mGluR5 Antagonist-Induced Psychoactive Properties: MTEP Drug Discrimination, a Pharmacologically Selective Non-NMDA Effect with Apparent Lack of Reinforcing Properties

ABSTRACT Fenobam [N-(3-chlorophenyl)-N9-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], a potent metabotropic glutamate mGluR5 receptor antagonist, reported to have analgesic effects in animals and anxiolytic effects in humans, also caused adverse events, including psychostimulant-type effects and "derealization phenomena." Recent electrophysiologic, pharmacologic, and anatomic data show that the mGluR5 antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and (E)-2-methyl-6-styryl-pyridine (SIB-1893) can inhibit NMDA receptor-mediated activity and that mGluR5 receptors are highly expressed in limbic and forebrain regions. The present studies first evaluated the potential of mGluR5 receptor antagonists to cause PCP-like psychoactive effects in a rat drug discrimination procedure and, second, explored and characterized the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) as a discriminative stimulus and compared MTEP with other drugs known to be psychoactive in humans. Additionally, the reinforcing potential of MPEP and MTEP was compared with phencyclidine (PCP) in a rat intravenous self-administration procedure. Dizocilpine [(1)-MK-801] and ketamine caused full PCP-appropriate responding. Memantine and the mGluR5 antagonists caused no or weak partial PCPappropriate responding. In MTEP-trained rats, MTEP, MPEP, and fenobam caused full and equipotent MTEP-appropriate responding. (1)-MK-801 and memantine caused MTEPappropriate responding below 70%, whereas PCP, chlordiazepoxide and LSD caused MTEP-appropriate responding below 50%. D 9 -Tetrahydrocannabinol, yohimbine, arecoline, and pentylenetetrazole all caused MTEP-appropriate responding below 20%. Rats self-administered PCP but not MPEP or MTEP, indicating a lack of reinforcing effects of the mGluR5 antagonists. These data suggest that the mGluR5 antagonists appear not to have reinforcing properties, that the discriminative effects of mGluR5 antagonists and PCP are dissimilar, and that mGluR5 antagonists may produce psychoactive effects different from NMDA-antagonists and other drugs with known psychotomimetic properties

Neurobiological effects of early life cannabis exposure in relation to the gateway hypothesis

The use of Cannabis sativa preparations, such as hashish and marijuana, is wide-spread among young people, including pregnant women. Despite this concern, the consequences of cannabis exposure on the brain during periods of active brain development, such as the prenatal phase and adolescence, is not well known. Several epidemiological studies support the cannabis gateway hypothesis, where early cannabis use is suggested to increase the risk of initiating use of other illicit drugs, e.g., amphetamine or heroin. However, the nature of such direct links are unclear. Therefore, the aim of this thesis was to test experimentally the cannabis gateway hypothesis, i.e., to determine whether cannabis exposure during periods of active brain development alters reward-related behavior and neurobiology for psychostimulant and opioid drugs by the use of animal models. In the first study, we examined the effects of early adolescent exposure (postnatal day; PND; 28-32, one injection per day) with the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 and the main psychoactive substance in C. sativa, Δ9-tetrahydrocannabinol (THC) on amphetamine-induced motor behavior and dopamine release in the nucleus accumbens during adolescence. No alterations were evident in the cannabinoid exposed rats, results which did not support the cannabis gateway hypothesis in relation to subsequent psychostimulant abuse. Next, we investigated the effects of adolescent exposure on subsequent opioid reward-related behavior and the neurobiology of opioid and cannabinoid systems during adulthood. We studied THC exposure across the full adolescent period (PND 28-49), and administered the drug once every third day in order to better mimic the pattern of intermittent use seen in teenagers. The results revealed discrete opioid-related alterations within brain regions highly implicated in reward and hedonic processing (e.g., increased proenkephalin gene expression in the nucleus accumbens and increased mu opioid receptors in the ventral tegmental area). This was coupled to increased heroin intake in a self-administration paradigm and increased morphine conditioned place preference, indicating altered sensitivity to the reinforcing properties of opioids. Furthermore, in evaluating the adolescent ontogeny of the opioid and cannabinoid systems within limbic-related brain areas, we found that active endocannabinoid- and opioid- related neurodevelopment takes place to a very high extent during this period. Most pronounced were the alterations in endocannabinoid levels in cognitive brain areas, even though alterations were also apparent in reward-related regions. Finally, we investigated the effects of prenatal cannabis exposure (gestational day 5- PND 2) on subsequent opioid reward-related behavior and neurobiology of the opioid and cannabinoid systems in adulthood. Similar to adolescent cannabis exposure, prenatal exposure induced discrete opioid-related alterations within brain regions highly implicated in reward and hedonic processing. Moreover, elevated heroin-seeking observed during extinction and after food deprivation was evident in the THC exposed rats, suggesting an increased motivation for drug use under conditions of stress. Taken together, this thesis presents neurobiological support for the cannabis gateway hypothesis in terms of adult opiate, but not amphetamine, abuse, with underlying long-term disturbances of discrete opioid-related systems within limbic brain regions

