High Addictive Potential Research Articles

AH-7921: From Potential Analgesic Medicine to Recreational Drug

Dear Editor, In recent years, there has been a worrying increase in the use of new synthetic opioids worldwide. These substances are sold in specialized stores known as “smart” or “head” shops or online, although they were originally synthesized as potential analgesic medicines. The medicinal use of these substances was abandoned due to their severe adverse effects, including addiction. In particular, since 2012, a new synthetic opioid known as AH-7921 has become available on the recreational drug market (1). AH-7921, the IUPAC name of which is 3,4-dichloro-N-[[1(dimethylamino)cyclohexyl]methyl]benzamide, is an Nsubstituted cyclohexylmethylbenzamide wherein the benzamide moiety is dichlorinated at positions 3 and 4 of the ring, while the aminocyclohexane moiety is N,Ndimethylated (1, 2). It was synthesized in the 1970s by Allen and Hanburys Ltd. as a potential medicine, but its development was abandoned due to its addictive properties (1, 2). AH-7921 has never been marketed as a medicine and it has no other known industrial use (1, 2). Recently, AH-7921 has been associated with several cases of non-fatal and fatal intoxication in Europe and the USA. For instance, five analytically confirmed non-fatal AH7921 intoxications were registered between December 2012 and March 2013 by the Swedish poison information centre. Furthermore, ten deaths associated with the consumption of AH-7921 in combination with other psychoactive substances occurred between January and September 2013 in Sweden. In two of these cases, the consumption of AH-7921 was considered to be the cause of death. In nine cases, AH7921 was detected in the femoral blood and its concentration ranged between 0.03 and 0.99 mg/L. In the last case, AH-7921 was detected in hair samples. In Norway, between December 2012 and August 2013 there were two fatalities associated with the consumption of AH-7921. In one case, AH-7921 was detected in the peripheral blood at a concentration of 0.43 mg/L, while in the other, it was found in a syringe used by the deceased. In both cases, other psychotropic substances were detected. In the United Kingdom, three AH-7921-related deaths were reported between January and November 2013. In all cases, AH-7921 (the femoral blood concentration ranged between 0.05 and 4.46 mg/L) was detected in combination with other psychotropic drugs. Finally, a fatality has been reported in the USA. In this case, the presence of AH-7921 was analytically confirmed in the peripheral blood at a concentration of 9.1 mg/L. Other psychotropic substances were also detected in the sample (1-3). Very little is currently known regarding the pharmacology and toxicology of this synthetic opioid. Studies performed in guinea pig brain preparations have shown that AH-7921 acts as an agonist at the μ and κ opioid receptors with a Ki of 10 and 50 nM, respectively (4). Animal model studies have demonstrated that AH-7921 can produce an analgesic effect that is approximately as potent as morphine (5). Furthermore, it was found to be only slightly less potent than morphine in reducing the respiratory rate, body temperature, and pupil diameter (6). Additionally, the addictive properties of AH-7921 have been tested in rats and rhesus monkeys pre-treated with the opioid. In these animals, the administration of naloxone or nalorphine produced an opioid-like withdrawal syndrome that was alleviated by a single dose of AH-7921 (7). Preclinical studies have identified pharmacological similarities between AH-7921 and morphine, including a narrow therapeutic window between the desired and undesired effects (6). In particular, the two substances are equipotent in inducing analgesia, respiratory depression, hypothermia, and addictive behavior. In conclusion, the information currently available confirms that AH-7921 is a potent respiratory depressant with a narrow therapeutic window. Additionally, AH-7921 has a high addictive potential. Finally, considering that the human dose is currently unknown, packages of the drug sold

ON THE TUK-TUK EXPRESS: Has methamphetamine hit the Cape Flats?

Crystal methamphetamine is a drug with a high addiction potential that can elicit bizarre and aggressive behaviour. Preliminary research with gang members on the Cape Flats suggests that the drug may be growing in that community. If so, this is an issue for law enforcement to watch, because speed and violent criminals are not a good combination.

