Different Drugs Of Abuse Research Articles

Amphetamine and morphine may produce acute-withdrawal related hypoactivity by initially activating a common dopamine pathway

Rats given drugs of abuse such as amphetamine or morphine show longer-term effects, that is, signs of acute withdrawal, including hypoactivity, hypophagia, and blunted affect, sometime between 12 and 24h after treatment. This research explores the possibility that signs of acute withdrawal produced by different drugs of abuse are instigated by overlapping mechanisms. The specific objectives of the research were to see if amphetamine and morphine produced longer-term hypoactivity, and to see if any longer-term hypoactivity elicited by the drugs could be blocked by SCH23390, a dopamine D1 antagonist. Six groups of rats, with eight rats in each group, were exposed to a series of five-day tests. Near light onset of Test Day 1, each animal was given control administrations, consisting of a saline treatment (1.0ml/kg) followed 30m later by a saline posttreatment, and locomotor activity was monitored for the next 24h. On Test Day 3, each animal was given experimental administrations, and locomotor activity was again monitored for 24h. Each group received only one combination of experimental administrations across tests. Experimental administrations consisted of saline, amphetamine (2.0mg/kg), or morphine (5.0mg/kg), followed by saline or SCH23390 (0.05mg/kg). All administrations were subcutaneous. Amphetamine and morphine produced longer-term hypoactivity, having similar time courses and magnitudes. SCH23390 blocked the longer-term hypoactivity produced by both drugs. Saline and SCH23390 produced no changes in longer-term activity in their own right. The time course of amphetamine-elicited longer-term hypoactivity resembled that of amphetamine-elicited longer-term hypophagia observed in a prior study. Approximately 1/4 of the animals given amphetamine or morphine did not show longer-term hypoactivity (“low withdrawal” rats). Amphetamine and morphine may initiate the cascade of events resulting in signs of acute withdrawal by producing activation in a common pathway that uses dopamine as a neurotransmitter. Different signs of acute withdrawal (hypoactivity and hypophagia) may involve the short-term activation of the same common pathway. Low withdrawal rats may have a different vulnerability to amphetamine and may show differences in drug assessment outcomes relative to animals that manifest distinct signs of acute withdrawal.

Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.

Nicotine, the main psychoactive component of tobacco, and (-)-Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.

Effects of acute ethanol exposure on class I HDACs family enzymes in wild-type and BDNF+/− mice

BackgroundAlterations of brain-derived neurotrophic factor (BDNF) have been associated with the development of addiction to different drugs of abuse, including ethanol (EtOH). EtOH exposure activates the BDNF-signaling cascade in dorsal striatum, which in turn affects further EtOH intake. Different alcohol exposures have been widely demonstrated to modulate chromatin remodeling, affecting histone acetylation/deacetylation balance. Recently, class I histone deacetylases (HDACs) inhibition has been reported to modulate BDNF mRNA expression and to attenuate morphological and behavioral phenomena related to EtOH exposure. However, the role played by different HDAC isoforms in EtOH-induced plasticity is still unclear. MethodsWe investigated the effects induced by acute EtOH exposure on the protein levels of class I HDAC 1–3 isoforms of wild-type (WT) and BDNF heterozygous mice (BDNF+/−), in nuclear and cytoplasmic extracts of specific brain regions associated with EtOH addiction. ResultsNuclear HDAC 1–3 levels were markedly reduced after acute EtOH treatment in the caudate putamen (CPu) of WT mice only. Furthermore, CPu basal levels of nuclear HDAC isoforms were significantly lower in BDNF+/− mice compared to WT. With the exception of nuclear HDAC 3, no significant changes were observed after acute EtOH treatment in the prefrontal cortex (PFCx) of BDNF+/− and WT mice. In this area, the nuclear HDAC basal levels were significantly different between the two experimental groups. ConclusionsThese results provide details about EtOH effects on class I HDAC isoforms and strongly support a correlation between BDNF and class I HDACs, suggesting a possible influence of BNDF on these enzymes.

Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys.

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been suggested to play an important role in mediation of drug-reinforced behaviors, as well as in the mechanisms underlying relapse in abstinent subjects. The prototypical mGluR2/3 agonist, LY379268, has been shown to attenuate nicotine reinforcement and cue-induced reinstatement of drug seeking in rats, as well as reinstatement induced by drug-associated stimuli and contexts across different drugs of abuse (i.e., cocaine, heroin, and methamphetamine). However, in primates, LY379268 has been shown to produce conflicting results on abuse-related effects of cocaine, and there are no data available for nicotine. To explore the therapeutic potential of mGluR2/3 agonists, we compared the effects of LY379268 (0.03-1.0mg/kg) on nicotine, cocaine, and food self-administration under a fixed-ratio (FR10) schedule in three separate groups of squirrel monkeys. Moreover, we studied the effects of LY379268 on nicotine/cocaine priming-induced and cue-induced reinstatement of drug-seeking behavior in nicotine- and cocaine-experienced groups of animals. LY379268 blocked nicotine, but not cocaine, self-administration in monkeys. There was a partial overlap between doses that affected nicotine and food self-administration. In abstinent monkeys, LY379268 dose-dependently blocked nicotine, but not cocaine, priming-induced reinstatement of drug seeking. In both cocaine-experienced and nicotine-experienced groups of animals, LY379268 potently reduced cue-induced reinstatement of drug-seeking behavior. The present findings provide strong support for the potential utility of mGlu2/3 receptor agonists for the treatment of nicotine dependence and suggest their utility for prevention of relapse induced by environmental cues associated with drug taking.

Chronic Cocaine Use Causes Changes in the Striatal Proteome Depending on the Endogenous Expression of Pleiotrophin.

The neurotrophic factor pleiotrophin (PTN) is upregulated in different brain areas after the administration of different drugs of abuse, including psychostimulants. PTN has been shown to prevent cocaine-induced cytotoxicity in NG108-15 and PC12 cells. We previously demonstrated that specific phosphoproteins related to neurodegeneration processes are differentially regulated in the mouse striatum by a single cocaine (15 mg/kg) administration depending on the endogenous expression of PTN. Since neurodegenerative processes are usually observed in patients exposed to toxicants for longer duration, we have now performed a striatal proteomic study using samples enriched in phosphorylated proteins from PTN knockout (PTN-/-) mice, from mice with transgenic PTN overexpression (PTN-Tg) in the brain, and from wild type (WT) mice after a chronic treatment with cocaine (15 mg/kg/day for 7 days). We have successfully identified 23 proteins significantly affected by chronic cocaine exposure, genotype, or both. Most of these proteins, including peroxiredoxin-6 (PRDX6), triosephosphate isomerase (TPI1), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), and annexins A5 (ANXA5) and A7 (ANXA7), may be of significant importance because they were previously identified in proteomic studies in animals treated with psychostimulants and/or because they are related to neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. The data support a protective role of PTN against chronic cocaine-induced neural alterations.

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress.

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse.

Usos Lícito e Ilícito dos Fármacos

Drugs of abuse are a heterogeneous group of xenobiotics or endobiotics that alter synaptic organization in the central nervous system in a transient or permanent basis, often leading to a compulsively use. What unites its members is that they confer pleasure (hedonism) to the abusers, namely by their action in the mesolimbic dopamine system. To exert its effects, different drugs of abuse will act on receptors and neurotransmitter transporters, modeling neurotransmitter release into the synaptic cleft. Besides acting on presynaptic neurons also function in neurotransmitter receptors and ion channels in postsynaptic neurons, thereby modifying the signaling pathways. In this work, the pharmacodynamic and the potential of some psychoactive substances that are typically subjected to abuse in Portugal, is reviewed. With this approach it was also possible a discussion of drugs of abuse that exhibit very different toxicological effects such as stimulants, depressants and hallucinogens. Particularly, the potential to induce dependence and addition, as well as to undergo illicit and licit uses, of central nervous system depressants, stimulants, anticholinergic antiparkinson drugs, opioids, cannabinoids and hallucinogens, is discussed.

Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR)

Pharmacological evidence has accumulated showing that glucocorticoids and glucocorticoid receptor (GR) facilitate several responses to different drugs of abuse. Recent findings have attributed a prominent role to the mineralocorticoid receptor (MR) in modulating behavior during the addictive process. The purpose of this study was to investigate the effects of MR blockade on: brain stress system responses to naloxone-induced morphine withdrawal, the somatic signs of abstinence; the effects of morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), c-Fos expression and tyrosine hydroxylase (TH) phosphorylated at Ser31 levels in the nucleus tractus solitarius noradrenergic cell group (NTS-A2); and finally, hypothalamus-pituitary-adrenocortical (HPA) axis activity. The role of MR signaling was assessed with i.p. pretreatment with the MR antagonist, spironolactone. Rats were implanted with two morphine (or placebo) pellets. Six days later rats were pretreated with spironolactone or vehicle 30min before naloxone. The physical signs of abstinence, NA turnover, TH activation, c-Fos expression and the HPA axis activity were measured using HPLC, immunoblotting and RIA. Spironolactone attenuated the somatic signs of withdrawal that were seen after naloxone administration to chronic morphine treated animals. On the other hand, pretreatment with spironolactone resulted in no significant modification of the increased NA turnover, TH activation, c-Fos expression or HPA axis activity that occurred during morphine withdrawal. These results suggest that somatic signs of opiate withdrawal are modulated by MR signaling. However, blockade of MR did not significantly alter the brain stress system response to morphine withdrawal.

The involvement of accumbal glycine receptors in the dopamine-elevating effects of addictive drugs

The ability of drugs of abuse to increase mesolimbic levels of dopamine is a characteristic associated with their rewarding effects. Exactly how these effects are produced by different substances is not as well characterised. Our previous work in rats has demonstrated that accumbal glycine receptors (GlyRs) are involved in mediating the dopamine-activating effects of ethanol, and in modulating ethanol intake. In this study the investigation of GlyR involvement was extended to include several different drugs of abuse. By using microdialysis and electrophysiology we compared effects of addictive drugs, with and without the GlyR antagonist strychnine, on dopamine levels and neurotransmission in nucleus accumbens. The dopamine-increasing effect of systemic ethanol and the drug-induced change in neurotransmission in vitro, as measured by microdialysis and field potential recordings, were dependent on GlyRs in nAc. Accumbal GlyRs were also involved in the actions of tetrahydrocannabinol and nicotine, but not in those of cocaine or morphine. These data indicate that accumbal GlyRs play a key role in ethanol-induced dopamine activation and contribute also to that of cannabinoids and nicotine.

Parenting under the influence: The effects of opioids, alcohol and cocaine on mother–child interaction

Nearly 20% of adults receiving treatment for a substance use disorder live with their minor children (Stanger et al., 1999) and women in drug use treatment are twice as likely as men to have children in their household (Wechsberg et al., 1998). Parental drug use impacts the family through reduced family resources such as money and food, and researchers consistently note parenting deficits among substance users (Solis, Shadur, Burns, & Hussong, 2012). Little is known about differences in parenting and mother–child interaction among mothers with different drugs of choice or among mothers of older children, between 8 and 16years. This study reports the findings from a sample of treatment seeking opioid, alcohol and cocaine using mothers and their 8–16-year-old child. Findings from a mother–child observational task and self-reported parenting measure indicated less undermining autonomy and higher mother maternal acceptance among opioid compared to alcohol addicted mothers. African American mothers were observed to have fewer negative interactional behaviors than Whites and both African American mothers and children self-reported higher firm control and maternal acceptance. Overall, mothers appeared to struggle with effective discipline with older versus younger children. Findings offer useful information to clinicians seeking to effectively tailor their interventions to women and children who present with different drugs of abuse, race/culture and developmental stage of child.

Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse

Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs.

Phosphoproteomic analysis of the striatum from pleiotrophin knockout and midkine knockout mice treated with cocaine reveals regulation of oxidative stress-related proteins potentially underlying cocaine-induced neurotoxicity and neurodegeneration

The neurotrophic factors pleiotrophin (PTN) and midkine (MK) are highly upregulated in different brain areas relevant to drug addiction after administrations of different drugs of abuse, including psychostimulants. We have previously demonstrated that PTN and MK modulate amphetamine-induced neurotoxicity and that PTN prevents cocaine-induced cytotoxicity in NG108-15 and PC12 cells. In an effort to dissect the different mechanisms of action triggered by PTN and MK to exert their protective roles against psychostimulant neurotoxicity, we have now used a proteomic approach to study protein phosphorylation, in which we combined phosphoprotein enrichment, by immobilized metal affinity chromatography (IMAC), with two-dimensional gel electrophoresis and mass spectrometry, in order to identify the phosphoproteins regulated in the striatum of PTN knockout, MK knockout and wild type mice treated with a single dose of cocaine (15mg/kg, i.p.). We identified 7 differentially expressed phosphoproteins: 5′(3′)-deoxyribonucleotidase, endoplasmic reticulum resident protein 60 (ERP60), peroxiredoxin-6 (PRDX6), glutamate dehydrogenase 1 (GLUD1), aconitase and two subunits of hemoglobin. Most of these proteins are related to neurodegeneration processes and oxidative stress and their variations specially affect the PTN knockout mice, suggesting a protective role of endogenous PTN against cocaine-induced neural alterations. Further studies are needed to validate these proteins as possible targets against neural alterations induced by cocaine.

Rapid screening of drugs of abuse in human urine by high-performance liquid chromatography coupled with high resolution and high mass accuracy hybrid linear ion trap-Orbitrap mass spectrometry

A novel analytical toxicology method has been developed for the analysis of drugs of abuse in human urine by using a high resolution and high mass accuracy hybrid linear ion trap-Orbitrap mass spectrometer (LTQ-Orbitrap-MS). This method allows for the detection of different drugs of abuse, including amphetamines, cocaine, opiate alkaloids, cannabinoids, hallucinogens and their metabolites. After solid-phase extraction with Oasis HLB cartridges, spiked urine samples were analysed by HPLC/LTQ-Orbitrap-MS using an electrospray interface in positive ionisation mode, with resolving power of 30,000 full width at half maximum (FWHM). Gradient elution off of a Hypersil Gold PFP column (50mm×2.1mm) allowed to resolve 65 target compounds and 3 internal standards in a total chromatographic run time of 20min. Validation of this method consisted of confirmation of identity, selectivity, linearity, limit of detection (LOD), lowest limits of quantification (LLOQ), accuracy, precision, extraction recovery and matrix effect. The regression coefficients (r2) for the calibration curves (LLOQ – 100ng/mL) in the study were ≥0.99. The LODs for 65 validated compounds were better than 5ng/ml except for 4 compounds. The relative standard deviation (RSD), which was used to estimate repeatability at three concentrations, was always less than 15%. The recovery of extraction and matrix effects were above 50 and 70%, respectively. Mass accuracy was always better than 2ppm, corresponding to a maximum mass error of 0.8 millimass units (mmu). The accurate masses of characteristic fragments were obtained by collisional experiments for a more reliable identification of the analytes. Automated data analysis and reporting were performed using ToxID software with an exact mass database. This procedure was then successfully applied to analyse drugs of abuse in a real urine sample from subject who was assumed to be drug addict.

Genetic Variation of the Ghrelin Signalling System in Individuals with Amphetamine Dependence

The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.

