Effects Of Chronic Cocaine Use Research Articles

Exercise Influences the Brain's Metabolic Response to Chronic Cocaine Exposure in Male Rats.

Cocaine use is associated with negative health outcomes: cocaine use disorders, speedballing, and overdose deaths. Currently, treatments for cocaine use disorders and overdose are non-existent when compared to opioid use disorders, and current standard cocaine use disorder treatments have high dropout and recidivism rates. Physical exercise has been shown to attenuate addiction behavior as well as modulate brain activity. This study examined the differential effects of chronic cocaine use between exercised and sedentary rats. The effects of exercise on brain glucose metabolism (BGluM) following chronic cocaine exposure were assessed using Positron Emission Tomography (PET) and [18F]-Fluorodeoxyglucose (FDG). Compared to sedentary animals, exercise decreased metabolism in the SIBF primary somatosensory cortex. Activation occurred in the amygdalopiriform and piriform cortex, trigeminothalamic tract, rhinal and perirhinal cortex, and visual cortex. BGluM changes may help ameliorate various aspects of cocaine abuse and reinstatement. Further investigation is needed into the underlying neuronal circuits involved in BGluM changes and their association with addiction behaviors.

Cingulate cortical thickness in cocaine use disorder: mediation effect between early life stress and cocaine consumption.

The cingulate gyrus is implicated in the neurobiology of addiction, such as chronic cocaine consumption. Early life stress (ELS) is an important moderator of cocaine use disorder (CUD). Therefore, we investigated the effect of CUD on cingulate cortical thickness and tested whether a history of ELS could influence the effects of CUD. Participants aged 18-50 years (78 with CUD due to crack cocaine consumption and 53 healthy controls) underwent magnetic resonance imaging and the cingulate thickness (rostral anterior, caudal anterior, posterior, and isthmus regions) was analysed. The clinical assessment comprised the Childhood Trauma Questionnaire (CTQ) and the Addiction Severity Index. Group comparisons adjusting by sex, age, and education were performed. Mediation models were generated where lifetime cocaine use, CTQ score, and cortical thickness corresponded to the independent variable, intermediary variable, and outcome, respectively. Group comparisons revealed significant differences in six out of eight cingulate cortices, showing lower thickness in the CUD group. Furthermore, years of regular cocaine use was the variable most associated with cingulate thickness. Negative correlations were found between CTQ scores and the isthmus cingulate (right hemisphere), as well as with the rostral anterior cingulate (left hemisphere). In the mediation analysis, we observed a significant negative direct effect of lifetime cocaine use on the isthmus cingulate and an indirect effect of cocaine use mediated by CTQ score. Our findings suggest that a history of ELS could aggravate the negative effects of chronic cocaine use on the cingulate gyrus, particularly in the right isthmus cingulate cortex.

White matter deficits in cocaine use disorder: convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomic analysis

White matter (WM) abnormalities in patients with cocaine use disorder (CUD) have been studied; however, the reported effects on the human brain are heterogenous and most results have been obtained from male participants. In addition, biological data supporting the imaging findings and revealing possible mechanisms underlying the neurotoxic effects of chronic cocaine use (CU) on WM are largely restricted to animal studies. To evaluate the neurotoxic effects of CU in the WM, we performed an in vivo diffusion tensor imaging assessment of male and female cocaine users (n = 75) and healthy controls (HC) (n = 58). Moreover, we performed an ex vivo large-scale proteomic analysis using liquid chromatography-tandem mass spectrometry in postmortem brains of patients with CUD (n = 8) and HC (n = 12). Compared with the HC, the CUD group showed significant reductions in global fractional anisotropy (FA) (p < 0.001), and an increase in global mean (MD) and radial diffusion (RD) (both p < 0.001). The results revealed that FA, RD, and MD alterations in the CUD group were widespread along the major WM tracts, after analysis using the tract-based special statistics approach. Global FA was negatively associated with years of CU (p = 0.0421) and female sex (p < 0.001), but not with years of alcohol or nicotine use. Concerning the fibers connecting the left to the right prefrontal cortex, Brodmann area 9 (BA9), the CUD group presented lower FA (p = 0.006) and higher RD (p < 0.001) values compared with the HC group. A negative association between the duration of CU in life and FA values in this tract was also observed (p = 0.019). Proteomics analyses in BA9 found 11 proteins differentially expressed between cocaine users and controls. Among these, were proteins related to myelination and neuroinflammation. In summary, we demonstrate convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomics analysis of WM disruption in CUD.