Emerging Trends and Prevalence of Drug Abuse: A Study Conducted at Swami Vivekananda Drug De-Addiction and Treatment Centre

Background: The epidemic of substance abuse in the present generation has assumed alarming dimensions in the state of Punjab. The success story of Punjab’s economy has seemingly come to an end. District Amritsar being close to border is deeply influenced. Maximum cases were registered under the NDPS Act in the year 2012 in Punjab, with the nationally highest drug-related crime rate of 51.6%, against the national average of 2.8% . The present study aims to identify the emerging trends and prevalence of drug abuse among the patients enrolling at Swami Vivekananda drug de-addiction and treatment centre, Amritsar. Methods and findings: In the year 2014 and 2015, consecutive patients on outpatient basis from the month of January 2014 till august 2015 were enrolled. Urine toxicology was done for the drugs abused with rapid immune-chromatographic assay kits available in the centre. A total of 10,568 patients were screened for urine toxicology. Out of 10,568 enrolled patients 9815 patients were found positive for morphine and out of 9815 patients addicted to morphine 5785(54.74%) of patients were abusing heroin in one or other form, which was concluded from the personal interview and general physical examination for scar marks of injectable drug users of heroin. Rest of the substances abused includes other opioids, alcohol, sedatives, cannabis, cocaine, amphetamines and tobacco. The dose of heroin used by the patients varied from person to person but on average most of patients abuse heroin from 500mg up to 2grams on daily basis either in the form of snorting, sniffing or as injectable. Conclusion: High numbers of heroin abusers indicate its high addiction potential. Due to its high cost majority of addicts are not able to procure it and get involved in illegal activities. This publication helps to provide the figure of current alarming rise of heroin abuse among the study population. Immediate steps like demand reduction via proper education of youth and proper treatment of addicts with individual or group counselling are required curtailing the current drug menace in Punjab. Increasing trends of heroin abuse among population is shattering the youth of Punjab. Such a drastic deviation towards heroin abuse can be attributed to its high addiction potential, easy availability, unemployment and socio-occupational pressure faced by youth of Punjab. Awareness regarding the side effects of drugs and their addictive potential should be focused and campaigns in the rural population regarding the preventive measures and treatment options available for addiction should be encouraged.

L-Scoulerine attenuates behavioural changes induced by methamphetamine in zebrafish and mice

Methamphetamine (METH), a substance with a high potential for abuse and addiction, is a serious worldwide public health problem. METH addicts often show extreme paranoia, anxiety, and depression. Thus, there is no effective medication for the treatment of METH-induced abnormalities. In the present study, we investigated the effects of l-Scoulerine (l-SLR), a tetrahydroprotoberberine (THPBS) alkaloid, on METH-induced anxiety-like behaviour in zebrafish and METH-induced addictive behavior in mice. In the novel tank test, acute administration of METH (2mg/L) induced a significant decrease in the number of total vertical transitions and time spent in the upper zone. Moreover, METH produced significant avoidance behaviour showing increased swimming time in the central area and high speed movement in the mirror area in the mirror stimulation test; these anxiety-like changes were attenuated by l-SLR. Chronic administration of METH (2mg/kg) produced a steady increase in locomotor activity and conditioned place preference in mice. l–SLR (5mg/kg) failed to reduce acute METH-induced hyperlocomotion, but attenuated chronic METH-induced behavioural sensitization and significantly blocked the expression of conditioned place preference induced by METH in mice. The present study suggests that l-SLR may be a promising agent for the treatment of addiction and anxiety induced by METH.

Electronic gaming machines and gambling disorder: A cross-cultural comparison between treatment-seeking subjects from Brazil and the United States

Aims: The objective of this paper is to perform a cross-cultural comparison of gambling disorder (GD) due to electronic gaming machines (EGM), a form of gambling that may have a high addictive potential. Our goal is to investigate two treatment-seeking samples of adults collected in Brazil and the United States, countries with different socio-cultural backgrounds. This comparison may lead to a better understanding of cultural influences on GD. Methods: The total studied sample involved 733 treatment-seeking subjects: 353 men and 380 women (average age=45.80, standard deviation ±10.9). The Brazilian sample had 517 individuals and the American sample 216. Subjects were recruited by analogous strategies. Results: We found that the Brazilian sample was younger, predominantly male, less likely to be Caucasian, more likely to be partnered, tended to have a faster progression from recreational gambling to GD, and were more likely to endorse chasing losses. Conclusion: This study demonstrated that there are significant differences between treatment-seeking samples of adults presenting GD due to EGM in Brazil and in the United States. These findings suggest that cultural aspects may have a relevant role in GD due to EGM.