Sex-dependent effects of early maternal deprivation on MDMA-induced conditioned place preference in adolescent rats: Possible neurochemical correlates

The early neonatal stage constitutes a sensitive period during which exposure to adverse events can increase the risk of neuropsychiatric disorders. Maternal deprivation (MD) is a model of early life stress that induces long-term behavioural and physiological alterations, including susceptibility to different drugs of abuse. In the present study we have used the conditioned place preference (CPP) paradigm to address the influence of MD on the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in adolescent animals of both sexes. We have previously observed in adolescent rats that MD induces modifications in the serotonergic and endocannabinoid systems, which play a role in the rewarding effects of MDMA. In light of this evidence, we hypothesized that MD would alter the psychobiological consequences of exposure to MDMA. Neonatal Wistar rats underwent MD (24h, on PND 9) or were left undisturbed (controls). The animals were conditioned with 2.5mg/kg MDMA during the periadolescent period (PND 34–PND 43) and were tested in the open-field test at the end of adolescence (PND 60). Animals were sacrificed on PND 68–75 and levels of serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid were measured in the striatum, hippocampus and cortex, while the expression of hippocampal CB1 cannabinoid receptor (CB1R) and circulating levels of corticosterone and leptin were also measured. Control males showed CPP after administration of MDMA. However, no MDMA-induced CPP was detected in control females or MD males, and MD had no effect on open field activity in any group. A reduction in striatal and cortical 5-HT levels, increased expression of hippocampal CB1R and a marked trend towards higher circulating leptin levels were observed in MDMA-treated MD males. Our results demonstrate for the first time that MD reduces the rewarding effects of MDMA in a sex-dependent manner. We propose that this effect is related, at least in part, with alterations of the serotonergic and cannabinoid systems.

Nicotina y modelos animales: ¿qué nos aporta el paradigma de enriquecimiento ambiental?

The Environmental Enrichment (EE) paradigm is a housing condition which aims is to provide physical, cognitive and sensorial stimulation to rodents. Animals are housed in larger cages containing inanimate objects such as tunnels, toys and running wheels. The main aim of the current work is to tackle the arguments which suggest that EE may diminish vulnerability to developing addiction to nicotine and other drugs of abuse and to review recent experimental studies performed in relation to this subject. We discuss the major changes induced by EE at physical, neurobiological and behavioral levels and review the results of recent studies which indicate that EE promotes both neurochemical (potentiation of the increase in dopamine release induced by nicotine in the brain cortex) and behavioral changes (increased ability to discriminate the presence of reward and decreased impulsivity), thus supporting the hypothesis put forward. In light of these results, EE can be proposed as a model for the study of vulnerability to addiction to different drugs of abuse, including cocaine and nicotine, though further studies are needed in order to establish the neurobiological implications of the effects of exposure to enriched environments and their possible relationship with changes in brain reward systems.

Pressurized-liquid extraction for determination of illicit drugs in hair by LC–MS–MS

An LC-MS-MS-based procedure for determination in hair of 14 different drugs of abuse belonging to the classes cocaine, amphetamine-like compounds, opiates, and hallucinogens has been developed. A pressurized-liquid extraction procedure was used and proved useful for quantitative recovery of all the analytes tested. This procedure, in conjunction with a simple decontamination step, performed to avoid false-positive samples, enabled the detection of all the analytes with LOQ ranging from 1.8 to 16 pg mg(-1) and accuracy varying from 85 to 111 %. The procedure was validated in accordance with the SOFT/AAFS guidelines and seems to be suitable for routine determination of the drugs tested in hair.

