Cocaine Levels Research Articles

Body Stuffer and Death by Cocaine Overdose: Case Report

The practice of ingesting illicit substances to avoid detection by the police, known as Body Stuffing (BS), is a reality that poses significant risks to the health and safety of those involved. This article objective is to promote discussion about the challenges in identifying signs and symptoms in cases of BS, in addition to the importance of training the attending professional to identify the scenario, given its complex manifestation and the high mortality associated with this practice. This is a descriptive study reporting the case of a death from cocaine overdose following the practice of SB. The victim was a 24-year-old man, arrested by the police, who suffered a cardiorespiratory arrest when he was taken into custody by the Civil Police. The witnesses reported that he had ingested a package containing a white powder. The case analysis reports the sequence of conditions involved in this type of situation, ranging from diagnosis, treatment and identification of the cause of death. The autopsy examination confirmed the absence of fatal lesions and findings compatible with an overdose, obtained from the results of toxicological tests that confirmed high levels of cocaine in the body. The case analysis reinforces the need for a multidisciplinary approach to address the medical, legal and social complexities of this problem.

Are decreased cocaine- and amphetamine regulated transcript and Agouti- related peptide levels associated Eating behavior in medication-free children with attention deficit and hyperactivity disorder?

This study aimed to investigate plasma levels of cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AgRP), cholecystokinin (CCK) and peptide YY (PYY) and their relationship with eating behaviors among children with attention deficit hyperactivity disorder (ADHD) and healthy controls. A total of 94 medication-free children with ADHD and 82 controls aged 8–14 years were included in this study. The Plasma levels of CART, AgRP, CCK and PYY were measured using enzyme-linked immunosorbent assay kits. The Children's Eating Behavior Questionnaire (CEBQ) was used to assess eating behaviors in children. CART and AgRP levels were found to be significantly lower in the ADHD group than in the control group, while CCK levels were found to be significantly higher in the ADHD group than in the control group. However, there was no significant difference in PYY levels between the groups. Compared to controls, those with ADHD demonstrated significantly higher scores on the CEBQ subscales of food responsiveness, emotional overeating, desire to drink, enjoyment of food, and food fussiness, and significantly lower scores on the slowness of eating subscale. CART was significantly correlated with emotional overeating and enjoyment of food scores, while AgRP was significantly correlated with emotional undereating scores. Covariance analysis was performed by controlling potential confounders such as body mass index, age and sex, and the results were found to be unchanged. It was concluded that CART, AgRP, and CCK may play a potential role in the pathogenesis of ADHD.

A multivariable analysis delineating hair color, hair dyeing, and hat wearing as predictors of level of cocaine and MDMA detection in human hair samples.

Research suggests that hair color, hair dyeing, and perspiration can bias hair test results regarding drug exposure, but research is needed to examine such associations in a multivariable manner. In this epidemiology study, adults were surveyed entering nightclubs and dance festivals in New York City, and 328 provided hair samples, which were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry to determine the level of detection of cocaine and 3,4-methylenedioxymethamphetamine (MDMA). Reporting use was not an inclusion criterion for analysis. We used two-part multivariable models to delineate associations of hair color, past-year hair dyeing, and frequency of past-month hat wearing (which may increase perspiration) in relation to any vs. no detection of cocaine and MDMA as well as level of detection, controlling for hair length, self-reported past-year cocaine/ecstasy/MDMA use, and age, sex, and race/ethnicity. Those reporting having dyed their hair were at increased odds of having any level of cocaine detected (adjusted odds ratio [aOR] = 3.75, 95% CI confidence interval [CI]: 1.85-6.70), and compared to those with brown hair, those with blond(e) hair on average had lower levels of cocaine (ng/mg) detected (beta = -7.97, p = 0.025). Those reporting having dyed their hair were at increased odds of having any level of MDMA detected (aOR =3.05, 95% CI: 1.44-6.48), and compared to those who reported never wearing a hat, those who reported wearing a hat daily or almost daily on average had lower levels of MDMA (ng/mg) detected (beta = -6.61, p = 0.025). This study demonstrates the importance of using multivariable models to delineate predictors of drug detection.

