amphetamine, and bupropion dose-dependently and fully substituted for cocaine. Bicifadine and desipramine produced a maximum mean cocaine-lever selection of 80 and 69%, respectively, but doses yielding peak substitution strongly suppressed response rates. Microdialysis studies in normal waking rats indicated that d-amphetamine increased dopamine levels in the nucleus accumbens and striatum to a much greater degree than bicifadine, but bicifadine increased 5-hydroxytryptamine levels in the nucleus accumbens and striatum more than d-amphetamine. Bicifadine was also tested for intravenous self-administration in rhesus monkeys experienced with cocaine administration. Reinforcing effects of bicifadine were observed in only two of four subjects, whereas cocaine, d-amphetamine, and bupropion served as reinforcers in all four monkeys. When evaluated under a progressive ratio procedure, no dose of bicifadine maintained responding to the extent of cocaine, d-amphetamine, or bupropion. The discriminative stimulus effects associated with bicifadine were similar, but not identical, to those of psychostimulants. Although bicifadine maintained self-administration behavior in some subjects, its reinforcing efficacy was very low relative to cocaine, d-amphetamine, and bupropion. These results are consistent with the microdialysis findings of lower dopamine levels and higher 5-hydroxytryptamine levels after administration of bicifadine relative to d-amphetamine. Overall, the current findings support a low abuse potential of bicifadine, more resembling that of antidepressants than psychostimulants.

Smoking Behaviors in Arab Americans: Acculturation and Health Beliefs.

INTRODUCTION: Arab Americans are a growing population in the United States. In the 2011 American Community Survey, the U.S. Census Bureau reported there were close to 1.8 million Arab Americans living within the United States, a 47% increase in population size from 2000. According to the Arab American Institute, currently, that estimate has grown to approximately 3.7 million. They have high rates of smoking and low rates of smoking cessation. In this study, the researchers investigated factors influencing desire to quit smoking among Arab Americans, and their association with acculturation and health beliefs. METHODOLOGY: Cross-sectional descriptive study investigating smoking behaviors and factors influencing the desire to quit smoking among adult Arab American. Data were collected to measure tobacco use, nicotine dependence, desire to quit smoking, acculturation, and health beliefs. RESULTS: The sample ( N = 96) was 55% female, mean age of 44 years (±14.79). The desire to quit smoking was positively associated with perceived severity (p < .05) and susceptibility to cancer (p < .05), perceived benefits of quitting smoking ( p < .01); and negatively associated with smoking barriers (addiction barriers p < .05, external barriers p = .27, internal barriers p < .05), and nicotine dependence (p < .05). Being female, having a lower level of nicotine dependence, and a higher perception of cancer severity predicted higher desire to quit smoking ( p < .01). DISCUSSION: Smoking cessation intervention studies need to target appropriate health beliefs, especially the high risk of cancer caused by smoking among Arab Americans.

Answering questions about electronic cigarettes using a multidisciplinary model.

Electronic cigarettes (ECIGs) are a relatively new class of tobacco products and a subject of much debate for scientists and policymakers worldwide. Objective data that address the ECIG risk-benefit ratio for individual and public health are needed, and addressing this need requires a multidisciplinary approach that spans several areas of psychology as well as chemistry, toxicant inhalation, and physiology. This multidisciplinary approach would benefit from methods that are reliable, valid, and swift. For this reason, we formed a multidisciplinary team to develop methods that could answer questions about ECIGs and other potential modified risk tobacco products. Our team includes scientists with expertise in psychology (clinical, community, and experimental) and other disciplines, including aerosol research, analytical chemistry, biostatistics, engineering, internal medicine, and public health. The psychologists on our team keep other members focused on factors that influence individual behavior, and other team members keep the psychologists aware of other issues, such as product design. Critically, all team members are willing to extend their interests beyond the boundaries of their discipline to collaborate effectively with the shared goal of producing the rigorous science needed to inform empirically based tobacco policy. In addition, our trainees gain valuable knowledge from these collaborations and learn that other disciplines are accessible, exciting, and can enhance their own research. Multidisciplinary work presents challenges: learning other scientists' languages and staying focused on our core mission. Overall, our multidisciplinary team has led to several major findings that inform the scientific, regulatory, and public health communities about ECIGs and their effects. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Drug withdrawal, cocaine and sedative use disorders increase the need for mechanical ventilation in medical patients.

