Search

A new ecstasy-like substance, meta-chlorophenylpiperazine (mCPP), has been detected in street drugs in the Netherlands. Theoretically, mCPP possesses the potential to become a non-neurotoxic alternative for methylenedioxymethamphetamine (MDMA), the regular psychoactive substance of ecstasy. Since its introduction on the Dutch market of synthetic drugs, the percentage of mCPP-containing tablets has increased, including both tablets that contain only mCPP and tablets containing a combination of mCPP and MDMA. These tablets occur in many different colours, shapes and sizes and with various logos, making it impossible to distinguish mCPP-containing tablets from regular MDMA tablets. In addition, the reports of users concerning the effects of mCPP are predominantly negative. All these aspects together lead to the conclusion that mCPP is an undesired addition to the ecstasy market from the user's perspective. [ABSTRACT FROM AUTHOR]

Adolescence is a period of dramatic neural reorganization creating a period of vulnerability and the possibility for the development of psychopathology. The maturation of various neural circuits during adolescence depends, to a large degree, on one's experiences both physical and psychosocial. This occurs through a process of plasticity which is the structural and functional adaptation of the nervous system in response to environmental demands, physiological changes and experiences. During adolescence, this adaptation proceeds upon a backdrop of structural and functional alterations imparted by genetic and epigenetic factors and experiences both prior to birth and during the postnatal period. Plasticity entails an altering of connections between neurons through long-term potentiation (LTP) (which alters synaptic efficiency), synaptogenesis, axonal sprouting, dendritic remodeling, neurogenesis and recruitment (Skaper et al., 2017). Although most empirical evidence for plasticity derives from studies of the sensory systems, recent studies have suggested that during adolescence, social, emotional, and cognitive experiences alter the structure and function of the networks subserving these domains of behavior. Each of these neural networks exhibits heightened vulnerability to experience-dependent plasticity during the sensitive periods which occur in different circuits and different brain regions at specific periods of development. This report will summarize some examples of adaptation which occur during adolescence and some evidence that the adolescent brain responds differently to stimuli compared to adults and children. This symposium, "Experience during adolescence shapes brain development: from synapses and networks to normal and pathological behavior" occurred during the Developmental Neurotoxicology Society/Teratology Society Annual Meeting in Clearwater Florida, June 2018. The sections will describe the maturation of the brain during adolescence as studied using imaging technologies, illustrate how plasticity shapes the structure of the brain using examples of pathological conditions such as Tourette's' syndrome and attention deficit hyperactivity disorder, and a review of the key molecular systems involved in this plasticity and how some commonly abused substances alter brain development. The role of stimulants used in the treatment of attention deficit hyperactivity disorder (ADHD) in the plasticity of the reward circuit is then described. Lastly, clinical data promoting an understanding of peer-influences on risky behavior in adolescents provides evidence for the complexity of the roles that peers play in decision making, a phenomenon different from that in the adult. Imaging studies have revealed that activation of the social network by the presence of peers at times of decision making is unique in the adolescent. Since normal brain development relies on experiences which alter the functional and structural connections between cells within circuits and networks to ultimately alter behavior, readers can be made aware of the myriad of ways normal developmental processes can be hijacked. The vulnerability of developing adolescent brain places the adolescent at risk for the development of a life time of abnormal behaviors and mental disorders., (Copyright © 2019. Published by Elsevier Inc.)

Background: The number of people entering specialist drug treatment for cannabis problems has increased considerably in recent years. The reasons for this are unclear, but rising cannabis potency could be a contributing factor., Methods: Cannabis potency data were obtained from an ongoing monitoring programme in the Netherlands. We analysed concentrations of δ-9-tetrahydrocannabinol (THC) from the most popular variety of domestic herbal cannabis sold in each retail outlet (2000-2015). Mixed effects linear regression models examined time-dependent associations between THC and first-time cannabis admissions to specialist drug treatment. Candidate time lags were 0-10 years, based on normative European drug treatment data., Results: THC increased from a mean (95% CI) of 8.62 (7.97-9.27) to 20.38 (19.09-21.67) from 2000 to 2004 and then decreased to 15.31 (14.24-16.38) in 2015. First-time cannabis admissions (per 100 000 inhabitants) rose from 7.08 to 26.36 from 2000 to 2010, and then decreased to 19.82 in 2015. THC was positively associated with treatment entry at lags of 0-9 years, with the strongest association at 5 years, b = 0.370 (0.317-0.424), p < 0.0001. After adjusting for age, sex and non-cannabis drug treatment admissions, these positive associations were attenuated but remained statistically significant at lags of 5-7 years and were again strongest at 5 years, b = 0.082 (0.052-0.111), p < 0.0001., Conclusions: In this 16-year observational study, we found positive time-dependent associations between changes in cannabis potency and first-time cannabis admissions to drug treatment. These associations are biologically plausible, but their strength after adjustment suggests that other factors are also important.

