In the striatum, signaling through G protein-coupled dopamine receptors mediates motor and reward behavior, and underlies the effects of addictive drugs. The extent of receptor responses is determined by RGS9-2/Gbeta5 complexes, a striatally enriched regulator that limits the lifetime of activated G proteins. Recent studies suggest that the function of RGS9-2/Gbeta5 is controlled by the association with an additional subunit, R7BP, making elucidation of its contribution to striatal signaling essential for understanding molecular mechanisms of behaviors mediated by the striatum. In this study, we report that elimination of R7BP in mice results in motor coordination deficits and greater locomotor response to morphine administration, consistent with the essential role of R7BP in maintaining RGS9-2 expression in the striatum However, in contrast to previously reported observations with RGS9-2 knockouts, mice lacking R7BP do not show higher sensitivity to locomotor-stimulating effects of cocaine. Using a striatum-specific knockdown approach, we show that the sensitivity of motor stimulation to cocaine is instead dependent on RGS7, whose complex formation with R7BP is dictated by RGS9-2 expression. These results indicate that dopamine signaling in the striatum is controlled by concerted interplay between two RGS proteins, RGS7 and RGS9-2, which are balanced by a common subunit, R7BP.Neuropsychopharmacology advance online publication, 30 December 2009; doi:10.1038/npp.2009.212. less...

Government figures suggest that there has been an increase in the number of young people using cocaine. Emergency and minor injury unit nurses are therefore increasingly likely to care for these people. This article describes the presenting symptoms and management of a patient who had an adverse reaction to cocaine, briefly examines the issues of 'adolescent consent' and discusses cocaine use among young people. less...

OBJECTIVES: The goal of this study is to identify co-morbidities associated with acute myocardial infarction in Tobago. METHODS: This was a longitudinal retrospective study of myocardial infarction at the Tobago Regional Hospital in two selected periods: January 2007 to April 2007 and January 2008 to April 2008. Data were retrieved from the patients' medical records. These included co-morbid conditions eg hypertension, diabetes mellitus, dyslipidaemia, ESRD, whether history of smoking or cocaine use and if any prior care. In the former period, 11 cases were confirmed as having myocardial infarction and 27 cases in the latter period. RESULTS: In 2007 and 2008, all cases had dyslipidaemia (LDL > 100 mg/dL) and were hypertensive. There were 36.4% of cases in 2007 that had diabetes mellitus, compared to 33.3% cases in 2008 and 9.1% had chronic kidney disease in 2007, compared to 25.9% in 2008. CONCLUSION: The most common co-morbidities associated with acute myocardial infarction in Tobago are dyslipidaemia, hypertension and diabetes mellitus, with ESRD, smoking and cocaine use less so. Many of these patients had never received prior care. less...

Central stress regulatory pathways utilize various neuropeptides, such as urocortin-1 (Ucn1) and cocaine- and amphetamine-regulated transcript peptide (CART). Ucn1 is most abundantly expressed in the non-preganglionic Edinger-Westphal nucleus (npEW). In addition to Ucn1, CART and nesfatin-1 are highly expressed in neurons of the npEW, but the way these three neuropeptides act together in response to acute stress is not known. We hypothesized that Ucn1, CART and nesfatin-1 are colocalized in npEW neurons and that these neurons are recruited by acute stress. Using quantitative immunocytochemistry and the reverse transcriptase polymerase chain reaction (RT-PCR), we support this hypothesis, by showing in B6C3F1/Crl mice that Ucn1, CART and nesfatin-1 occur in the same neurons of the npEW nucleus. More specifically, Ucn1 and CART revealed a complete colocalization in the same perikarya, while 90% of these neurons are also nesfatin-1-immunoreactive. Furthermore, acute (restraint) stress stimulates the general secretory activity of these npEW neurons (increased presence of Fos) and the production of Ucn1, CART and nesfatin-1: Ucn1, CART and nesfatin-1(NUCB2) mRNAs have been increased compared to controls by x1.8, x2.0 and x2.6, respectively (p<0.01). We conclude that Ucn1, CART and nesfatin-1/NUCB2 are specifically involved in the response of npEW neurons to acute stress in the mouse. less...