The ascending limb of the cocaine unit dose–response function in rats as an experimental artifact

The cocaine unit dose–response function is an inverted U with the ascending and descending limbs representing the positive and rate limiting cocaine effects, respectively. Higher fixed ratio (FR) schedules and/or time-out periods make the ascending limb more prominent. Alternatively, a pharmacokinetic/pharmacodynamic interaction theory demonstrates that cocaine-induced lever pressing occurs only when cocaine levels are within a range termed the compulsion zone. The inter-injection intervals of self-administration increase with cocaine unit dose because of the longer time required to eliminate higher doses. However, this theory has not been applied to high FR schedules. Rats acquired cocaine self-administration on a FR1 schedule and then were changed to sessions that started with both FR1 and then FR50 over a range of unit doses with a set number of self-administrations allowed for each dose. On FR1, rats completed the maximum number of injections at all but the lowest unit dose. In contrast, on FR50 the proportion of the permitted injections increased as a function of unit dose. However, this ascending limb was the result of averaging data from sessions where rats completed or failed to complete the allowed number of injections. Rats completed all injections when cocaine levels were maintained in the compulsion zone. The FR50 schedule and low unit doses decreased this probability of maintaining cocaine levels in the compulsion zone when the rate of cocaine elimination exceeded the rate of cocaine input during the time required to complete the 50 presses. It is concluded that the ascending limb is an experimental artifact and that the entire dose–response function and the FR50-induced increase in inter-injection intervals are explained in terms of the compulsion zone theory of cocaine self-administration behavior.

SCH23390 and a humanized anti-cocaine mAb decrease the latency to cocaine-induced reinstatement of lever pressing behavior in rats that self-administer cocaine

In rats that self-administer cocaine, the latency to the reinstatement of lever pressing behavior induced by a single dose of cocaine is due to the time taken for cocaine levels to fall to the satiety threshold. The D1 dopamine receptor antagonist SCH23390, and the recombinant humanized anti-cocaine mAb h2E2 increase the cocaine satiety threshold and would be expected to alter the latency to reinstatement. Male rats acquired cocaine self-administration behavior on an FR1 schedule. These rats received a single injection of cocaine (12 µmol/kg i.v.) after an i.v. injection of SCH23390 or an infusion of h2E2 or vehicle. The latency to, and the duration of, lever pressing was measured but the presses had no consequence. SCH23390 decreased the latency to lever pressing consistent with dose-dependent increases in satiety threshold. The duration of lever pressing behavior was inversely proportional to the SCH23390 dose suggesting that SCH23390 also increased the cocaine compulsion zone. The mAb h2E2 also produced a similar decrease in latency to responding that gradually reversed over 2 weeks. SCH23390 and h2E2 had an additive effect on the decreased latency to cocaine-induced lever pressing. The single cocaine dose reinstatement paradigm within the context of the compulsion zone theory is a useful pharmacological bioassay system to explore potential pharmacotherapies for relapse prevention in cocaine use disorder.

The cocaine compulsion zone theory explains the reinstatement of lever pressing behavior in rats in response to a single cocaine dose

A single non-contingent dose of cocaine reinstates extinguished lever pressing behavior in rats trained to self-administer cocaine. This represents a model of relapse in cocaine use disorder and the number of lever presses has been the standard measure. Lever pressing behavior during self-administration occurs only when cocaine levels are below the satiety threshold and above the remission/priming threshold, a range termed the compulsion zone. Calculated cocaine levels at the time of each lever press during an FR1 self-administration session and following a single non-contingent dose of cocaine were compared. The mean latency to lever pressing behavior was dose dependent and ranged from 1 to 11 min after cocaine doses of 2 or 12 μmol/kg, respectively. This is consistent with higher cocaine doses producing levels above satiety threshold that take more time to fall back to that threshold. The level of cocaine when lever pressing occurred was similar whether cocaine was self-administered or after a single dose of cocaine. The number of lever presses after a single cocaine dose was variable and poorly dose dependent. The latency to the start of lever pressing behavior is a more reliable dependent measure than the number of lever presses. In addition, lever pressing behavior occurs only when cocaine levels are within the compulsion zone. The compulsion zone theory not only explains maintained cocaine self-administration behavior, but also explains the reinstatement of lever pressing behavior in response to a single non-contingent cocaine dose.