The Netherlands has seen an increase in Δ9-tetrahydrocannabinol (THC) concentrations from approximately 8% in the 1990s up to 20% in 2004. Increased cannabis potency may lead to higher THC-exposure and cannabis related harm. The Dutch government officially condones the sale of cannabis from so called 'coffee shops', and the Opium Act distinguishes cannabis as a Schedule II drug with 'acceptable risk' from other drugs with 'unacceptable risk' (Schedule I). Even in 1976, however, cannabis potency was taken into account by distinguishing hemp oil as a Schedule I drug. In 2011, an advisory committee recommended tightening up legislation, leading to a 2013 bill proposing the reclassification of high potency cannabis products with a THC content of 15% or more as a Schedule I drug. The purpose of this measure was twofold: to reduce public health risks and to reduce illegal cultivation and export of cannabis by increasing punishment. This paper focuses on the public health aspects and describes the (explicit and implicit) assumptions underlying this '15% THC measure', as well as to what extent these are supported by scientific research. Based on scientific literature and other sources of information, we conclude that the 15% measure can provide in theory a slight health benefit for specific groups of cannabis users (i.e., frequent users preferring strong cannabis, purchasing from coffee shops, using 'steady quantities' and not changing their smoking behaviour), but certainly not for all cannabis users. These gains should be weighed against the investment in enforcement and the risk of unintended (adverse) effects. Given the many assumptions and uncertainty about the nature and extent of the expected buying and smoking behaviour changes, the measure is a political choice and based on thin evidence., (Copyright © 2016 Springer. Published by Elsevier B.V. All rights reserved.)

Background: In several countries, including the Netherlands, the use of GHB seems to be increasing. Many recreational users of GHB consider the drug to be harmless and to have no serious side effects. In recent years the number of patients with GHB addition has been increasing steadily., Aim: To draw attention to the possible development of neurotoxicity due to chronic and intensive use of GBH., Method: We reviewed the literature using PubMed., Results: Several studies point to an increase in the number of incidents arising from the risky use of GHB or from a GHB overdose. Other drugs, such as ketamine and alcohol, are known to cause neurotoxicity, leading to cognitive impairment. As outlined in this review article, GHB , alcohol and ketamine show clear similarities in their mechanism of action. This suggests that GHB might have almost the same neurotoxic effects as ketamine and alcohol. An overdose of GHB, just like binge-drinking and a high dose of ketamine, may lead to a coma that probably harms the brain, particularly if comas occur repeatedly., Conclusion: The risk of neurotoxicity is likely to increase with chronic, intensive use of GHB, which is a feature of GHB-addition. We therefore advocate research into the possible toxic effects of GHB in the long term, involving, for instance, the study of lasting effects on the cognitive functions of GHB users and former users.

The discovery of endogenous opioids has markedly influenced the research on the biology of addiction and reward brain processes. Evidence has been presented that these brain substances modulate brain stimulation reward, self-administration of different drugs of abuse, sexual behaviour and social behaviour. There appears to be two different domains in which endogenous opioids, present in separate and distinct brain regions, are involved. One is related to the modulation of incentive motivational processes and the other to the performance of certain behaviours. It is concluded that endogenous opioids may play a role in the vulnerability to certain diseases, such as addiction and autism, but also when the disease is present, such as alcoholism.

In the present study, the effects of morphine exposure in utero on social behavior in juvenile male rats was investigated. Pinning, a measure for play behavior, and social grooming of the offspring were measured at postnatal day 21. The subjects were offspring of Wistar rat dams given sc. injections of 1 or 10 mg/kg body weight morphine HCl daily from gestational days 8 (GD8)-GD 21 and control dams injected daily with saline. Pinning and social grooming of the morphine-treated offspring were significantly elevated compared to saline controls. The doses of morphine used neither affected the gestation of pregnant mother rats nor sensorimotor development of the juvenile rats. Prenatal exposure to morphine of 10 mg/kg daily increased both pinning and social grooming, prenatal exposure to a lower dose of 1 mg/kg increased pinning behavior but not social grooming in the offspring. To study the importance of the gestational period, offspring of dams given 10 mg/kg body weight morphine HCl from GD8-GD15 and saline from GD16-parturition or morphine from GD16-parturition and saline from GD8-GD15 was tested. Pinning was only increased when morphine exposure occurred during the third week of gestation, social grooming was increased when morphine exposure had been in the second week of gestation. Subcutaneous administration of 1 mg/kg naltrexone 1 h before the test significantly decreased play behavior in control rats, but not in animals prenatally exposed to morphine. From these experiments we conclude that the long term effect of in utero exposure to morphine on play behavior is established by affecting the endogenous opioid system.