AIMS: Alcohol use disorders increase the need for mechanical ventilation (MV) in critically ill medical, surgical and trauma patients. Studies examining other drug use disorders (DUD) in trauma patients have not demonstrated heightened rates of intensive care unit (ICU) complications. Patients with asthma and concurrent cocaine or heroin use disorders have an increased need for MV. The objective of this study is to determine if the presence of DUD and drug withdrawal syndromes are associated with increased need for MV in medical patients. DESIGN: Analysis of a national database. SETTING: The Nationwide Inpatient Sample, the largest all-payer in-patient database was utilized for the years 2002-2004. PARTICIPANTS: Adult patients with one of the six common diagnoses associated with medical ICU admission were included. INTERVENTION: None. MEASUREMENTS: Univariate analysis and multivariate logistic regression were performed to determine if DUD and drug withdrawal were associated independently with the use of MV. FINDINGS: A total 1 218 875 patients fulfilled one of the six diagnoses; 22 827 (1.9%) had DUD, and 102 841 (8.4%) underwent MV. Independent of the medical diagnosis, DUD was associated with an increased risk for requiring MV by univariate analysis (relative risk = 1.50, P < 0.0001). By multivariate analyses, sedative and cocaine use disorders remained associated with increased need for MV. Independent of medical diagnosis and substance, drug withdrawal was associated with increased odds of MV by both univariate and multivariate analysis (odds ratio = 2.94, P < 0.0001). CONCLUSIONS: DUD are associated with increased need for MV in medical patients. This study demonstrates the importance of screening all medical patients for DUD.

Inhalant use among incarcerated adolescents in the United States: prevalence, characteristics, and correlates of use.

OBJECTIVE: To characterize patterns and correlates of inhalant use among incarcerated youth. METHOD: Residents (N=723) of 27 Missouri Division of Youth Services facilities completed interviews assessing substance use, psychiatric symptoms, antisocial traits, trauma, suicidality, and criminality. RESULTS: Participants averaged 15.5 (S.D.=1.2) years of age, were ethnically diverse, and predominantly male. More than one-third (36.9%) reported lifetime inhalant use; 47.9% of users had tried four or more inhalant products. Comparatively high rates of use were observed for Hispanic and small town/rural youth. Commonly abused agents included gasoline (22%), permanent markers (15%), computer "air duster," (15%) and spray paint (12%). Inhalant users evidenced significantly higher levels of criminal behavior, antisocial attitudes, current psychiatric symptoms, earlier onset of offending and substance use, and more extensive histories of head injury, kidney disease, hormonal problems, mental illness, suicidality, trauma, and substance-related problems than nonusers. In multiple logistic regression models, race/ethnicity, geographic area of residence, fearlessness, suicidality, and polydrug use distinguished inhalant users and nonusers. Measures of cognitive impairment, impulsivity, fearlessness, blame externalization, polydrug use, and substance-related problems were positively associated with lifetime frequency of inhalant use. CONCLUSIONS: Inhalant use was widespread in this sample and associated with serious physical and mental health impairments.

Characterizing early cigarette use episodes in novice smokers.

Retrospective self-report data indicate that early cigarette use episodes may be important predictors of smoking. Unfortunately, recall of early experiences are confounded with current smoking. The current study is the first to examine early cigarette use episodes (EUEs) prospectively in novice smokers (less than 15 lifetime cigarettes). Smoking amount, context and subjective experiences for up to five of the first cigarette episodes during their first year of college were collected using weekly internet-based questionnaires and structured interviews. Data were obtained on 538 EUEs from 163 students. EUEs generally occurred within a social/party context; over 90% of EUEs occurred when participants were with other people who were smoking and over 65% occurred while participants were drinking alcohol. Subjective effects across episodes were reported as generally mild and factor analysis yielded Positive, Negative and Sensory/Peripheral effects scales. Subjective effects were related to the amount smoked and inhalation, whereas EUE context, including alcohol use and social context, was not. This study demonstrates that it is possible to study EUEs in college students within days or weeks of their occurrence and that most of these occur in social settings with the concurrent use of alcohol.

Availability and characteristics of betel products in the U.S.