Cocaine use and HIV-infection modify coronary plaque morphology differently than conventional cardiovascular risk factors

Abstract Background/Introduction Cardiovascular risk factors are assumed to propagate coronary artery disease (CAD) through the lipid and/or inflammatory pathologic pathways. However, we currently do not have any in-vivo information whether these effects may alter CAD morphology and structure differently. Purpose We wished to assess whether conventional cardiovascular risk factors (which are assumed to affect CAD primarily through the lipid pathway), and unconventional risk factors such as cocaine use and human immunodeficiency virus (HIV)-infection (which are assumed to propagate CAD primarily through the inflammatory pathway) affect different coronary plaque structures as assessed by radiomics. Methods In our prospective longitudinal observational study of 300 individuals without cardiovascular symptoms but with coronary CT angiography (CCTA)-confirmed atherosclerosis (210 male, age: 48±7 years) of whom 161 were cocaine users at baseline with or without HIV-infection (226 HIV-infected), underwent CCTA at two time points (mean follow-up: 4.0±2.3 years). Precision phenotyping of CAD was done by calculating 1276 radiomic features on the 861 plaques. Linear mixed models corrected for plaque volume, high-sensitivity C-reactive protein, statin use and positive family history were used to assess the effects of chronic cocaine use, HIV-infection and elevated atherosclerotic cardiovascular disease risk (ASCVD≥7.5%). Hierarchical clustering was used to assess potential clusters among significant radiomic features. Bonferroni corrected p&amp;lt;0.00004 (0.05/1276) was considered significant. Results Overall, 32.0% (409/1276) of the radiomic features showed any significant association, of which 74.1% (303/409), 4.2% (17/409) and 25.4% (104/409) were affected by cocaine use, HIV-infection and elevated ASCVD risk, respectively. There was no overlap among radiomic features significantly associated with increased ASCVD risk and cocaine use or HIV-infection, while 88,2% (15/17) of HIV-infection associated parameters were also affected by cocaine use. Cluster analysis indicated 13 different structural components among significant features, of which eight were unique to chronic cocaine use, three unique to ASCVD risk, and two contained parameters associated with chronic cocaine use, elevated ASCVD risk and/or HIV-infection. Interpretation Chronic cocaine use and HIV-infection modify different CAD morphological components than conventional cardiovascular risk factors, potentially implying independent pathological pathways of disease progression irrespective of each other. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health, National Institute on Drug Abuse

Effect of chronic cocaine use on fine motor coordination tested during ophthalmic vitreoretinal simulated performance

We conducted a case-control study using the Eyesi simulator to assess the surgical performance of 24 chronic cocaine users (CCUs) and 24 sex-/age-matched controls to numerically quantify ophthalmic microsurgical simulator performance and fine motor deficiencies. The inclusion criteria were no exposure to illicit drugs other than cocaine, marijuana, or alcohol within the previous month and no health conditions that could impact manual task performance. The outcomes included surgical scores (0–100, worst-best) and task completion time (minutes). Fisher's exact test, analysis of variance, Mann-Whitney U test, and Kruskal-Wallis test followed by Dunn-Bonferroni post-hoc were conducted for statistical analysis. The Eyesi scores were lower among CCUs compared to controls for bimanual tasks (4.50 ± 14.30 vs. 18.46 ± 26.64, p = 0.012), for exercises demanding upper and lower limb coordination (both hands and two foot pedals, respectively) (74.13 ± 35.01 vs. 85.21 ± 24.1, p = 0.045), and in the overall score for all three tasks (27.38 ± 15.06 vs. 39.5 ± 18.66, p = 0.021). CCUs took longer to complete tasks when performing exercises demanding upper and lower limb coordination compared to controls (1.26 ± 0.38 vs. 1.02 ± 0.44 min, p = 0.006). Individuals who used cocaine during the previous month had an independent lower bimanual score compared to controls (1.42 ± 4.91 vs. 18.46 ± 26.64, p = 0.018). No differences in performance among the CCUs were attributable to sporadic cannabis or alcohol use. Chronic use of cocaine negatively impacted fine dexterity as measured by bimanual tasks or maneuvers that required simultaneous coordination of the upper and lower limbs. This was most notable among individuals who used cocaine during the 1-month period before the simulation.