The Psychobiological Problems of Continued Nicotine Dependency in E-Cigarette 'Vapers'. Commentary: "Electronic Cigarettes".

The Psychobiological Problems of Continued Nicotine Dependency in E-Cigarette 'Vapers'. Commentary: "Electronic Cigarettes".

Psychological and Neurobiological Mechanisms of Pathological Internet Use

Background Studies on internet gaming disorders indicate that especially online role-playing games have a high addictive potential in particular in male adolescents. These games enable the parallel gaming of multiple users in online virtual worlds with or against each other via their graphical agent (avatar). Recent findings suggest online role-playing addicts to have a deficient self-concept. The latter's potential compensation by means of a higher identification with the own avatar might be an etiological factor in the development of an online role-playing game addiction. On a neurobiological level, especially the left Angular Gyrus (AG) seems to be associated with identification and empathy processes. An according fMRI-based study on long-term gamers of online role-playing games indicated increased brain activations in the left AG during the rating of personality traits referring to the avatar relative to self-referencing and the referencing of close others (Ganesh et al., 2011). However, the extent to which these results represent specific neurobiological mechanisms that are associated with self-concept deficits or a stronger identification with the own avatar in the development of online role-playing game addiction remains unknown to date. Methods N=16 addicted and n=17 regular gamers of online role-playing games (mean age=28 and 26 years, respectively) underwent functional Magnetic Resonance Imaging (fMRI) while 1) completing a Giessen-Test (GT)-derived paradigm assessing participants’ concepts of self, ideal and avatar and 2) while viewing and evaluating images of the own person, the own avatar as well as unknown persons. Additionally, a questionnaire referring to the own body image and a Visual Analogue Scale (VAS) for the evaluation of the own as well as avatar's attractiveness, sympathy and gender identity were applied. Results Addicts of online role-playing games rated their body image, gender identity and social response (i.e. social popularity) significantly lower. Neurobiologically, they showed increased left AG activations during the reflection about their avatar (relative to their ideal and/or their self) compared to non-addicted gamers. Furthermore, within-group differences revealed left AG response during the perception of images showing their avatar (relative to images of themselves). In addition, addicted gamers had hypoactivations in the bilateral AG during the perception of images of their own person compared to the perception of unknown persons. The left-lateral AG hypoactivation positively correlated with the degree of the gender identity. Discussion In line with previous findings, our results indicate self-concept deficits in online role-playing game addicts and a stronger identification with the own avatar, which might neurobiologically be reflected in AG activations. The results could point towards problems in the formation of an own identity as a cause for online role-playing game addiction development. Longitudinal studies may shed light on these potentially causal relations.

Computerised cognitive behaviour therapy for depression in adolescents: study protocol for a feasibility randomised controlled trial

IntroductionThe 1 year prevalence of depression in adolescents is about 2%. Treatment with antidepressant medication is not recommended for initial treatment in young people due to concerns over high side...

P.1.g.027 Effects of traumatic exposure on corticosterone levels and levels after dexamethasone application in rats

Recently there has been a dramatic rise in the abuse of so-called “bath salts” products that are purchased as legal alternatives to illicit drugs like cocaine and 3,4-methylenedioxymethamphetamine (MDMA). Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses of bath salts produce euphoria and increase alertness, but high doses or chronic use can cause serious adverse effects such as hallucinations, delirium, hyperthermia and tachycardia. Owing to the risks posed by bath salts, the governments of many countries have made certain cathinones illegal, namely: 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV). Similar to other psychomotor stimulants, synthetic cathinones target plasma membrane transporters for dopamine (i.e., DAT), norepinephrine (i.e., NET) and serotonin (i.e, SERT). Mephedrone and methylone act as non-selective transporter substrates, thereby stimulating non-exocytotic release of dopamine, norepinephrine and serotonin. By contrast, MDPV acts as a potent blocker at DAT and NET, with little effect at SERT. Administration of mephedrone or methylone to rats increases extracellular concentrations of dopamine and serotonin in the brain, analogous to the effects of MDMA. Not surprisingly, synthetic cathinones elicit locomotor activation in rodents. Stimulation of dopamine transmission by synthetic cathinones predicts a high potential for addiction and may underlie clinical adverse effects. As popular synthetic cathinones are rendered illegal, new replacement cathinones are appearing in the marketplace. More research on the pharmacology and toxicology of abused cathinones is needed to inform public health policy and develop strategies for treating medical consequence of bath salts abuse.