GM1 pretreatment enhanced the rewarding properties of cocaine as assessed in the conditioned place preference paradigm. This effect was shown by the lower dosage of cocaine necessary to induce conditioning compared with rats receiving cocaine alone, as well as by the fewer number of sessions necessary to induce place preference. GM1 pretreatment did not modify the plasma level of cocaine, but it induced a significant increase in the brain cocaine level compared with animals receiving cocaine alone. In order to evaluate the possibility that GM1 pretreatment may alters the pharmacokinetic parameters of cocaine, the brain and plasma esterases activities, the plasma bound/free cocaine ratio and the brain blood barrier permeability to i.v. Evans Blue administration were assessed. None of these parameters were modified by the GM1 administration. In addition, GM1 (100microM) did not alter the dopamine transporter inhibition induced by cocaine (10(-7)-10(-5)M), as determined by the uptake of [(3-)H]-dopamine in the microsacs of nucleus accumbens. In conclusion, GM1 pretreatment, which did not have any effect per se, increased the rewarding effect of cocaine, a phenomenon correlated with a significant increase in the brain cocaine levels. The different pharmacokinetic parameters evaluated, as well as the inhibitory effect of cocaine on the dopamine transporter, were not modified by GM1, but it modifies the brain cocaine disposition. Thus, the mechanisms by which GM1 enhanced the rewarding effects of cocaine merits further study. less...

Cocaine alters brain function from the early days of development throughout the entire life of an individual. Since the first preclinical research on cocaine sensitization was published, sex differences in response to the drug in adult rats have been noted. With the appearance of reports on "crack babies" during the 1980s, sex differences in response to prenatal (developmental) exposure have been identified in both clinical and preclinical reports. Cocaine administered during early development in the rat produces wide-spread alterations in function which depend on the timing of drug administration as well as the sex of the animal. In males, the response patterns following postnatal days (PND) 11-20 cocaine administration (equivalent to the late prenatal period in humans) are quite similar to those seen following prenatal exposure (equivalent to the first half of pregnancy in humans). There is a general decrease in dopaminergic (DA) markers and reactivity perhaps due to the uncoupling of the D1 receptor from its second messenger system. While similar changes in D1 uncoupling are seen in females, behavioral and metabolic responses to drug challenges generally show increases in DA responsivity (except adolescents) perhaps due to the activational effects of estrogen and/or decreases in serotonin (5-HT) mediated regulation of DA function. We have found that a significant factor in the hyper-responsivity of the female is the role of the testing environment and the responses to stress which can obscure underlying neurochemical dysregulation. Whether parallel factors are operational in adult males and females is currently under investigation. less...

BACKGROUND: In addicts drug cues attract attention, elicit approach, and motivate drug-seeking and drug-taking behavior, and addicts find it difficult to resist such cues. In preclinical studies we have found, however, that food cues acquire incentive motivational properties only in a subset of individuals. For example, a food cue becomes attractive, eliciting approach and engagement with it, and acts as an effective conditional reinforcer in some rats but not others. We asked, therefore, whether rats that have a propensity to attribute incentive salience to a food cue are the same ones that attribute incentive value to a drug (cocaine) cue. METHODS: We first used a Pavlovian conditioned approach procedure to determine which individual rats attributed incentive salience to a food cue. A second cue was then associated with the IV self-administration of cocaine. Later, the ability of the cocaine cue to maintain self-administration behavior and to reinstate self-administration after extinction was assessed. RESULTS: We report that in individuals that had a propensity to attribute incentive salience to a food cue, a cocaine cue spurred motivation to take drugs (its removal greatly diminished self-administration) and reinstated robust drug-seeking after extinction. However, in those individuals that failed to attribute incentive salience to a food cue, the cocaine cue was relatively devoid of incentive motivational properties. CONCLUSIONS: We conclude that it is possible to determine, before any drug experience, which individuals will most likely have difficulty resisting drug cues, a trait that might confer susceptibility to addiction. less...