Cannabis och hjärnans belöningssystem

Allt sedan amerikanen Olds av en ren slump upptäckte belöningssystemet på 1950-talet har forskningen om hur droger påverkar hjärnan intensifierats. Senare års forskning har visat att cannabis påverkar specifika receptorer (mottagarmolekyler) i hjärnan och därmed aktiverar hjärnans belöningssystem, i likhet med alkohol, nikotin, heroin, amfetamin och kokain. Kunskapssökandet har nu kommit så långt att vi även börjar få en del svar på hur den psykoaktiva substansen delta-9-tetrahydrocannabinol (THC) mer specifikt påverkar belöningssystemet. Delta-9-tetrahydrocannabinol (THC; the main psychoactive substance in cannabis) acts on specific receptors in the brain and thereby activates the reward system, a feature common to all addictive drugs. Extensive research has started to provide specific information on how THC acts on the reward system and an overview of this knowledge is presented here. Keywords: delta-9-tetrahydrocannabinol, cannabinoid receptor, reward, nucleus accumbens, revie

Declining cookies – how hard can it be? : Persuasive design and usability in cookie consent notices on Swedish websites

Consent to the processing of personal data online is what drives the profit of the growing data economy. Therefore, certain websites have a strong interest in maximising user consent by optimising the design of cookie consent notices (notice) in a persuasive manner. Persuasive design uses psychological theories to influence users to make certain choices. When implemented in a way that goes against the user’s own interest this practice is known as a ‘dark pattern’. However, if implemented to promote the user’s own interests it can benefit them instead, and therefore be more likely to result in a usable (effective, efficient and satisfactory) design. This study aims to explore how persuasive design affects the usability in notices when the user goal is to decline third-party cookies.  To gain insights in respect of the above, the study was conducted in three steps: (a) the use of persuasive design through dark patterns in two different notices was examined by way of content analysis; (b) how users experienced the usability in the same notices was examined via a usability test; and (c) similarities and differences between these findings were explored through a comparative analysis. The results suggest that the mere presence of dark patterns does not determine the usability of a notice, but when they are combined in a way that affects the efficiency of the design – and therefore the cognitive load of the users – it is particularly hard for them to say no

Evaluating the drug use "gateway" theory using cross-national data: consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys

BACKGROUND: It is unclear whether the normative sequence of drug use initiation, beginning with tobacco and alcohol, progressing to cannabis and then other illicit drugs, is due to causal effects of specific earlier drug use promoting progression, or to influences of other variables such as drug availability and attitudes. One way to investigate this is to see whether risk of later drug use in the sequence, conditional on use of drugs earlier in the sequence, changes according to time-space variation in use prevalence. We compared patterns and order of initiation of alcohol, tobacco, cannabis, and other illicit drug use across 17 countries with a wide range of drug use prevalence. METHOD: Analyses used data from World Health Organization (WHO) World Mental Health (WMH) Surveys, a series of parallel community epidemiological surveys using the same instruments and field procedures carried out in 17 countries throughout the world. RESULTS: Initiation of "gateway" substances (i.e. alcohol, tobacco and cannabis) was differentially associated with subsequent onset of other illicit drug use based on background prevalence of gateway substance use. Cross-country differences in substance use prevalence also corresponded to differences in the likelihood of individuals reporting a non-normative sequence of substance initiation. CONCLUSION: These results suggest the "gateway" pattern at least partially reflects unmeasured common causes rather than causal effects of specific drugs on subsequent use of others. This implies that successful efforts to prevent use of specific "gateway" drugs may not in themselves lead to major reductions in the use of later drugs.These activities were supported by the United States National Institute of Mental Health (R01MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International Center (FIRCA R01-TW006481). The ESEMeD project is funded by the European Commission (Contracts QLG5-1999-01042; SANCO 2004123), the Piedmont Region (Italy), Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain (FIS 00/0028), Ministerio de Ciencia y Tecnología, Spain (SAF 2000-158-CE), Departament de Salut, Generalitat de Catalunya, Spain, Instituto de Salud Carlos III (CIBER CB06/02/0046, RETICS RD06/0011 REM-TAP). The World Mental Health Japan (WMHJ) Survey is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013) from the Japan Ministry of Health, Labour and Welfare. The Mexican National Comorbidity Survey (M-NCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT-G30544-H). The South Africa Stress and Health Study (SASH) is supported by the US National Institute of Mental Health (R01-MH059575). The Ukraine Comorbid Mental Disorders during Periods of Social Disruption (CMDPSD) study is funded by the US National Institute of Mental Health (RO1-MH61905). The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the Robert Wood Johnson Foundation (RWJF; Grant 044708). The work of L. Dierker was supported by a NIDA Center Grant (DA010075) awarded the Methodology Center, Penn State University, grant DA024260 and Investigator Awards from the National Institute on Drug Abuse (DA15454