Synthetic cathinones and their rewarding and reinforcing effects in rodents.

Synthetic cathinones, colloquially referred to as "bath salts", are derivatives of the psychoactive alkaloid cathinone found in Catha edulis (Khat). Since the mid-to-late 2000's, these amphetamine-like psychostimulants have gained popularity amongst drug users due to their potency, low cost, ease of procurement, and constantly evolving chemical structures. Concomitant with their increased use is the emergence of a growing collection of case reports of bizarre and dangerous behaviors, toxicity to numerous organ systems, and death. However, scientific information regarding the abuse liability of these drugs has been relatively slower to materialize. Recently we have published several studies demonstrating that laboratory rodents will readily self-administer the "first generation" synthetic cathinones methylenedioxypyrovalerone (MDPV) and methylone via the intravenous route, in patterns similar to those of methamphetamine. Under progressive ratio schedules of reinforcement, the rank order of reinforcing efficacy of these compounds are MDPV ≥ methamphetamine > methylone. MDPV and methylone, as well as the "second generation" synthetic cathinones α-pyrrolidinovalerophenone (α-PVP) and 4-methylethcathinone (4-MEC), also dose-dependently increase brain reward function. Collectively, these findings indicate that synthetic cathinones have a high abuse and addiction potential and underscore the need for future assessment of the extent and duration of neurotoxicity induced by these emerging drugs of abuse.

Top of mind at APA meeting: Adherence, opioids, PTSD

The largest meeting for experts in psychiatric disorders, this month's 167th annual meeting of the American Psychiatric Association (APA) delivered information on several key issues related to managing patients with psychiatric disorders. Many important topics on the agenda are reviewed in this article: medication adherence (including how pharmacists can help), new antidepressants, opioid therapy, medical and recreational use of marijuana, management of posttraumatic stress disorder, and use of antipsychotics in vulnerable children.

Emerging drugs of abuse: current perspectives on substituted cathinones.

Substituted cathinones are synthetic analogs of cathinone that can be considered as derivatives of phenethylamines with a beta-keto group on the side chain. They appeared in the recreational drug market in the mid-2000s and now represent a large class of new popular drugs of abuse. Initially considered as legal highs, their legal status is variable by country and is rapidly changing, with government institutions encouraging their control. Some cathinones (such as diethylpropion or pyrovalerone) have been used in a medical setting and bupropion is actually indicated for smoking cessation. Substituted cathinones are widely available from internet websites, retail shops, and street dealers. They can be sold under chemical, evocative or generic names, making their identification difficult. Fortunately, analytical methods have been developed in recent years to solve this problem. Available as powders, substituted cathinones are self-administered by snorting, oral injestion, or intravenous injection. They act as central nervous system stimulants by causing the release of catecholamines (dopamine, noradrenaline, and serotonin) and blocking their reuptake in the central and peripheral nervous system. They may also decrease dopamine and serotonin transporter function as nonselective substrates or potent blockers and may inhibit monoamine oxidase effects. Nevertheless, considerable differences have been found in the potencies of the different substituted cathinones in vitro. Desired effects reported by users include increased energy, empathy, and improved libido. Cardiovascular (tachycardia, hypertension) and psychiatric/neurological signs/symptoms (agitation, seizures, paranoia, and hallucinations) are the most common adverse effects reported. Severe toxicity signs compatible with excessive serotonin activity, such as hyperthermia, metabolic acidosis, and prolonged rhabdomyolysis, have also been observed. Reinforcing potential observed in animals predicts a high potential for addiction and abuse in users. In case of overdose, no specific antidote exists and no curative treatment has been approved by health authorities. Therefore, management of acute toxic effects is mainly extrapolated from experience with cocaine/amphetamines.

Morphine as a Potential Oxidative Stress-Causing Agent

Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress.