Changes in analgesia, play behavior, sexual behavior and responsiveness to stress and stimulants have been reported in rodents treated in utero with opiates. During development the endogenous opioids and opioid receptors are present in a tonic balance in the mammalian nervous system. The development of this balance is particularly sensitive to prenatal administration of opioid agonists and antagonists. The motivational and rewarding aspects of play behavior are probably controlled by endogenous opioid systems; low doses of opioids stimulate play behavior, whereas administration of opioid antagonists attenuates play behavior. We have analyzed the effect of morphine administration during the prenatal development of endogenous opioid systems on play behavior in juvenile rats. The doses of morphine used neither affected gestation of pregnant mother rats nor sensorimotor development of the juvenile rats. Levels of social play were elevated in juvenile rats after prenatal exposure to morphine. Social behaviors not related to play and non-social activities were not affected by the prenatal treatment procedure. To study these changes in more detail, social play was investigated using a sequential analysis in prenatally morphine-and saline-exposed pairs. The sequential structure of behavior was not altered by the in utero exposure to morphine. Quantitatively, increases in behavioral transitions were found between behaviors related to play. The prenatal morphine treatment did not affect transitions between behaviors not related to play. It is concluded that the prenatal exposure to morphine did not affect mechanisms underlying play behavior itself, but is probably affecting more general phenomena like reward or motivation to play.

Previously, morphine has been shown to influence social play behavior in rats on two levels. An increasing effect on social play was interpreted as an effect on the rewarding aspects of social play. A lower dose of morphine abolished the effects of an unfamiliar environment on social play, supposedly by affecting the integration of environmental stimuli. In the present study the effects of receptor-specific opioid drugs on social play and measures of social behavior unrelated to play were investigated. Fentanyl, a mu-opioid receptor agonist, seemingly mimicked both effects of morphine. The mu-opioid receptor antagonist, beta-funaltrexamine, decreased social play, although a low dose of this drug increased it. BUBUC (Tyr-D-Cys(StBu)-Gly-Phe-Leu-Thr(OtBu)) and naltrindole, a delta-opioid receptor agonist and delta-opioid receptor antagonist, respectively, had no effects on social behavior. The kappa-opioid receptor agonist, U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), dose dependently suppressed all measures of social behavior. The kappa-opioid receptor antagonist, nor-binaltorphimine, abolished the effect of an unfamiliar environment on social play. These studies suggest that the opioidergic effect on social play is mediated through mu- and kappa-opioid receptor systems.

Removal of the pituitary gland in rats leads to suppression of oral morphine and quinine intake behavior. Experiments measuring oral intake of solutions containing graded concentrations of morphine or quinine, revealed that the detection acuity for bitter taste is changed in hypophysectomized (hypox) animals. Treatment of these rats with ACTH 1--24 restored oral morphine intake towards that on intact rats. Morphine consumption in hypox rats was not affected by administration of ACTH 4--10 or ACTH 11--24, but was normalized by treatment with corticosterone. Adrenalectomy also diminished oral morphine intake. It is concluded that hypophysectomized animals refuse a morphine solution because their threshold for bitter taste quality is altered, presumably due to a diminished release of corticosteroids.

Frequencies of social interactions were higher in pairs of short-term individually housed male Wistar rats as compared to group-housed animals. This was most pronounced when an individually housed rat and a group-housed conspecific were tested together in the morning under red light conditions. Then, in particular the behavioral elements exploration partner, anogenital investigation, crawl over/mount and social grooming were enhanced. The increases in social interactions was dependent on the duration of the period of individual housing and appeared to be maximal after 4 to 7 days of individual housing. The effect extinguished after repeated testing. The observed behavioral changes were hardly affected by habituation to the test cage and were also present in young animals. The increase in social interactions is apparently not due to a general increase in locomotor or exploratory behavior, since no differences in ambulation between individually- and group-housed animals were observed when they were tested together in the social interaction test, and locomotor activities hardly differed in an open field test procedure.