Nucleus accumbens shell neurons’ early sensitivity to cocaine is associated with future increases in drug intake

The striatum, both dorsal and ventral, is strongly implicated in substance use disorder. Chronic consumption of abused substances, such as cocaine, can cause an oversaturation of mesostriatal dopamine, which results in alterations in the firing of striatal neurons. While most preclinical studies of drug self-administration (S-A) are focused on these alterations, individual differences in a subject's early responses to drugs can also account for substantial differences in addiction susceptibility. In this study, we modeled longitudinal pharmacokinetics using data from a previous longitudinal study (Coffey et al., 2015) and aimed to determine if firing in specific dorsal and ventral striatal subregions was subject to changes across chronic cocaine S-A, and if individual animal differences in striatal firing in response to early drug exposure correlated with increases in drug intake. We observed that the firing patterns of nucleus accumbens (NAc) core and shell neurons exhibited increasing sensitivity to cocaine over the first 6 S-A sessions and maintained a strong negative correlation between drug intake and neuronal firing rates across chronic S-A. Moreover, we observed that the early sensitivity of NAc shell neurons to cocaine correlated with future increases in drug intake. Specifically, rats whose NAc shell neurons were most inhibited by increasing levels of cocaine upon first exposure exhibited the strongest increases in cocaine intake over time. If this difference can be linked to a genetic difference, or druggable targets, it may be possible to screen for similar addiction susceptibility in humans or develop novel preemptive pharmacotherapies.

A humanized anti-cocaine mAb antagonizes the cardiovascular effects of cocaine in rats.

The recombinant monoclonal anti-cocaine antibody, h2E2, sequesters cocaine in plasma increasing concentrations more than 10-fold. The increased levels of cocaine in the plasma could have detrimental peripheral effects, particularly on the cardiovascular system. We investigated the duration and magnitude of the effect of cocaine on the rat heart, and if h2E2 could antagonize that effect. Echocardiography was used to evaluate cardiac function under isoflurane anesthesia, while a tail-cuff was used to measure blood pressure. Cocaine was delivered intravenously and the rats were continuously monitored for a total of 45 min. Echocardiography measurements were recorded every 5min and blood pressure measurements were recorded throughout the duration of the experiment using 30-s cycles. ECG recordings were taken simultaneously with the echocardiography measurements. An increase in ejection fraction was seen after the cocaine push with the maximum change occurring at 25 min. Treatment with h2E2 1 h before the cocaine push did not have any effect on cardiac parameters. Subsequent cocaine treatment had no effect on the ejection fraction, indicating that the antibody-bound cocaine does not affect the heart. This antagonism of cocaine's effects was greatly decreased after 1 week and entirely absent after 1 month. Cocaine in the presence of h2E2 is pharmacologically inert and h2E2 may have additional clinical utility for reversing cocaine effects on the cardiovascular system.

Differential Effect of Fixed Ratio Magnitude on the Rate of Lever-Pressing and Interinjection Intervals of Cocaine Self-Administration in Rats

Many features of self-administration behavior may be explained by reference to the properties of schedules of reinforcement. Schedules alter the probability of a behavior being reinforced and thereby increase, or decrease, the frequency of the behavior and fixed ratio (FR) magnitude reportedly alters the rate of responding to cocaine. A pharmacokinetic/pharmacodynamic interaction theory states that lever-pressing behavior is induced only when cocaine levels in the body are above the priming/remission threshold and below the satiety threshold-a range termed the compulsion zone. This theory successfully explains cocaine self-administration in rats on a progressive ratio and the FR1 schedule. To determine the effects of high FR magnitude on the rate of self-administration of cocaine and the rate of lever-pressing behavior when cocaine levels are within the compulsion zone. Rats acquired cocaine self-administration on an FR1 schedule and then were switched to sessions that started with FR1 and then FR 5, 10, 20, or 50. An only FR1 session was run each week between FR1/FR50 sessions and then only FR1 sessions were conducted for several weeks. Interinjection intervals at a unit dose of 3 µmol/kg were regular at both FR1 and FR50 but were longer by the time required to complete the 50 presses. When responding by rats was maintained under an FR50 schedule of cocaine presentations, compared to baseline FR1 sessions, dramatic increases in the number of lever-presses were observed after access to cocaine was terminated, a previously unreported finding. However, lever-pressing occurred only when cocaine levels were in the compulsion zone, and this duration was unchanged. The increase in lever-pressing persisted for weeks. Interinjection intervals at FR1 were not altered after exposure to FR50. Although previously considered key to understanding the regulation of cocaine self-administration behavior, FR magnitude simply increased interinjection intervals by the time required to complete 50 lever-presses. The dramatic increase in the rate of lever-pressing was caused by the high FR schedule rather than cocaine. The utility of the schedule-induced increase in the rate of lever-pressing is unclear. The compulsion zone theory provides a rational pharmacological basis for understanding cocaine self-administration behavior.