While it has been well documented that drugs of abuse such as cocaine can cause enhanced progression of HIV-Associated Neuropathological Disorders (HAND), the underlying mechanisms mediating these effects remain poorly understood. In the present study, we explored the impact of cocaine exposure (I muM and 10 muM) on the dendritic beading in rat primary hippocampal neurons. Using the approach of transfection with green fluorescent protein, we observed significant dendritic swelling in hippocampal neurons exposed to 10 muM but not 1 muM of cocaine when compared with the saline treated group. Cocaine exposure also resulted in decreased expression of the synaptic plasticity gene, Arc as evidenced by Western blotting. Intriguingly, cocaine exposure of primary neurons in the presence of the neurotoxin-HIV envelope protein gp 120, resulted in increased enhancement of neuronal beading as compared with exposure of neurons to either agent alone. Taken together these findings imply that cocaine in co-operation with HIV protein exacerbates neuronal damage in the brains of HIV-infected cocaine abusers. less...

This study examined the association between prenatal exposure to cocaine and physiological regulation across the first 7 months of age. Measures of respiratory sinus arrhythmia (RSA) were obtained from 169 (82 cocaine-exposed and 87 nonexposed) infants during baseline periods at 1 month and 7 months of age and during tasks designed to elicit positive and negative affect at 7 months of age. After controlling for maternal age, gestational age, and obstetrical risk, structural equation modeling indicated that the association between prenatal exposure to cocaine and baseline RSA at 7 months of age was direct even in the presence of an indirect effect through baseline RSA at 1 month of age. There were no indirect effects through maternal affect during mother-infant interactions assessed at 1 month of age. Analyses also indicated a direct association between prenatal exposure to cocaine and RSA regulation to negative affect at 7 months of age. less...

CONTEXT: Selective interventions targeting personality risk are showing promise in the prevention of problematic drinking behavior, but their effect on illicit drug use has yet to be evaluated. OBJECTIVE: To investigate the efficacy of targeted coping skills interventions on illicit drug use in adolescents with personality risk factors for substance misuse. DESIGN: Randomized controlled trial. SETTING: Secondary schools in London, United Kingdom. PARTICIPANTS: A total of 5302 students were screened to identify 2028 students aged 13 to 16 years with elevated scores on self-report measures of hopelessness, anxiety sensitivity, impulsivity, and sensation seeking. Seven hundred thirty-two students provided parental consent to participate in this trial. INTERVENTION: Participants were randomly assigned to a control no-intervention condition or a 2-session group coping skills intervention targeting 1 of 4 personality profiles. MAIN OUTCOME MEASURES: The trial was designed and powered to primarily evaluate the effect of the intervention on the onset, prevalence, and frequency of illicit drug use over a 2-year period. RESULTS: Intent-to-treat repeated-measures analyses on continuous measures of drug use revealed time x intervention effects on the number of drugs used (P < .01) and drug use frequency (P < .05), whereby the control group showed significant growth in the number of drugs used as well as more frequent drug use over the 2-year period relative to the intervention group. Survival analysis using logistic regression revealed that the intervention was associated with reduced odds of taking up the use of marijuana (beta = -0.3; robust SE = 0.2; P = .09; odds ratio = 0.7; 95% confidence interval, 0.5-1.0), cocaine (beta = -1.4; robust SE = 0.4; P < .001; odds ratio = 0.2; 95% confidence interval, 0.1-0.5), and other drugs (beta = -0.7; robust SE = 0.3; P = .03; odds ratio = 0.5; 95% confidence interval, 0.3-0.9) over the 24-month period. CONCLUSION: This study extends the evidence that brief, personality-targeted interventions can prevent the onset and escalation of substance misuse in high-risk adolescents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00344474. less...