Short-term social isolation increased socio-explorative behavior of pairs of adult male Wistar rats. Hypophysectomy or adrenomedullectomy did not prevent this increase in social behavior. No differences between 7-day isolated (I) and non-isolated (socially housed, S) animals were observed in basal plasma corticosterone levels and these levels increased to the same level in I- and S-rats during individual exposure to the observation cage. The increase in corticosterone levels found immediately after the social interaction test was higher in I- than in S-rats. When I- and S-rats were tested together, a negative correlation was present between plasma-corticosterone levels and frequencies of social interactions. Blood pressure and heart rate were not affected by the isolation procedure. ACTH1-24 (5 micrograms/100 g) did not affect the frequencies of social interactions, neither in I- nor in S-rats. Although a role for corticosterone in "basal" social behavior could not be excluded, it seems that pituitary-adrenal hormones are not important for the development and expression of socio-behavioral disturbances due to short-term isolation.

The effects of various neuropeptides on social behavior was studied in a test procedure in which 7-day isolated animals were tested together with non-isolated partners in dyadic encounters. The short-term isolation procedure increased the frequency and duration of social activities of the rats, but hardly affected non-social explorative behaviors of the animals. Systemic injection of certain neuropeptides, i.c. prolyl-leucyl-glycinamide (PLG), thyrotropin releasing hormone (TRH) and the ACTH 4-9 analog ORG 2766, reversed the isolation-induced increase in social activity, similarly as previously observed with antidepressant drugs. Subcutaneous treatment with beta-endorphin, alpha-endorphin and des-Tyr-gamma-endorphin increased social interactions in 7-day isolated animals. beta-Endorphin enhanced social behavior of non-isolated rats as well, whereas gamma-MSH decreased the social interactions of these animals. Both peptides affected especially social contact behavior. The potent action of beta-endorphin suggests that this peptide and opioid systems may play a physiological role in social behavior. It is proposed that a possible functional antagonism between ACTH-like peptides, especially gamma-MSH, and beta-endorphin may operate in social behavior. The action of the peptides may be rather specific for social behavior, since none of the neuropeptides affected non-social explorative behaviors of the rats during the social interaction test.

Pairs of male rats were tested for active social interaction, either in a familiar test arena under low illumination or in an unfamiliar test arena under high illumination conditions. Rats tested in an unfamiliar environment and under high light, spent less time in active social contact than rats tested under familiar, low light conditions. This effect was most pronounced during the first half of the 10 minute test period. Intraperitoneal injections of ACTH-(1-24) and ACTH-(4-10) (50 micrograms/kg) administered 5 minutes before the test decreased, whereas the same dose of the synthetic ACTH-(4-9) analog ORG 2766 increased the time spent in active social contact, when rats were tested under unfamiliar, high light conditions. The effects of ACTH-(4-10) and ORG 2766 were present in the second and first half of the test period respectively. Dose response relationship studies with ORG 2766 showed that 0.5 micrograms/kg of this peptide facilitated social contact under both test conditions and the dose response relation followed an inverted U-shaped curve under the familiar low light condition, but not under the unfamiliar, high light condition. ACTH-(4-10) and ORG 2766 failed to influence active social contact, when administered 30 minutes before the test. The change in social contact by ACTH-(4-10) and ORG 2766 was not accompanied by an alteration in ambulation of the rats. It is concluded that ACTH-(4-10) and ORG 2766 decrease and increase respectively social interaction of pairs of rats. The expression of these effects however, depends on the test and treatment conditions and may be related to the action of brain-born ACTH-like peptides.

Pinning, as a measure for play, and social grooming were simultaneously studied in juvenile rats. Short-term social isolation increased both behavioural responses. This increase was attenuated by the opioid antagonist naltrexone, whilst the opiate, morphine, and the opioid peptide beta-endorphin, increased the responses. Pinning was more sensitive to the effects of naltrexone, whilst beta-endorphin stimulated particularly social grooming. Small doses of the dopaminergic drug, apomorphine, decreased both pinning and grooming behaviour of the short-term isolated rats. Some of the effects were partially antagonized by the dopamine antagonist haloperidol, and the neurolepticum-like peptide, desenkephalin-gamma-endorphin (DE-gamma-E). A small dose of haloperidol and DE-gamma-E stimulated social grooming in particular, whilst a larger dose of haloperidol decreased pinning and social grooming. It is concluded that both opioid and dopaminergic systems are implicated in the increase of pinning and social grooming induced by short-term social isolation. The differences in sensitivity of pinning and social grooming for opioid and dopaminergic drugs and peptides are discussed in relation to possible differences in the neural systems underlying both social activities.

