Design and validation of an improved nonferrous smoking device for self-administration of smoked drugs with concurrent fMRI neuroimaging.

Several popularly abused drugs, such as nicotine (tobacco) and THC (delta9-tetrahydrocannabinol) (marihuana) are commonly self-administered by the smoked route. Although the neuronal substrates mediating the effect of smoked drugs are of interest, studies of their acute actions in living human brain has been difficult due to the unique constraints imposed by neuroimaging equipment and scanning environments. We have previously reported a device for the self-administration of smoked drugs with concurrent blood oxygen level dependent (BOLD) fMRI imaging. Here we report improvements to the device which result in improved drug delivery to the smoker. Gas chromatography/mass spectrometry (GCMS) analysis of nicotine recovered from filter extracts revealed that the amount of nicotine delivered to subjects smoking with our original device was reduced by approximately 44% compared to nicotine delivered by cigarettes smoked normally. Improvements were made to the smoke delivery component of our apparatus in an attempt to improve drug delivery, while not interfering with collection of MRI data. Nicotine plasma levels in 9 subjects smoking both with and without the improved smoking device in the laboratory were not significantly different. Similarly, the device produced no significant difference in either ratings of the subjective effects of nicotine, or changes in cardiovascular parameters in this experiment. The improved device does not interfere with typical drug effects produced by normal smoking. Phantom scans revealed that BOLD signal was not found to be altered by the (in-bore) installation and operation of the improved device. Preliminary data analysis of smoking induced changes in the BOLD response to visual stimulation suggest that this response is not affected by the improved device, the act of smoking, air puffing, nicotine, or other components of cigarette smoke. The improved device does not interfere with the collection of MRI neuroimaging data. Use of this device will facilitate investigations of the acute neuronal effects of smoked drugs.

Imaging of the brain cannabinoid system.

This review covers two major strategies for imaging of the brain cannabinoid system: autoradiography and in vivo neuroimaging. Cannabinoid receptors can be imaged directly with autoradiography in brain slices using radiolabeled cannabinoid receptor ligands. In addition, the effects of pharmacologic doses of unlabeled cannabinoid drugs can be autoradiographically imaged using indicators of blood flow or indicators of metabolism such as glucose analogs. Although cannabinoid imaging is a relatively new topic of research compared to imaging of other drugs of abuse, autoradiographic strategies have produced high-quality information about the distribution of brain cannabinoid receptors and the effects of cannabinoid drugs on brain metabolism. In vivo neuroimaging, in contrast to autoradiography, utilizes noninvasive techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) to image both the binding and the effects of drugs within living brain. These techniques are well developed; however, in vivo imaging of cannabinoid systems is in a very preliminary state. Early results have been promising yet hard to generalize. Definitive answers to some of the most important questions about cannabinoid drugs and their effects await development of suitable in vivo neuroimaging ligands for cannabinoid systems.

Self-administration of cocaine and the cocaine analog RTI-113: relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys.

Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. The present study examined the reinforcing effects of 3beta-(4-chlorophenyl)tropane-2beta-carboxylic acid phenyl ester (RTI-113), a long-acting, selective, high-affinity dopamine uptake inhibitor. Additionally, the effects of RTI-113 pretreatment on cocaine self-administration were determined. Monkeys were trained to respond under a second-order schedule for intravenous cocaine administration (0.10 or 0.17 mg/kg/infusion). When responding was stable, cocaine (0.0030-1.0 mg/kg/infusion) and RTI-113 (0.010-0.30 mg/kg/infusion) were substituted for the cocaine training dose. Cocaine and RTI-113 were equipotent for their reinforcing effects. However, cocaine maintained higher response rates in two of the three monkeys tested. When administered as a pretreatment, RTI-113 (0.10-0.30 mg/kg) dose-dependently reduced responding maintained by two doses of cocaine. Drug effects on behavior were related to dopamine transporter (DAT) occupancy in monkey striatum during neuroimaging with positron emission tomography. DAT occupancy was determined by displacement of 8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. DAT occupancy did not differ markedly across RTI-113 pretreatment doses and ranged between 72-84%. The results suggest that the pharmacokinetic profile of RTI-113 (i.e., long-acting) may influence its ability to maintain self-administration, and therefore its abuse liability. Additionally, high DAT occupancy is required for RTI-113 to reduce cocaine-maintained responding.

Effects of sodium valproate on corticotropin-releasing factor systems in rat brain.

We hypothesized that divalproex sodium, an anticonvulsant effective in the acute treatment of mania, may act upon neuropeptide systems that utilize corticotropin-releasing factor (CRF). Pharmacokinetic studies demonstrated that valproate has an apparent elimination half life of 17 minutes in rats after acute administration and that there is a nonlinear relationship between chronic dose and serum drug concentration. Acute valproate treatment neither altered plasma adrenocorticotropic hormone (ACTH) or corticosterone concentrations nor produced changes in CRF concentration in any of 10 brain regions examined. Subchronic treatment via SC-implanted osmotic minipumps (875 mg/kg/day x 7 days) resulted in decreased CRF concentrations in the median eminence and raphe nuclei. Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus. The benzodiazepine alprazolam, also a positive modulator of GABAergic function, similarly decreases CRF mRNA expression in the CeA. These results suggest that the mood stabilizing effects of valproic acid may be mediated in part by alterations in CRF neuronal activity.

Involuntary commitments to public mental institutions: issues involving the overrepresentation of blacks and assessment of relevant functioning.

This article contributes to the debate in the mental health and legal systems concerning involuntary commitments to mental hospitals. The focus is on issues involving the overrepresentation of Black people among adults committed to U.S. public mental institutions and issues involving the assessment of relevant behavioral functioning in particular. Empirical findings, legal principles and procedures, and methodological limitations are reviewed to identify problems in current practice and relevant evidence bearing on those problems. Special emphasis is placed on the possible explanations for the overrepresentation of Blacks and on dependable assessments of relevant functioning that are needed to justify the state's coercive power to involuntarily confine people, regardless of race. The article concludes with a summary and recommendations for research and practice.

Urban psychiatric commitments: disability and dangerous behavior of black and white recent admissions.

Nationally black patients are overrepresented in public psychiatric institutions and are more likely than white patients to be committed involuntarily. This study of patients from 12 treatment units in the Chicago area, where these patterns were also true, compared the functioning of 227 acute admissions grouped by race (white or black) and admission status (voluntary or involuntary). Patients were assessed by highly trained independent observers using objective measures of dangerous behavior and disability levels, the relevant classes of functioning based on common principles underlying commitment statutes. No evidence was found that racial bias and discrimination in commitment and retention decisions would account for the overrepresentation of blacks among involuntary commitments to public institutions. Rather, the same factors that account for the overrepresentation of blacks compared with whites among all admissions may also explain their overrepresentation among the involuntarily confined. Changes in treatment programming and assessment practices are suggested.