Cholinergic modulation of food and drug satiety and withdrawal

Although they comprise only a small portion of the neurons in the region, cholinergic interneurons in the dorsal striatum appear to play an important role in the regulation of various appetitive behaviors, in part, through their interactions with mesolimbic dopamine (DA) systems. In this review, we describe studies that suggest that the activity of cholinergic interneurons in the nucleus accumbens (NAc) and cholinergic projections to the ventral tegmental area (VTA) affect feeding behavior. In vivo microdialysis studies in rats have revealed that the cessation of a meal is associated with a rise in acetylcholine (ACh) levels in the NAc. ACh activation will suppress feeding, and this is also associated with an increase in synaptic accumulation of ACh. Further, we discuss how, in addition to their role in the ending of a meal, cholinergic interneurons in the NAc play an integral role in the cessation of drug use. Another cholinergic system involved in different aspects of appetitive behavior is the projection from the pedunculpontine nuclei directly to the VTA. Activation of this system enhances behaviors through activation of the mesolimbic DA system, and antagonism of ACh receptors in the VTA can reduce drug self-administration. Finally, we discuss the role of accumbens ACh in both drug and palatable food withdrawal. Studies reveal that accumbens ACh is increased during withdrawal from several different drugs of abuse (including cocaine, nicotine and morphine). This rise in extracellular levels of ACh, coupled with a decrease in extracellular levels of DA, is believed to contribute to an aversive state, which can manifest as behaviors associated with drug withdrawal. This theory has also been applied to studies of overeating and/or “food addiction,” and the findings suggest a similar imbalance in DA/ACh levels, which is associated with behavioral indications of drug-like withdrawal. In summary, cholinergic neurons play an important role in the modulation of both food and drug intake, as well as the aversive aspects of food- and drug-related addictive behaviors.

Drug specificity in extended access cocaine and heroin self‐administration

Increased drug availability can precipitate a rapid escalation of drug consumption in both vulnerable humans and laboratory animals. Drug intake escalation is observed across a broad spectrum of drugs of abuse, including stimulants, opiates, ethanol and phencyclidine. Whether and to what extent the processes underlying escalated levels of drug intake vary across different substances is poorly understood. The present study sought to address this question in rats self-administering both cocaine and heroin-two addictive drugs with both common and different neurobiological effects. In experiment 1, we determined how cocaine intake is initially related to heroin intake in non-escalated rats with a limited access to both drugs. In experiment 2, two groups of rats were initially allowed to self-administer either cocaine or heroin for 1 hour per day and then after behavioral stabilization, for 6 hours per day to precipitate drug intake escalation. In each group, dose-injection functions for cocaine and heroin self-administration were generated. In experiment 1, regardless of the dose, rats with a high intake of one drug did not necessarily have a high intake of the alternate drug. In experiment 2, escalated levels of heroin or cocaine self-administration did not generalize to the other drug. This outcome was confirmed in a third drug substitution experiment following different access lengths to cocaine self-administration (i.e. 1, 4 and 8 hours). The processes underlying spontaneous and escalated drug overconsumption appear thus to vary across different drugs of abuse. More research should be devoted in the future to these differences.

Cocaine and MDMA Induce Cellular and Molecular Changes in Adult Neurogenic Systems: Functional Implications

The capacity of the brain to generate new adult neurons is a recent discovery that challenges the old theory of an immutable adult brain. A new and fascinating field of research now focuses on this regenerative process. The two brain systems that constantly produce new adult neurons, known as the adult neurogenic systems, are the dentate gyrus (DG) of the hippocampus and the lateral ventricules/olfactory bulb system. Both systems are involved in memory and learning processes. Different drugs of abuse, such as cocaine and MDMA, have been shown to produce cellular and molecular changes that affect adult neurogenesis. This review summarizes the effects that these drugs have on the adult neurogenic systems. The functional relevance of adult neurogenesis is obscured by the functions of the systems that integrate adult neurons. Therefore, we explore the effects that cocaine and MDMA produce not only on adult neurogenesis, but also on the DG and olfactory bulbs. Finally, we discuss the possible role of new adult neurons in cocaine- and MDMA-induced impairments. We conclude that, although harmful drug effects are produced at multiple physiological and anatomical levels, the specific consequences of reduced hippocampus neurogenesis are unclear and require further exploration.