Social isolation for 7 days increases the frequency of social interactions of rats, when they are tested with non-isolated partners in dyadic encounters. Subcutaneous administration of beta-endorphin enhances the social interactions of the isolated animals. Especially contact behavior, which includes crawl over, mounting and social grooming is stimulated by beta-endorphin, whereas social explorative behavior and approaching/following are less or not changed by peptide treatment. Already 10 ng/kg of the peptide increases the social interactions, especially social contacts of the rats. Treatment with naltrexone does not interfere with the social interactions of the isolated animals, but completely antagonizes the beta-endorphin-induced increase of social behavior, suggesting that this effect of beta-endorphin is mediated by opiate receptor systems. It is postulated that beta-endorphin modulates close and intimate social contacts probably by its reward-inducing properties.

In a situation in which a short-term isolated (I) and a group-housed (S) rat were placed together, the influence of various drugs on social behaviour was analysed. It was found that a single intraperitoneal injection of 7.5 mg/kg of the antidepressant drugs clomipramine, nortriptyline and mianserine normalized the increased social interactions of the isolated rat to the level of the group-housed rat, without affecting the social behaviour of that animal. This action of the drugs was not due to changes in locomotor activity. An opiate (morphine), an opiate antagonist (naloxone), a tranquilizer (diazepam), a neuroleptic (haloperidol) and a psychostimulant (amphetamine) did not preferentially influence the social behaviour of the isolated rat. Chronic treatment with the antidepressants did not reduce the increased social interactions of isolated animals. In spite of this it is clear that the increased social behaviour of short-term isolated rats was specifically affected by the antidepressant drugs. This suggests that this behavioural procedure might be useful for predicting antidepressant activity.

Disrupting circadian organization in rats by phase-shifting the illumination cycle or by exposure to a reversed day/night cycle or to continuous light, resulted in retrograde amnesia for passive avoidance behavior. This retrograde amnesia induced by phase-shifting lasted at least 2 days, and gradually diminished the longer the rats were exposed to the new illumination cycle. Retention performance was not impaired when rats were exposed to phase-shifting for 3-5 days before the learning trial. The retrograde amnesia due to changing the illumination cycle is probably due to retrieval disturbances. Extinction of active avoidance behavior was facilitated in rats exposed to a phase-shifted illumination cycle, but social and explorative behavior of rats tested in dyadic encounters were not affected by changing the normal illumination cycle. It is concluded that phase-shifting may result in amnesia for newly learned behavioral responses, but not for more innate behavioral patterns.

Treatment with gamma-endorphin antiserum twice daily for 12 days, by injection into the nucleus accumbens did not change the basal level of social activity or explorative behaviour when pairs of rats were tested in a social interaction test. The decrease in social interactions due to increased light level as observed in placebo-treated rats, was not present in animals treated with gamma-endorphin antiserum. Significantly more freezing and fly-responses were observed in the rats treated with antiserum, as reactions to penetrating sound stimuli. These changed responses to light and sound stimuli persisted for at least 3 days following discontinuation of treatment. It is concluded that treatment with gamma-endorphin antiserum, injected into the nucleus accumbens results in disturbances in the integration of environmental stimuli in social behaviour and in enhanced responsiveness to stressful stimuli. It is suggested that these effects may be related to increased dopaminergic transmission in some dopaminergic systems in the nucleus accumbens, implicating these systems in the environmental control over social behaviour.

A low and a high dose of delta 1-tetrahydrocannabinol (delta 1-THC) and of cannabidiol (CBD) were IP injected in rats that had been isolated for 7 days. Forty-five minutes after injection, the rats were tested for social interactions with non-isolated, untreated test partners in dyadic encounters under standardized conditions. Different aspects of social behavior were analyzed. The high dose of delta 1-THC (10 mg/kg) prevented nearly all social interactions. The low dose of delta 1-THC (1 mg/kg) exerted selective and specific effects on social interactions. Social contact behavior, including crawl over/mounting, and social grooming, and aggressive behavior, including fighting, kicking, and biting, were markedly decreased, whereas social exploratory behavior (exploration of the partner and anogenital investigation) and the behavioral item, approach/follow, were hardly affected by delta 1-THC treatment. Both doses of CBD (2 and 20 mg/kg) failed to change the various aspects of social interaction. It is postulated that the effects of delta 1-THC on close and intimate contact behavior of rats may contribute to the understanding of marihuana taking in humans.