Regulierung des Glücksspiels in Deutschland: Das Glücksspielgesetz Schleswig-Holsteins und der Glücksspieländerungsstaatsvertrag aus ökonomischer Perspektive

Abstract This paper compares the two laws effective for the regulation of gambling in Germany from an economic perspective. On the one hand there is the new and relatively liberal federal Gaming Amendment Act of Schleswig- Holstein (GAA) and on the other hand the German State Treaty on Gambling (GST), which was signed by the remaining 15 German federal states. First, two goals are derived that should be pursued by the regulation of gambling realization of tax revenues and the reduction of problem gambling. Channeling gambling into the regulated market is a necessary condition to achieve both objectives. As the GAA can be expected to realize a higher degree of channeling due to more competitive tax rates as well as the inclusion of online poker and casinos, it appears to be overall superior to the GST. It is in particular incomprehensible that online poker and casinos are not included in the GST, since on one side they have a high potential for addiction and should thus be regulated and on the other side allow to generate higher tax revenues compared to sports betting for example.

Involvement of the NLRP3 inflammasome in the modulation of an LPS-induced inflammatory response during morphine tolerance

BackgroundMorphine is widely used for its analgesic effects. In addition to its high potential for addiction and tolerance, morphine also induces immunosuppression. Inflammasomes, NLRP3 being the most characterized, is a platform for activation of pro-inflammatory cytokines, particularly IL-1β. We have explored the effects of lipopolysaccharide (LPS) during morphine tolerance on expression of the NLRP3 inflammasome and related inflammatory genes. MethodsMorphine-pellet administration was used to induce morphine tolerance in F344 rats. Control rats were given a placebo. On day 5, the animals received either saline or 250μg/kg LPS. LPS-induced protein expression of TNF-α, IL-1β, and IL- 6 was examined in the spleen of rats with and without morphine tolerance. A PCR array was used to examine LPS-induced expression of 84 inflammasome-related genes with and without morphine tolerance. ResultsLPS-induced IL-1β and TNF-α protein expression was significantly lower in the spleen of the morphine-tolerant animals than in the placebo-control animals. In response to LPS, expression of 27 genes, including NLRP3, TNF-α, IL-1β, and IL-6, was significantly increased, and expression of 3 genes was significantly decreased in both the morphine-tolerant and placebo-control groups compared to the saline-treated animals. However, there was only a 2.7-fold increase in NLRP3 expression in response to LPS in the morphine-tolerant rats compared to a 4.5-fold increase in the placebo-control animals. ConclusionOur data indicate that, in the morphine-tolerant state, LPS-induced expression of NLRP3 is suppressed and cytokine/chemokine expression is inhibited, which may be one of the mechanisms involved in morphine-induced immunosuppression.

Effect of Zeolite Nano-Materials and Artichoke (Cynara scolymus L.) Leaf Extract on Increase in Urinary Clearance of Systematically Absorbed Nicotine

Nicotine, the main pharmacologically active component in tobacco and cigarette, has some toxic effects and also high potential for addiction. In this study, the effect of artichoke (Cynara scolymus L.) and zeolite nano-materials on urinary excretion of nicotine and consequently elimination of systematically absorbed nicotine was investigated. A simple, valid and highly sensitive high performance liquid chromatography method has been developed for determination of nicotine in rat urine according to guidelines for bioanalysis.It was found that nano-zeolites can cause increase in urinary concentration of nicotine due to its high surface adsorption. Artichoke leaf extract can cause increase in urinary excretion of nicotine in longer post administration times. It was observed that co-administration of nanozeolites and the leaf extract has the synergetic effect on increasing the urinary excretion of nicotine.