Betel use involves oral placement of shards of areca nut (Areca catechu palm seed containing the cholinergic agonist arecoline) wrapped with slaked lime in a betel leaf (Piper betle plant) or various chopped or powdered products containing areca nut and/or parts of the betel plant. Additives to this mixture include catechu (areca palm extract), spices/ sweeteners (e.g., saccharin, cloves), and/or tobacco. Betel use is most common in Asia and East India; however, little is known about the availability and characteristics of these products outside of this region. Thus, a representative sample of betel products and additives was purchased in the Richmond, Virginia area. Five venues were visited between March and May, 2006. Products successfully purchased were those containing betel alone (seven), betel/tobacco (three), tobacco alone (four), and additives (four). Most betel products listed ingredients on the packaging, though some did not explicitly distinguish between those with versus without tobacco. Importantly, seven of seven betel alone and one of three betel/tobacco products omitted any health-related warnings. All products were inexpensive and relatively obtainable in the groceries visited. More research is warranted in order to accurately estimate product emergence into the U.S. and other world markets, and the consequent impact on public health.

Addiction epidemiology in adolescents receiving inpatient psychiatric treatment.

This study sought to characterize adolescent psychiatric inpatient populations from two sites and to determine correlates of substance use disorders (SUD). Screening procedures for SUD differ substantially between these sites. A retrospective review of adolescent inpatients (n=636) revealed that the populations were similar in gender, race and age. Rates of SUD at the site with a formalized SUD screening regimen were higher (39%) than those at the other site (16.5%). Similar correlates of SUD were observed across sites, including older age, legal involvement, sexual activity, childhood disruptive disorder, and tobacco use. These results suggest that SUD is a major issue in adolescent psychiatric patients. More rigorous screening for SUD and its correlates may facilitate earlier detection of substance use in this vulnerable population.

An exploratory study of drug abuse and dependence information in package inserts.

Information about drug abuse and dependence from package inserts of centrally acting drugs was evaluated for content. Of the 77 labels reviewed, 40 were opiate agonists, 18 were stimulants, and the remainder fell into other selected categories. The amount of information ranged from 0-66 sentences, with greatest variability found in the opiate agonists (range 9-66). Information amount was significantly correlated with the year of drug approval (p < 0.001) but not with the latest label revision (p = 0.749). Information amount did not differ significantly with warning strength or schedule. While most package inserts explain physical dependence, tolerance, and withdrawal, there is a lack of information about psychological dependence. Variability in information about abuse and dependence potential is high and can affect prescribing by physicians and counseling by pharmacists, underscoring the need for further studies.

Tolerance and sensitization to inhaled 1,1,1-trichloroethane in mice: results from open-field behavior and a functional observational battery.

RATIONALE: 1,1,1-Trichloroethane (TCE), a representative abused solvent, has well described acute behavioral effects in animals. Much less is known about repeated high-concentration exposures as would be encountered in inhalant abusers. Tolerance has been demonstrated in some, but not all, studies with TCE while sensitization has also been seen with other abused solvents. OBJECTIVE: The present study was designed to further characterize changes in the effects of repeated exposure to TCE on a variety of mouse behaviors. METHODS: Mice were tested using locomotor activity as well as a functional observational battery (FOB) both before and after a regimen of daily exposures to various concentrations of TCE. RESULTS: The initial locomotor effects of acute 30-min exposures to TCE were biphasic with concentration-dependent increases in activity at lower concentrations and decreases observed at higher concentrations. The profile of acute effects as measured by the FOB included changes in posture, decreased arousal, disturbances in gait, delayed righting reflexes, and decreased sensorimotor reactivity. Animals were then divided into five groups and exposed 30 min/day to either air or one of four concentrations of TCE (2,000, 6,000, 10,000, or 13,300 ppm) for 15 consecutive days. The TCE concentration used primarily affected the magnitude of change, not whether tolerance or sensitization occurred. Tolerance developed on the measures of forelimb grip strength, inverted screen, and number of rears. Conversely, sensitization developed to measures of locomotor activity. CONCLUSION: Depending on the behavioral measure, both tolerance and sensitization can occur in mice with repeated exposure to TCE. Both of these phenomena are characteristic of drugs of abuse.

Dose, duration, and pattern of nicotine administration as determinants of behavioral dependence in rats.