Smoked cannabis reduces peak cocaine plasma levels and subjective effects in a controlled drug administration study of polysubstance use in men

BackgroundDespite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, yet little is known about how interactions between the two drugs might contribute to continued co-use. MethodsThe aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N = 9, all males) completed a 13-day inpatient protocol. On session days, cannabis [0.0 or 5.6 % tetrahydrocannabinol (THC)] was administered 28 min prior to cocaine (0, 12, or 25 mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects. ResultsActive cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in ‘Hunger’ and ‘Calm.’ ConclusionsCannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaine’s reinforcing effects.

Prelimbic and infralimbic medial prefrontal cortex neuron activity signals cocaine seeking variables across multiple timescales.

The prefrontal cortex is critical for execution and inhibition of reward seeking. Neural manipulation of rodent medial prefrontal cortex (mPFC) subregions differentially impacts execution and inhibition of cocaine seeking. Dorsal, or prelimbic (PL), and ventral, or infralimbic (IL) mPFC are implicated in cocaine seeking or extinction of cocaine seeking, respectively. This differentiation is not seen across all studies, indicating that further research is needed to understand specific mPFC contributions to drug seeking. We recorded neuronal activity in mPFC subregions during cocaine self-administration, extinction, and cue- and cocaine-induced reinstatement of cocaine seeking. Both PL and IL neurons were phasically responsive around lever presses during cocaine self-administration, and activity in both areas was reduced during extinction. During both cue- and, to a greater extent, cocaine-induced reinstatement, PL neurons exhibited significantly elevated responses, in line with previous studies demonstrating a role for the region in relapse. The enhanced PL signaling in cocaine-induced reinstatement was driven by strong excitation and inhibition in different groups of neurons. Both of these response types were stronger in PL vs. IL neurons. Finally, we observed tonic changes in activity in all tasks phases, reflecting both session-long contextual modulation as well as minute-to-minute activity changes that were highly correlated with brain cocaine levels and motivation associated with cocaine seeking. Although some differences were observed between PL and IL neuron activity across sessions, we found no evidence of a go/stop dichotomy in PL/IL function. Instead, our results demonstrate temporally heterogeneous prefrontal signaling during cocaine seeking and extinction in both PL and IL, revealing novel and complex functions for both regions during these behaviors. This combination of findings argues that mPFC neurons, in both PL and IL, provide multifaceted contributions to the regulation of drug seeking and addiction.

The progressive ratio and fixed ratio 1 schedules of cocaine self-administration in rats convey the same information

Progressive ratio (PR) schedules of drug delivery are used to determine the ‘motivational’ state of an animal and drug ‘reinforcing efficacy’. This widely held interpretation is supported mainly by the observation that the PR breakpoint (BP) is proportional to the unit dose of self-administered drug. The compulsion zone theory of cocaine self-administration was applied to determine whether it can explain the pattern of lever-pressing behavior and cocaine injections under the PR schedule in rats. This theory states that cocaine induces lever pressing when levels are below the satiety threshold and above the priming/remission threshold. Rats were trained to self-administer cocaine on a fixed ratio FR1 schedule over a range of cocaine unit doses. Then they were switched to a PR schedule. Typical for the self-administration under a PR schedule, long post-injection pauses occurred when calculated cocaine levels were in the satiety zone. The compulsion zone theory interprets BP simply as the maximal number of responses which rats can perform after an injection while cocaine levels remain within the compulsion zone. The thresholds delineating the compulsion zone were very stable and independent of the self-administration schedule. PR and fixed ratio schedules convey the same pharmacokinetic/pharmacodynamic information, i.e., these two schedules are invariant.

