Haemorrhagic stroke related to the use of 4-fluoroamphetamine.

INTRODUCTION: The use of the new psychoactive substance 4-fluoroamphetamine (4-FA) and the number of 4-FA-related intoxications substantially increased in The Netherlands in recent years. We describe two patients with severe 4-FA-related complications and the characteristics of a large sample of 4-FA-intoxicated patients. METHODS: Information on patients with 4-FA-related intoxications between January 2009 and June 2017 was available from the Monitor Drug-related Incidents. Detailed clinical information was obtained of two patients with haemorrhagic stroke after toxicologically confirmed 4-FA use. RESULTS: We report on two patients who presented with headache and mild hypertension after 4-FA use. Patient A developed one-sided weakness and decreased consciousness after a few hours. A computed tomography scan showed a left-sided intracerebral haemorrhage. Because of life-threatening cerebral herniation, haematoma evacuation was performed. Postoperatively, she suffered from a right-sided hemiparalysis and severe aphasia, requiring clinical rehabilitation. Patient B had a subarachnoid haemorrhage without neurological deficits. In total, 939 4-FA-intoxicated patients were registered. These patients used 4-FA alone (44%) or in combination with alcohol (13%) and/or other drugs (43%). DISCUSSION: Patients using 4-FA are at risk for life-threatening health problems, including intracranial haemorrhage. Additional brain imaging should be considered in 4-FA-intoxicated patients, not only in the presence of neurological deficits, but also in the case of severe headache.

[Cognitive impairment due to intensive use and overdoses of gammahydroxybutyric acid (GHB)]. / Cognitieve schade door intensief gebruik en overdoses van GHB.

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.

mCPP: an undesired addition to the ecstasy market.

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.

Methylone and mCPP, two new drugs of abuse?

Recently, two new ecstasy-like substances, methylone and mCPP, were found in street drugs in the Netherlands by the Drugs Information and Monitoring System (DIMS). Methylone (3,4-methylenedioxymethcathinone) is the main ingredient of a new liquid designer drug that appeared on the Dutch drug market, called 'Explosion'. mCPP (meta-chlorophenylpiperazine) is a substance often used as a probe for the serotonin function in psychiatric research, and has now been found in street drugs, both in tablets and powders. Methylone as well as mCPP act on monoaminergic systems, resembling MDMA (3,4-methylenedioxymethamphetamine), with mCPP mainly affecting the serotonin system. The subjective effects of both new substances exhibit subtle differences with those of MDMA. Only little is known about the harmfulness of both methylone and mCPP. However, because of similarities between these substances and MDMA, risks common to MDMA cannot be excluded.

Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops.

The total concentration of THC has been monitored in cannabis preparations sold in Dutch coffee shops since 1999. This annual monitoring was issued by the Ministry of Health after reports of increased potency. The level of the main psychoactive compound, Delta9-tetrahydrocannabinol (THC), is measured in marijuana and hashish. A comparison is made between imported and Dutch preparations, and between seasons. Samples of cannabis preparations from randomly selected coffee shops were analyzed using gas chromatography (GC-FID) for THC, CBD and CBN. In 2004, the average THC level of Dutch home-grown marijuana (Nederwiet) (20.4% THC) was significantly higher than that of imported marijuana (7.0% THC). Hashish derived from Dutch marijuana (Nederhasj) contained 39.3% THC in 2004, compared with 18.2% THC in imported hashish. The average THC percentage of Dutch marijuana, Dutch hashish and imported hashish was significantly higher than in previous years. It nearly doubled over 5 years. During this period, the THC percentage in imported marijuana remained unchanged. A higher price had to be paid for cannabis with higher levels of THC. Whether the increase in THC levels causes increased health risks for users can only be concluded when more data are available on adjusted patterns of use, abuse liability, bioavailability and levels of THC in the brain.

Endogenous opioids and reward.

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.

Social behavior of juvenile rats after in utero exposure to morphine: dose-time-effect relationship.

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.

The neurobiology of social play behavior in rats.

Social play behavior is one of the earliest forms of non-mother-directed social behavior appearing in ontogeny in mammalian species. During the last century, there has been a lot of debate on the significance of social play behavior, but behavioral studies have indicated that social play behavior is a separate and relevant category of behavior. The present review provides a comprehensive survey of studies on the neurobiology of social play behavior. Evidence is presented that opioid and dopamine systems play a role in the reward aspect of social play behavior. The role of cholinergic, noradrenergic and opioid systems in attentional processes underlying the generation of social play behavior and the involvement of androgens in the sexual differentiation of social play behavior in rats is summarized. It is concluded that there is not only behavioral, but also neurobiological evidence to suggest that social play behavior represents a separate category of behavior, instead of a precursor for adult social, sexual or aggressive behavior.

Social play in juvenile rats after in utero exposure to morphine.

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.

Sequential analysis of social play behavior in juvenile rats: effects of morphine.