A preliminary longitudinal study of white matter alteration in cocaine use disorder subjects

BackgroundPrevious diffusion tensor imaging (DTI) studies have consistently shown that subjects with cocaine use disorder (CocUD) had altered white matter microstructure in the corpus callosum. It is believed that these alterations are due to preexisting factors, chronic cocaine use, or both. However, there is no published longitudinal DTI study on human cocaine users yet which could shed light on the relationship between cocaine use and DTI findings. MethodsThis study used a longitudinal design and DTI to test if the white matter microstructure shows quicker alteration in CocUD subjects than controls. DTI data were acquired from eleven CocUD subjects who participated a treatment study and eleven non-drug-using controls at baseline (Scan 1) and after ten weeks (Scan 2). The baseline fractional anisotropy (FA), a general measure of white matter microstucture, and the change in FA (ΔFA, equals Scan 1 FA minus Scan 2 FA) were both compared between groups. ResultsThe two groups did not show a difference in FA at baseline. The CocUD subjects had significantly greater ΔFA than the controls in the left splenium of the corpus callosum. In CocUD subjects, greater ΔFA in this region was associated with shorter lifetime cocaine use and greater number of positive cocaine urine samples collected during the treatment. ConclusionThe finding in the left splenium is consistent with previous animal studies and provide indirect evidence about the effects of chronic cocaine use on white matter alterations. The subject sample size is small, therefore the results should be treated as preliminary.

A new way to reduce drug seeking

Neuroscience![Figure][1] A methyl donor can reduce an addict's urge for ever more cocaine PHOTO: GBRUNDIN /ISTOCKPHOTO Relapse is a serious problem for many individuals trying to recover from addiction. Because DNA methylation regulates neural functions associated with synaptic plasticity, learning, and memory, Wright et al. investigated its role in sensitization to cocaine and reinstatement to cocaine and associated cues. A methyl donor, l-methionine, reduced behavioral sensitization to the locomotor-activating and drug-seeking effects of chronic cocaine use. l-methionine also blocked a cocaine-induced marker of neuronal activation after reinstatement in the nucleus accumbens and the medial prefrontal cortex, two brain regions responsible for drug seeking and relapse. J. Neurosci. , 35 , 8948 (2015). [1]: pending:yes

Bradycardia as a Marker of Chronic Cocaine Use: A Novel Cardiovascular Finding

Few studies have examined the effects of chronic cocaine use on the resting surface electrocardiogram (ECG) between exposures to cocaine. Researchers compared 12-lead ECGs from 97 treatment-seeking cocaine-dependent patients, with ECG parameters from 8,513 non-cocaine-using control patients from the Atherosclerosis Risk in Communities study. After matching and adjusting for relevant covariates, cocaine use demonstrated large and statistically reliable effects on early repolarization, bradycardia, severe bradycardia, and heart rate. Current cocaine dependence corresponds to an increased odds of demonstrating early repolarization by a factor of 4.92 and increased odds of bradycardia and severe bradycardia by factors 3.02 and 5.11, respectively. This study demonstrates the novel finding that long-lasting effects of cocaine use on both the cardiac conduction and the autonomic nervous system pose a risk of adverse cardiovascular events between episodes of cocaine use, and that bradycardia is a marker of chronic cocaine use.