RATIONALE: Relatively little is known about the role of dose, duration, and pattern of nicotine exposure in the development of dependence. Disruption of learned behavior during antagonist-precipitated withdrawal can be a sensitive, quantitative measure of behavioral dependence. OBJECTIVES: The present study sought to determine whether behavioral dependence upon nicotine could be induced in rats and, if so, what exposure conditions were essential for inducing it. Our primary focus was on whether continuous exposure over several days was necessary to produce dependence. METHODS: Male Sprague-Dawley rats were trained to lever press under fixed-ratio 10 schedules of food reinforcement during daily, 15-min experimental sessions. Nicotine was then administered s.c. via osmotic minipumps that delivered various nicotine dosage regimens, some including 24-h nicotine-free periods, to manipulate pattern of exposure. The presence of dependence was tested with challenges with the nicotinic acetylcholine receptor antagonist, mecamylamine, or during spontaneous withdrawal. RESULTS: After 7 days of 3, 6, and 12 mg kg(-1) day(-1) nicotine administration, response rates were significantly reduced in nicotinized, but not in saline-treated rats following mecamylamine challenges. Subsequent studies demonstrated that 4 days, but not 3 days, of cumulative 3 mg kg(-1) day(-1) nicotine administration was sufficient to induce dependence. The induction of dependence could be prevented by imposing a nicotine-free period between the first and second days during these 4-day regimens but not at other times. CONCLUSION: Behavioral dependence upon nicotine can be induced in the rat, and its induction is dependent upon its cumulative duration and pattern of exposure suggesting that tobacco dependencies could be controlled by similar determinants.

Impact of formulation on the abuse liability, safety and regulation of medications: the expert panel report.

A scientific meeting was held in April 2005 to consider how the formulation of medications might impact on their potential for abuse. The background papers prepared for this meeting, as well as abstracts of volunteered presentations, are published in this supplemental issue of Drug and Alcohol Dependence. This paper is the Expert Panel Report summarizing the discussions held following the formal presentations and including the suggested recommendations for additional research that emerged from these discussions. There was overwhelming consensus that formulation does play a role in prescription drug abuse, i.e., a formulation of an abused substance can be developed that will decrease its abuse potential, and several examples were cited. Nevertheless, it is imperative that new formulations have similar efficacy and in no way compromise medication access to doctors and patients. However, there was also consensus that a great deal of research and discussion was needed to fully implement a program of risk management through reformulation of existing products or tailoring the formulation of new products to retain clinical efficacy and safety while minimizing potential for abuse. Those who need to take part in this discussion include scientific groups, pharmaceutical companies, as well as governmental and regulatory agencies. The areas where more research is needed include development of standards for assessing tamper-resistance, improved animal models that can address formulation-related variables (e.g., onset, duration), the redesign of human laboratory studies providing appropriate models for comparing formulations, and improved post-marketing surveillance. Finally, knowledge and experience are needed to translate scientific work into a predictable, transparent and reliable regulatory process.

Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats.

RATIONALE: Because of their potential therapeutic effects, N-methyl-D-aspartate (NMDA) receptor antagonists have been investigated for clinical use. Unfortunately, many channel-blocking antagonists have been associated with the production of side effects, including motor impairment and phencyclidine (PCP)-like subjective effects. OBJECTIVE: This study investigated the relationship between NMDA receptor channel blockade and production of PCP-like side effects by evaluating a variety of NMDA channel blockers with different binding characteristics for the production of PCP-like discriminative stimulus effects. METHODS: The NMDA channel blockers were tested in rats trained to discriminate 2 mg/kg PCP, i.p., from saline using a standard two-lever drug discrimination procedure with responding under a fixed ratio (FR) 32 schedule of food reinforcement. RESULTS: The high-affinity channel blockers PD 138289, PD 137889 and FR 115427, produced full, dose-dependent substitution for PCP. Of the moderate-affinity channel blockers, MRZ 2/579 fully substituted for PCP while 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, 8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline and alaproclate produced partial substitution. Drugs with the lowest affinity for the channel site and/or higher affinity for non-NMDA CNS sites, antazoline, idazoxan, 1-phenyl-1,2,3,4-tetrahydroisoquinoline, alpha-benzyl- N-methylphenethylamine and orphenadrine, failed to substitute for PCP. CONCLUSIONS: The results demonstrate that the cellular actions of the individual channel-blocking NMDA antagonists, in particular affinity for the channel site and NMDA receptor specificity, are important determinants of their discriminative stimulus effects. While higher affinity channel blockers show a correlation between affinity and PCP-like discriminative stimulus effects, behavioral disruption through action at non-NMDA receptors probably prevents achieving sufficient concentrations of the lower affinity compounds at NMDA receptors to produce PCP-like discriminative stimulus effects.