Drug analysis of residues from used syringes collected at a syringe exchange programme in Gothenburg, Sweden

To study drug content in syringes collected from a needle and syringe exchange programme in Gothenburg, Sweden. Needle and syringe exchange programmes (NEPs) are available in many cities both in Sweden and internationally for individuals who inject drugs. Their main objective is to prevent the spread of bloodborne viruses such as hepatitis C virus and HIV via needle and syringe sharing. Knowledge of which drugs are injected by the visitors of these programmes is of great importance for health promotion and drug prevention, such as planning and design of harm reduction measures, treatment of substance use disorders, adjustment of the hospital laboratories’ range of analyses and detection of unknown NPSs. There are a few international studies of drug content in used syringes, showing that the substances injected vary greatly both over time and regarding geographical region. So far, no corresponding studies have been carried out in Sweden. This study aimed to assess drug content in disposed syringes in the NEP in Sweden's second largest city, Gothenburg. A total of 2250 syringes were collected during one week in November 2021 of which 150 were randomly selected. The syringes were rinsed with methanol, and the extract was analysed for presence of drugs using liquid chromatography coupled to high-resolution mass spectrometry. To distinguish between main drugs and impurities in syringes containing more than one drug, a dose-adjusted comparison of the concentrations in the extract was performed. Drugs were detected in 149 out of 150 analysed syringes (99%), and 6% of these contained more than one drug. Amphetamine was the most common (81%) followed by buprenorphine (7%) and heroin (6%). Other findings consisted of sedatives (alprazolam and zopiclone, in total 5%), other stimulants apart from amphetamine (MDMA and methylphenidate, in total 2%), and androgenic anabolic steroids (trenbolone and testosterone, in total 4%). In addition, low levels of cocaine, lisdexamphetamine, MDA, methamphetamine, gabapentin and pregabalin were detected. Many syringes also contained suspected adulterants such as caffeine, phenacetin, phenazone and paracetamol and natural or synthetic by-products such as acetylcodeine, noscapine and N-formylamphetamine. In Gothenburg, the main drug detected in disposed syringes was amphetamine, in contrast to previous studies in other European cities where heroin and cocaine are the most commonly injected drugs. Knowledge of drug content in syringes from needle exchange programmes is useful to adapt local harm reduction and drug treatment services. However, further studies are needed to gain a deeper insight into drug injection patterns in Sweden.

The Single Dose Cocaine Reinstatement of Lever‐Pressing Behavior in Rats is Explained by The Compulsion Zone Theory

The compulsion zone theory of the cocaine self‐administration paradigm states that lever‐pressing behavior is induced when cocaine levels fall to or below the satiety threshold. Single injections of cocaine are known to reinstate lever‐pressing in rats trained to self‐administer cocaine. We investigated whether this phenomenon can be explained by the compulsion zone theory. Male Sprague‐Dawley rats (n = 5) were trained to self‐administer cocaine i.v. on an FR‐1 schedule. Once trained, these rats were administered a single dose of cocaine (2 – 12 µmol/kg, i.v.) in four daily sessions per week, and the time to lever‐pressing, the number of presses and the duration of pressing were recorded. The latency from the start of an injection to the resumption of lever pressing increased with the cocaine dose and ranged from approximately 2 min at 2 µmol/kg to more than 15 min at 12 µmol/kg. The D1 dopamine receptor antagonist SCH23390 (10‐30 nmol/kg i.v.) decreased the latency to reinstatement of lever pressing, following a dose of 12 µmol/kg cocaine. The increasing latency to lever‐pressing is consistent with the increasingly higher cocaine levels taking longer to fall to the satiety threshold, while the lower doses are immediately within the compulsion zone. An antagonist‐induced elevation of the satiety threshold explains the reduced latency to reinstatement. The number and duration of lever presses may reflect the time that the cocaine levels are within the compulsion zone. The cocaine satiety threshold model explains the dose‐dependent delay in reinstatement of lever‐pressing behavior and the effect of dopamine antagonists.