Deficits in default mode network activity preceding error in cocaine dependent individuals

Background Cocaine dependence is associated with cognitive deficits and altered task-related cerebral activation in cognitive performance (see Li and Sinha, 2008, for a review). Relatively little is known whether these individuals are also impaired in regional brain activation of the default mode network (DMN). We demonstrated previously that greater activation of the default brain regions precedes errors in a stop signal task performed by healthy controls (SST, Li et al., 2007). We seek to determine whether individuals with cocaine dependence are impaired in DMN activity, specifically activity preceding error, as compared to the healthy people. We also examine the relation to years of cocaine use. Methods Individuals with cocaine dependence (CD, n = 23) and demographics-matched healthy controls (HC, n = 27) performed a SST that employed a tracking procedure to adjust the difficulty of stop trials and elicit errors approximately half of the time. Blood oxygenation level dependent (BOLD) signals of go trials preceding stop error as compared to those preceding stop success trials were extracted with generalized linear models using statistical parametric mapping. Results HC showed activation of bilateral precuneus and posterior cingulate cortices and ventromedial prefrontal cortex (vmPFC) preceding errors during the SST. In contrast, despite indistinguishable stop signal performance, CD did not show these error predicting activations. Furthermore, the effect size of error-preceding vmPFC activation was inversely correlated with years of cocaine use. Conclusions These findings indicate DMN deficits and could potentially add to our understanding of the effects of chronic cocaine use on cerebral functions in cocaine dependence. Work to further clarify potential changes in functional connectivity and gray matter volume is warranted to understand the relevance of DMN to the pathology of cocaine misuse.

Effect of Cocaine Use on Buprenorphine Pharmacokinetics in Humans

The effect of chronic cocaine use on buprenorphine pharmacokinetics was investigated to identify drug interactions and potential toxicities. In a retrospective analysis, pharmacokinetics were compared for 16 studies completed on subjects who were regular cocaine users and 74 studies on subjects who used cocaine only occasionally or not at all. All participants were stably maintained on buprenorphine/naloxone 16/4 mg daily. Participants who used cocaine regularly had lower buprenorphine exposure (AUC 34% lower; C(max) 27% lower and C(24) 37% lower; p <or= .001 for all comparisons). Regular cocaine users were younger (p = .0007), and used more heroin (p = .004) and cocaine (p < .0001). Regular cocaine use may result in lower buprenorphine plasma concentrations with potential for adverse clinical outcomes.

Cocaine-dependence and cocaine-induced paranoia and mid-latency auditory evoked responses and sensory gating

Cocaine-dependence has been shown to affect the amplitudes of the P50 mid-latency auditory evoked response (MLAER) as well as P50 sensory gating. The effects on subsequent MLAERs (N100 and P200) have not been examined. The objective of the current study was to further assess the effects of chronic cocaine use on the P50, N100, and P200 components. Thirty-four, at least three weeks abstinent, cocaine-dependent individuals and 34 age and gender matched healthy controls were examined. The amplitudes, latencies and gating measures were calculated and compared between the groups. The N100 and P200 were significantly smaller in patients as compared to control subjects. Sensory gating of the P50, the N100, and the P200 were deficient in cocaine-dependent subjects. Latencies of all measured components were prolonged in subjects who reported developing paranoia while intoxicated. Finally, a positive correlation was found between length of abstinence and evoked response amplitudes. We conclude that the effects of cocaine on sensory gating extend beyond the P50 to the N100 and the P200 components. The data also suggest that prolonged latency of the evoked potentials may be a correlate of cocaine-induced psychosis. Finally, the data suggest that some recovery of amplitude and gating occurs with abstinence.