Enhancement of the discriminative stimulus effects of phencyclidine by the tetracycline antibiotics doxycycline and minocycline in rats.

RATIONALE: Tetracycline antibiotics share some neuroprotective and CNS effects with N-methyl- D-aspartate (NMDA) receptor antagonists. OBJECTIVES: The acute effects of two tetracycline antibiotics were compared to those of the prototypic NMDA antagonist phencyclidine (PCP). METHODS: The effects of minocycline (10-56 mg/kg) and doxycycline (10-56 mg/kg) were evaluated in Sprague-Dawley rats trained to discriminate 2.0 mg/kg IP of PCP from saline under a fixed ratio schedule of food presentation. RESULTS: Even though minocycline and doxycycline did not substitute for PCP, pretreatment with 32 mg/kg of either drug produced leftward shifts in the PCP dose-response curve. The 32 mg/kg dose of minocycline also produced a leftward shift in the dose-response curve for dizocilpine (MK-801), another NMDA channel blocker, in the same subjects. CONCLUSIONS: Tetracycline antibiotics may interact either directly or indirectly with NMDA receptors. This suggests that they might be utilized in treatment of brain disorders in which NMDA receptor over-activation has been implicated.

Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.

RATIONALE: Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl- D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed. OBJECTIVES: The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors. METHODS: Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials. RESULTS: As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials. CONCLUSIONS: These results suggest that not all NMDA channel blockers share PCP's effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients).

Effects of inhaled toluene and 1,1,1-trichloroethane on seizures and death produced by N-methyl-D-aspartic acid in mice.

Evidence exists that some abused solvents have N-methyl-D-aspartic acid (NMDA) antagonist activity, although which of their effects may be related to this mechanism is not well understood. The effects of toluene and 1,1,1-trichloroethane (TCE) on NMDA-induced seizures in mice were studied using three experimental protocols: (a) animals injected i.p. with 120 or 170 mg/kg NMDA and immediately afterwards exposed to solvent vapors or air for 30 min (co-exposure protocol); (b) mice exposed for 30 min to solvent or air, then injected with NMDA and placed in the chamber for a second 30-min exposure (pre-exposure+co-exposure protocol); and (c) mice that inhaled 4000 ppm toluene or air for 30 min twice a day, 6 h apart, for 7 days, and were injected with 120 mg/kg NMDA immediately before a 30-min toluene exposure (repeated exposure protocol). When given acutely, toluene, but not TCE, produced concentration-dependent protection against NMDA-induced seizures. Higher concentrations of toluene were also effective against the lethal effects produced by 170 mg/kg NMDA. Clearer effects were seen when the pre-exposure+co-exposure protocol was followed. Under these conditions the IC(50) for toluene was 739 ppm (653-825) against seizure occurrence and 2127 ppm (1966-2288) against lethality. Repeated exposure to toluene did not result in tolerance to its anticonvulsant effects. These results are consistent with the in vitro effects described for toluene as a noncompetitive NMDA antagonist and as a compound that enhances GABAergic transmission. The lack of protective effects of TCE is not consistent with its in vitro actions.

Evaluation of the reinforcing effects of the cannabinoid CB1 receptor antagonist, SR141716, in rhesus monkeys.

The abuse liability of a selective cannabinoid CB1 receptor antagonist, SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), was evaluated in rhesus monkeys. Four rhesus monkeys with chronically indwelling venous catheters were initially trained to self-administer cocaine (30 microg/kg/injection) during daily 1-h sessions under a fixed ratio 50 (FR50) schedule of reinforcement. SR141716 was subsequently substituted for cocaine, and SR141716 dose was varied from 1 to 100 microg/kg/injection. Each dose of SR141716 was tested for four consecutive sessions and each unit dose was separated by at least three sessions of cocaine self-administration. Substitution of SR141716 for cocaine resulted in rapid extinction of lever pressing and none of the doses of SR141716 tested was self-administered above the vehicle levels. When the highest dose of SR141716 (100 microg/kg/injection) was evaluated, self-administration behavior was suppressed below vehicle levels suggesting that behaviorally active doses were evaluated. Since positive results in self-administration tests are generally predictive of abuse potential, the negative results with SR141716 suggest that this drug would likely have low abuse liability.