Dopamine Receptor Antagonist‐Induced Elevation of the Compulsion Zone Results in Differential Effects on Cocaine Self‐Administration and Lever‐Pressing Behavior

Dopamine receptor antagonists raise both the cocaine priming and satiety thresholds (the lower and upper limits of the compulsion zone, respectively), so antagonists will decrease the probability of cocaine priming self‐administration behavior. However, if priming occurs in the presence of dopamine receptor antagonists, then cocaine consumption will accelerate. The compulsion zone also explains the lever‐pressing after access to cocaine is terminated, but the effects of antagonists on the compulsion zone are unexplored. The compulsion zone theory predicts that antagonists will decrease the duration of unloading activity. Male rats were trained to self‐administer cocaine on an FR1 schedule. Upon lever‐pressing, a unit dose (3 umol/kg i.v.) was administered. The dopamine receptor antagonists, SCH23390 (10‐30 nmol/kg), eticlopride (10‐30 nmol/kg), or molindone (750‐3000 nmol/kg) were administered i.v. either while cocaine was accessible during the maintenance phase or following termination of access denoting the start of the unloading phase. The lever‐pressing activity was recorded during the unloading phase. Antagonists accelerated self‐administration during the maintenance phase due to the elevated satiety threshold, consistent with previous studies. Antagonists administered immediately prior to the unloading phase shortened the duration of lever‐pressing, and lever‐pressing began at a higher calculated cocaine level. This is consistent with the antagonists elevating the compulsion zone. The faster elimination of cocaine at these elevated levels results in cocaine levels transiting the compulsion zone more rapidly. The differential effect of dopamine receptor antagonists on lever‐pressing behavior may provide insights to the appropriate use of antagonists as medications for cocaine use disorder.

Environmental cocaine places mussels at risk by increasing neurotransmitters

When going to the beach for a swim, probably the last thing on your mind is whether you are swimming in a thin soup of drug traces. Whether prescribed over the counter or illegal, many drugs taken by people wind up in our waterways. These drugs cannot be removed by wastewater treatment plants and thus get released back into the environment. A famous coastal region in Brazil, the Bay of All Saints (Baía de Todos os Santos in Portuguese), has been the subject of multiple environmental contaminant studies and researchers have found measurable quantities of cocaine in the seawater, sediment and mussels (Perna perna) of the bay. Although the environmental concentrations are too low to affect humans, whether cocaine at these levels has an effect on the nervous system of aquatic species that reside in the bay was unknown. So, Mayana Fontes and a team of researchers from Universidade Estadual Paulista Júlio de Mesquita Filho, Brazil, and other universities in Brazil investigated how levels of cocaine in the seawater affect the nervous system of P. perna mussels.Fontes and colleagues placed adult mussels in tanks containing seawater with two different concentrations of cocaine that were realistic for the Bay of All Saints (0.2 and 2 μg l−1) for 2, 4 or 7 days. Then, they collected the adductor muscles, which open and close the shell, and gonads of these mussels. In the adductor muscle, they measured the activity of acetylcholine esterase, an enzyme essential for a functioning nervous system. In the gonads, they measured the levels of two major neurotransmitters, serotonin and dopamine, the activity of the enzyme that breaks down these neurotransmitters, monoamine oxidase, and the activity of cyclooxygenase, an enzyme that is a sign of inflammation and is important for egg release in mussels. In addition, the authors also measured how much energy the mussels spent during the exposure to cocaine by measuring mitochondrial electron transport activity, and how much energy they set aside by measuring the level of total lipids in the gonads.The team found that mussels exposed to cocaine had a decreased acetylcholine esterase activity in the adductor muscle, which shows that cocaine disrupted the normal activity of the nervous system. They also found that mussels exposed to cocaine had raised levels of dopamine and serotonin. These neurotransmitters are essential for reproduction, and changes could lead to an unsustainable population in the wild. The mussels also increased cyclooxygenase activity in the gonads, which shows an inflammatory response to low doses of cocaine. In addition, the scientists found changes in the mitochondrial electron transport chain – which converts the energy from oxygen into ATP in the mitochondria – directly increasing the amount of energy the mussels spent after exposure to the drug, which decreases the amount of energy they can access for reproduction as energy is limited. Finally, they also found that there was an increase in levels of total lipid, which act as a convenient and easy to access energy source for the animals.Fontes and colleagues have shown that the current concentration of cocaine in the seawater around the Bay of All Saints can negatively impact the area's mussels in complex ways and this may put them at a greater risk from other chemicals that we dump into the environment.