Serotonin transporters upregulate with chronic cocaine use

Cocaine potently inhibits serotonin (5-HT) reuptake in cell bodies and at nerve terminals and 5-HT has been implicated as a modulator of dopaminergic neurotransmission. Chronic use of cocaine may lead to a ‘serotonin-deficit’ form of 5-HT dysregulation. We have examined the status of the 5-HT transporter (SERT) using ligand binding and autoradiographic methods in subgroups of cocaine overdose deaths. Quantitative autoradiography of [ 125I]RTI-55 was used to map and measure the effect of chronic cocaine use on SERT densities in the striatum, substantia nigra, amygdala, and adjacent paralimbic cortical areas of cocaine overdose (CO) victims with and without preterminal evidence of excited delirium (ED). SERT densities were elevated in the nucleus accumbens and throughout the anterior and posterior sectors of striatum in CO victims compared with age-matched and drug-free control subjects. In contrast, SERT densities were increased significantly in the anterior striatum, but not the posterior sectors in ED victims. Significant elevations in SERT were measured in the orbitofrontal gyrus (Brodmann area 11), the anterior portion of the insular cortex and the cingulate gyrus (Brodmann area 24) in CO and ED victims. Saturation binding site analysis demonstrated an increase in the density of RTI-55 binding sites with no change in the affinity of the radioligand for the SERT. Chronic cocaine exposure upregulated SERT densities in the substantia nigra of the CO, but not ED victims. The lack of SERT upregulation in the substania nigra and posterior striatum suggests the possibility of a distinct phenotype for fatal ED victims that exhibited an acute onset of bizarre and violent behavior prior to death. Adaptive changes in the SERT densities may contribute to depressed mood and drug craving associated with acute cocaine abstinence.

Cocaine use and the mid-latency auditory evoked responses

To examine the effects of chronic cocaine use on the mid-latency auditory evoked responses (MLAERs), we recorded the evoked responses of 15 cocaine-dependent subjects and 13 age-matched healthy control subjects. Two evoked response paradigms were used: a trains paradigm with four different inter-stimulus intervals (ISIs) and a paired-click paradigm. Our data suggest that cocaine-dependent subjects generate smaller P50 components when long ISIs are used with multiple repetitions (in the trains paradigm). In a single repetition paradigm (paired clicks), a significant decrease in the ability to attenuate the N100 component was seen in the cocaine-dependent subjects.

Attentional functioning in abstinent cocaine abusers

The effect of chronic cocaine use on attention is directly relevant to the treatment of cocaine dependence, since attention underlies most other cognitive processes, and thus the ability to profit from cognitively-based interventions. This paper reviews 17 studies examining attention in patients with cocaine abuse or dependence. Findings have been inconsistent, largely due to various methodological difficulties. There has been some suggestion of reduced cognitive speed, while focused and sustained attention have generally been unimpaired. Divided attention has been largely unexplored. Thus, there is insufficient evidence either to accept or reject the hypothesis of attentional dysfunction associated with chronic cocaine use.

Cocaine and metabolite concentrations in plasma during repeated oral administration: development of a human laboratory model of chronic cocaine use.

Long-term use of cocaine may produce neurophysiological and metabolic alterations that differ from acute drug use. A laboratory model that was capable of evaluating the effects of chronic cocaine administration in human subjects was needed. Chronic oral administration of cocaine was considered a feasible route because of the ease of administration, control of dosing patterns, and possible reduction in medical risks compared with the intravenous and smoked routes. This clinical study was conducted to evaluate chronically administered oral cocaine as a means of studying cocaine addiction and withdrawal in humans. Cocaine-abusing volunteers were given multiple doses of oral cocaine each day in up to 16 daily sessions (including three placebo sessions). In each daily session, volunteers received five equal doses separated by hourly intervals. Across sessions, the dose was increased from an initial dose of 100 mg (500 mg/day) to 400 mg (2000 mg/day) in the last session. The dose for each consecutive cocaine session was increased by 25 mg/dose/session (125-mg total increase per session). Twelve subjects were enrolled in the study; however, three subjects dropped out prior to completion of at least three sessions. Two subjects completed all 13 cocaine sessions. The remaining seven subjects completed from 3 to 11 sessions; their participation was terminated early for safety and behavioral reasons. Plasma was collected during all sessions and analyzed for cocaine and metabolites by solid-phase extraction followed by gas chromatography-mass spectrometry. Oral cocaine administration resulted in peak plasma concentrations of cocaine approximately 1 h after administration. Accumulation of cocaine was evident between hourly doses and there was evidence of dose-proportional increases in area under the curve (AUC) measures across sessions. A variety of cocaine metabolites was measured in plasma including benzoylecgonine, ecgonine methyl ester, norcocaine, benzoylnorecgonine, and p and m-hydroxy metabolites of cocaine and benzoylecgonine. During chronic oral dosing, there appeared to be a trend for AUC ratios (AUCmetabolite/AUCcocaine) of benzoylecgonine and ecgonine methyl ester to decrease and norcocaine to increase, indicating the possibility of dose-, time-, or route-dependent changes in the absorption and/or metabolism of cocaine. Overall, this study demonstrated that chronic oral dosing of cocaine produced dose-related increases in plasma cocaine concentration, and this model could be useful for studying the effects of chronic cocaine use in human subjects.