Psychoactive “bath salts”: Not so soothing

Recently there has been a dramatic rise in the abuse of so-called “bath salts” products that are purchased as legal alternatives to illicit drugs like cocaine and 3,4-methylenedioxymethamphetamine (MDMA). Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses of bath salts produce euphoria and increase alertness, but high doses or chronic use can cause serious adverse effects such as hallucinations, delirium, hyperthermia and tachycardia. Owing to the risks posed by bath salts, the governments of many countries have made certain cathinones illegal, namely: 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV). Similar to other psychomotor stimulants, synthetic cathinones target plasma membrane transporters for dopamine (i.e., DAT), norepinephrine (i.e., NET) and serotonin (i.e, SERT). Mephedrone and methylone act as non-selective transporter substrates, thereby stimulating non-exocytotic release of dopamine, norepinephrine and serotonin. By contrast, MDPV acts as a potent blocker at DAT and NET, with little effect at SERT. Administration of mephedrone or methylone to rats increases extracellular concentrations of dopamine and serotonin in the brain, analogous to the effects of MDMA. Not surprisingly, synthetic cathinones elicit locomotor activation in rodents. Stimulation of dopamine transmission by synthetic cathinones predicts a high potential for addiction and may underlie clinical adverse effects. As popular synthetic cathinones are rendered illegal, new replacement cathinones are appearing in the marketplace. More research on the pharmacology and toxicology of abused cathinones is needed to inform public health policy and develop strategies for treating medical consequence of bath salts abuse.

Exposure to nicotine and carcinogens among Southwestern Alaskan Native cigarette smokers and smokeless tobacco users.

The prevalence of tobacco use, both cigarette smoking and smokeless, including iqmik (homemade smokeless tobacco prepared with dried tobacco leaves mixed with alkaline ash), and of tobacco-related cancer is high in Alaskan Native people (AN). To investigate possible mechanisms of increased cancer risk we studied levels of nicotine and tobacco-specific nitrosamines (TSNA) in tobacco products and biomarkers of tobacco toxicant exposure in Southwestern AN people. Participants included 163 cigarette smokers, 76 commercial smokeless tobacco, 20 iqmik, 31 dual cigarette smokers and smokeless tobacco, and 110 nontobacco users. Tobacco use history, samples of tobacco products used, and blood and urine samples were collected. Nicotine concentrations were highest in cigarette tobacco and TSNAs highest in commercial smokeless tobacco products. The AN participants smoked on average 7.8 cigarettes per day. Nicotine exposure, assessed by several biomarker measures, was highest in iqmik users, and similar in smokeless tobacco and cigarette smokers. TSNA exposure was highest in smokeless tobacco users, and polycyclic aromatic hydrocarbon exposure was highest in cigarette smokers. Despite smoking fewer cigarettes per day, AN cigarette smokers had similar daily intake of nicotine compared to the general U.S. population. Nicotine exposure was greatest from iqmik, likely related to its high pH due to preparation with ash, suggesting high addiction potential compared to other smokeless tobacco products. TSNA exposure was much higher with smokeless tobacco than other product use, possibly contributing to the high rates of oral cancer. Our data contribute to an understanding of the high addiction risk of iqmik use and of the cancer-causing potential of various forms of tobacco use among AN people.

A Nurse with Pethidine Addiction

Pethidine is a synthetic opioid substance with high addiction potential. It is commonly used in medicine pre and postoperatively to relieve the pain. A Pethidine addiction generally starts as iatrogenic and may be a problem for the clinicians when there is a real pain. Its opioid analgesic usage is legal, yet it is possible that it can be abused by the health care workers and addiction may become a frequent case. In order to attract attention to this issue a case of a nurse who was given pethidine after an operation to ease her pain and whom addiction is developed was presented. When the medicines with high addiction potential are given for the treatment, the patients must be followed closely in terms of addiction and drug abuse.

Neuronal circuits underlying acute morphine action on dopamine neurons

Morphine is a highly potent analgesic with high addictive potential in specific contexts. Although dopamine neurons of the ventral tegmental area (VTA) are widely believed to play an essential role in the development of drug addiction, neuronal circuits underlying morphine action on dopamine neurons have not been fully elucidated. Here we combined in vivo electrophysiology, tract-tracing experiments, and targeted neuronal inactivation to dissect a neural circuit for acute morphine action on dopamine neurons in rats. We found that in vivo, morphine targets the GABAergic tail of the VTA, also called the rostromedial tegmental nucleus, to increase the firing of dopamine neurons through the activation of VTA μ opioid receptors expressed on tail of the VTA/rostromedial tegmental nucleus efferents. Our data also reveal that in the absence of VTA glutamatergic tone, there is no morphine-induced activation of dopamine neurons. These results define the anatomical organization and functional role of a neural circuit for acute morphine action on dopamine neurons.