Abstract 9046: Effects of Acute Doses of Cocaine on Arterial Left Ventricular Coupling and Left Ventricular Mechanical Efficiency in Conscious, Chronically-Instrumented Dogs

Background: Cocaine, one of the most commonly used illegal drugs, exaggerates sympathetic nervous activity and has profound effects on the cardiovascular system. It is well known that acute doses of cocaine raise the heart rate, and cause acute hypertension, arrhythmia, and reduce coronary blood flow. However, its role and mechanism on the arterial-left ventricular (LV) coupling (ALVC) and LV mechanical efficiency remain to be critically examined. We hypothesized cocaine may impair ALVC and produce myocardial contractile and metabolic abnormalities, and thus impair LV ability to convert metabolic energy to external work. Methods: We examined the effect of cocaine (4 mg/kg/iv) on ALVC and the conversion of metabolic energy [measured as myocardial oxygen consumption (MVO 2 )] to mechanical work [measured as pressure (P)-volume (V) area (PVA)], and PVA to external work (SW) in 6 conscious chronically instrumented dogs. The control MVO 2 -PVA relation was generated by altering loading conditions using three graded doses of Phenylephrine after autonomic blockade with hexamethonium and atropine. Results: Ten minutes after cocaine administration, blood cocaine level was 7.3±2.4 mg/L. There were significant decreases in the slope (E ES ) of LV end-systolic P-V relation (5.0±0.09 vs 6.7±1.4 mmHg/ml, p<0.05), SW (1379±284 vs 1739±204 mmHg•ml, p<0.05) and increases in arterial elastance (E A ) (13.6±2.6 vs 7.6±1.8 mmHg•ml, p<0.05). Despite the decrease in E ES , energy utilization as calculated from LV MVO 2 was increased (0.13±0.01 vs 0.10±0.02 ml O 2 /beat/100g LV, p<0.01) and the MVO 2 -PVA point was shifted above the control MVO 2 -PVA relation by 0.010±0.002 ml O 2 /beat/100g LV, (p<0.05). The SW/PVA ratio decreased (56±8% vs 75±12%, p<0.05) as impaired arterial-LV coupling indicated by a significantly increased the ratio of E A to E ES (from 1.2±0.4 of baseline to 2.8±0.05 after cocaine (p<0.05). Thus, SW/MVO 2 , representing LV mechanical efficiency, decreased from 11.0±1.9 to 8.8±1.2% (p<0.05) with cocaine. Conclusions: Acute doses of cocaine impair arterial LV coupling and decrease LV mechanical efficiency due to the decreased conversion of mechanical energy (PVA) to external work (SW) which mainly resulted from the deterioration of arteria-LV coupling.

Safety and Preliminary Efficacy of Lorcaserin for Cocaine Use Disorder: A Phase I Randomized Clinical Trial.

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined.Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions.Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of “feel irritable,” “feel hungry,” and “I am craving.” For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine.Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine.Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users.

Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter.

Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.

Anorexic action of fusarenon-x in the hypothalamus and intestine

There is a lack of information available on the anorexic action of fusarenon-x (FX), which is a sesquiterpenoid mycotoxin. In this study, we investigated the changes in the hypothalamus and small intestine related to appetite after oral FX exposure. The time-course change of food intake after oral FX exposure (0.5, 1.0, and 2.5 mg/kg bw) in B6C3F1 mice showed that 2.5 mg/kg bw of FX significantly suppressed food intake during 3–6 h compared to the control. Furthermore, the total food intake for 24 h was lower in the group exposed to FX than in the control. The FX exposure (2.5 mg/kg bw for 3 h) significantly increased mRNA levels of anorexic hormones (pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcription (CART)) without changing the mRNA levels of orexigenic hormones. In addition, FX exposure indicated significantly higher mRNA levels of possible downstream targets of anorexic POMC neurons, such as the melanocortin 4 receptor (MC4R), brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), in the hypothalamus compared to the control. FX exposure also significantly increased the mRNA level of inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)) and activated nuclear factor-kappa B (NF-κB), which is a regulatory factor for POMC in the hypothalamus. In the intestine, FX exposure did not affect the mRNA level of anorexic peptide YY but significantly elevated that of anorexic cholecystokinin (CCK) and regulatory factors for CCK (calcium-sensing receptor (CaSR), the transient receptor potential ankyrin-1 channel (TRPA1), and transient receptor potential cation channel subfamily M member 5 (TRPM5)). These results suggest that FX sequentially induces inflammatory cytokine expression, NF-κB activation, and POMC expression in the hypothalamus. FX also induces CCK expression in the intestine possibly via induction of CaSR, TRPM5, and TRPA1 expression. These changes will eventually lead to the anorexic action of FX.