The effects of morphine on social play behavior in juvenile rats were investigated using sequential analysis. Social play behavior of 21-day-old rats treated with 1.0 mg/kg of morphine or saline was analyzed for 15 min. Frequencies and durations of measures of social play behavior, such as pinning, boxing/wrestling and following/chasing were significantly increased after treatment with morphine. Social behaviors not related to play, such as social exploration and crawling over/under were slightly decreased, while social grooming and non-social behavior were not affected by morphine treatment. Using sequential analysis, the dissociation between social behaviors related and unrelated to play was confirmed. Pinning and boxing/wrestling were highly significantly associated. In addition, crawling over/under significantly often preceded social grooming, and an association between social exploration and non-social behavior was found as well. Pinning and boxing/wrestling appeared to be negatively associated with non-social behaviors, social exploration and crawling over/under. A negative association between social grooming and social exploration was also found. Upon treatment with morphine, no major effects on the sequential structure of social behavior were observed: pinning and boxing/wrestling appeared more associated with following/chasing, and the negative association between pinning and boxing/wrestling on the one hand and social exploration on the other was enhanced. Thus, morphine slightly increased the coherence of social play behavior. It is concluded that morphine exerts its effects on social play behavior by increasing social play behavior as a whole rather than by changing its structure, suggesting a key role for opioid systems in the regulation of social play behavior.

Influence of environmental factors on social play behavior of juvenile rats.

The effects of light level and familiarity to the testing environment on social behaviors related and unrelated to play were investigated in juvenile rats accustomed to dim light conditions. Pinning, a measure characteristic for social play in rats, was completely suppressed under intense light conditions. Following/chasing and boxing/wrestling, social behaviors related to play, were also decreased under intense light. Of the measures of social behavior not related to play, contact behavior was decreased under intense light whereas social exploration was hardly affected. Levels of social exploration and following/chasing gradually declined during the 15-min test period. Frequency of contact behavior decreased, whereas duration increased with time. Under dim light conditions, unfamiliarity to the test cage suppressed pinning and boxing/wrestling but not the other social behaviors in the first part of the test period. These findings show that social behavior in juvenile rats, as in adult rats, can be influenced by light level and familiarity to the test cage. Social behaviors related and unrelated to play seem to be differentially influenced by environmental stimuli.

Mu- and kappa-opioid receptor-mediated opioid effects on social play in juvenile rats.

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.

Effects of morphine on different aspects of social play in juvenile rats.

To clarify the influence of opioids on social play, the effects of morphine on playful and non-playful social behavior in juvenile rats was investigated under different conditions. Environmental variables employed were different (dim and intense) levels of illumination during testing, familiarity to the test cage, and different periods of social isolation prior to testing. Under dim light conditions, morphine markedly increased playful social behavior, such as pinning, boxing/wrestling and following/chasing, whereas non-playful social behavior such as social exploration and contact behavior was hardly affected. This effect of morphine was independent of duration of previous isolation and dose-dependent, with a maximal effect at 1.0 mg/kg. The mechanism of this effect is interpreted as an action on the rewarding aspects of play. A dose of 0.1 mg/kg of morphine abolished the initial suppression of play induced by unfamiliarity to the test cage, without influencing total levels of play. This may be an effect of morphine on the integration of sensory stimuli. Under intense light conditions, whereas playful behavior was completely suppressed, morphine itself hardly affected such behavior, but decreased some aspects of non-playful social behavior. These results suggest that in juvenile rats playful and non-playful forms of social behavior are differentially regulated. In addition, opioid systems may be involved at different levels in the regulation of social play.

Prenatal exposure to morphine enhances cocaine and heroin self-administration in drug-naive rats.

Drugs of abuse putatively exert their rewarding actions by activating specific mechanisms in the brain. Sensitivity of these mechanisms to stimulation by drugs may be a factor in the development of drug dependence. As endogenous opioid systems may be involved in drug reward, manipulation of the functional state of opioid systems may affect this development. In the present study male rats exposed to morphine or placebo during their foetal period were tested for the development of intravenous self-administration of either heroin, cocaine or saline. Heroin and cocaine represent two fundamentally different classes of abused drugs. Prenatal exposure to morphine enhanced rates of heroin and of cocaine, but not of saline self-administration. The data indicate that this was not simply the result of increased motor activity. Given the fact that the unit-doses of heroin and cocaine were threshold doses for the development of intravenous drug self-administration behaviour, it is concluded that the reinforcing efficacy of both drugs is enhanced by prenatal morphine treatment, and that such treatment possibly facilitates development of drug dependence in general.

Involvement of opioid and dopaminergic systems in isolation-induced pinning and social grooming of young rats.

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.

Disrupting circadian rhythms in rats induces retrograde amnesia.

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.

Neuropeptides and social behavior of rats tested in dyadic encounters.

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.

Analysis of the facilitatory effect of the ACTH-(4-9) analog ORG 2766 on active social contact in rats.

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.

delta 1-Tetrahydrocannabinol but not cannabidiol reduces contact and aggressive behavior of rats tested in dyadic encounters.

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.

Normalizing effect of an adrenocorticotropic hormone (4-9) analog ORG 2766 on disturbed social behavior in rats.

Short-term isolation increased the frequency of social interactions in rats tested in pairs, while pairs of rats placed in an unfamiliar test cage and subjected to a high level of illumination spent less time in active social contact. These changes in social behavior elicited by environmental manipulations were counteracted by treatment with the adrenocorticotropic hormone (4-9) analog ORG 2766. The peptide's normalizing effect may be mediated by endogenous opioid systems.