The relationship between chronic cocaine or alcohol use and blood pressure in black men during uncomplicated tooth extraction

Purpose: The object of this study was to determine whether a history of cocaine or alcohol use is associated with blood pressure changes in patients undergoing an uncomplicated mandibular molar extraction. Patients and Methods: The blood pressure (BP) values of middle-aged (30 to 40 years of age) black men with different chronic drug histories were compared during extraction procedures. The four different groups were 1) no-drug control, (n = 10); 2) alcohol (n = 15); 3) “crack” cocaine (n = 9); and 4) cocaine (n = 22). Results: The cocaine group's blood pressures were significantly different compared with the blood pressures within the no-drug and alcohol groups ( P < .05). The cocaine group's BPs decreased throughout the procedure, and the BPs of the no-drug and alcohol groups rose during administration of the local anesthetic and extraction, and then fell. The BPs of the crack group were highly variable and not significantly different when compared with other groups. Conclusion: There is a paradoxical effect of chronic cocaine use on blood pressure that needs to be considered when treating such patients.

Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities.

The effects of chronic cocaine use on D3 receptor mRNA expression in the human nucleus accumbens was assessed by reverse transcription-polymerase chain reaction. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased 6-fold in cocaine overdose victims as compared to age-matched and drug-free control subjects. This finding demonstrates that chronic cocaine exposure leads to adaptive increases in the expression of D3 receptor mRNA in a critical reward center in brain.

Reply

Associate Professor (Bernards); Professor (Cullen), University of Washington School of Medicine, 1959 NE Pacific Street, Box 356540, Seattle, Washington 98195–6540.In Reply:-As noted in our article, [1]we are in complete agreement with Drs. Morishima and Whittington's assertion that there are significant pharmacokinetic differences between humans and sheep with respect to cocaine metabolism. However, the object of our study was to understand the pharmacodynamic impact of chronic cocaine exposure, not the pharmacokinetics of cocaine metabolism, and, despite the pharmacokinetic differences between sheep and humans, the pharmacodynamic effects of cocaine are remarkably similar.For example, Morishima's laboratory found that sheep demonstrate a gradually diminishing hemodynamic response to repeated short-term cocaine boluses (personal communication). This identical pharmacodynamic phenomenon has been clearly demonstrated in humans and other mammals as well. [2]Similarly, sheep demonstrate sensitization to the locomotor and stereotypic effects of cocaine, just as do animals with more human-like cocaine metabolism. [3]Too, after only 4–6 days of cocaine exposure, sheep clearly demonstrate “drug seeking behavior,” as do other species whose pattern of cocaine metabolism more closely resembles humans. Therefore, whereas the ovine model may well be a poor choice to model human cocaine pharmacokinetics, there are ample data to support the use of sheep as a pharmacodynamic model. Consequently, we believe our finding of a reversible increase in isoflurane MAC after chronic cocaine exposure in sheep is qualitatively applicable to humans.Morishima and Whittington also suggest that we should have “kept plasma cocaine concentrations in the range occurring in human “binge” users.” We disagree for two reasons. First, human cocaine use patterns are extremely varied, so it is simply not possible to identify a cocaine plasma concentration that is “representative” of the typical human binge. Second, the purpose of the binge was to study the consequences of repeated short-term cocaine exposure in the absence of a significant plasma concentration of cocaine. Consequently we waited 3 h after the last cocaine bolus to measure MAC. This was done to mimic the increasingly common situation of a patient presenting for surgical repair of a traumatic injury associated with cocaine abuse. [4]By the time many of these patients arrive in the operating room, several hours may have elapsed since their last cocaine dose. Therefore, their plasma cocaine concentrations may be physiologically insignificant at that point, but the physiologic consequences of their preceding binge may not be.Finally, as Morishima and Whittington point out, the duration of cocaine exposure for any given cocaine dose is shorter in sheep than in humans. If anything, this fact should have biased our study against finding a pharmacodynamic effect of chronic cocaine use on MAC. Therefore, that we clearly demonstrated a reversible increase in MAC after chronic cocaine exposure in this model strongly suggests that the same qualitative effect of cocaine can be expected in humans.Again, we appreciate the valid issues raised by Morishima and Whittington, and we agree that sheep, like all animal models, have shortcomings. However, for the reasons presented earlier, we do not think these shortcomings invalidate the qualitative applicability of our data to humans.Christopher M. Bernards, M.D.Associate ProfessorBruce F. Cullen, M.D.ProfessorUniversity of Washington School of Medicine1959 NE Pacific Street; Box 356540; Seattle, Washington 98195–6540(Accepted for publication December 12, 1996.)

Radioligand binding and immunoautoradiographic evidence for a lack of toxicity to dopaminergic nerve terminals in human cocaine overdose victims

Radioligand binding to and immunolabeling of transport sites associated with monoamine-containing synaptic vesicles affords a novel approach for mapping the integrity of dopaminergic (DAergic) nerve terminals. The present study used [ 125I]iodovinyltetrabenzine ([ 125I]TBZ) and a fusion protein antibody directed at the large intraluminal loop of the neuronal vesicular monoamine transporter (hVMAT2-loop) as probes to assess the effects of chronic cocaine use on the integrity of DAergic nerve terminals in the striatum of cocaine fatalities. Visualization of [ 125I]TBZ binding in human brain revealed a distinct pattern of labeling throughout the rostral-caudal extent of the striatum. Saturation binding of [ 125I]TBZ in striatal membranes demonstrated a single high affinity site ( K d = 2.3 ± 0.9 nM and B max = 55.5 ± 8.1 pmol/g tissue) with a pharmacological profile (tetrabenazine ≥ iodovinyltetrabenazine > ketanserin ≥ reserpine > haloperidol > GBR 12909) consistent with the specific labeling of hVMAT2. Quantitative in vitro autoradiography demonstrated no significant alteration in the density of [ 125I]TBZ binding sites in the anterior and posterior sectors of the striatum in cocaine fatalities with and without preterminal excited delirium as compared to drug-free and age-matched control subjects. Similarly, the levels of hVMAT2-loop immunoreactivity were not significantly different across control and cocaine fatality groups. The results demonstrate the lack of an alteration in [ 125I]TBZ binding sites and hVMAT2 protein in the striatum from a young cohort of cocaine fatalities. Since striatal VMAT2 is primarily associated with DAergic nerve terminals, these results suggest that chronic cocaine use failed to affect the integrity of striatal DAergic nerve terminals.

Effects of chronic cocaine use on physical health: a prospective study in a general population sample

Few studies have examined long-term effects of chronic cocaine use on physical health in the general population. The current study assesses the effects of chronic cocaine use by the late twenties on physical health by the mid thirties in a longitudinal cohort from the general population. Measures of physical health included self-reported health status, cardiovascular, neurological, and somatic symptoms, and number of hospital or sick days within the last year. The causal analyses were restricted to males because few females used cocaine heavily and the relationships between females' cocaine use and physical health were rarely significant. Among males, chronic cocaine use increased physical health problems, controlling for prior health status, current cocaine use, use of other drugs and sociodemographic characteristics. In turn, poor health contributed to continued cocaine use. Variance partitioning based on cocaine use patterns (frequency and chronicity) indicated that chronic users experienced the most adverse consequences on subsequent physical health. Implications for understanding how chronic cocaine use affects a broad spectrum of physical functioning are discussed.