[Review] the Neuropathology of Drug Abuse_2011

Neuropathology and Applied Neurobiology (2011), 37, 118134

doi: 10.1111/j.1365-2990.2010.01131.x

Review: The neuropathology of drug abuseA. Bttner Institute of Forensic Medicine, University of Rostock, Rostock, Germany

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A. Bttner (2011) Neuropathology and Applied Neurobiology 37, 118134 The neuropathology of drug abuseDrug abuse represents a signicant health issue. The major substances abused include cannabis, opiates, cocaine, amphetamine, methamphetamine and ecstasy. Alterations of intracellular messenger pathways, transcription factors and immediate early genes within the brain reward system seem to be fundamentally important for the development of addiction and chronic drug abuse. Genetic risk factors and changes in gene expression associated with drug abuse are still poorly understood. Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of drug toxicity. A broad spectrum of changes affecting the central nervous system is seen in drug abusers. The major ndings result from the consequences of ischaemia and cerebrovascular diseases. Except for a few observations of vasculitis, the aetiology of these cerebrovascular accidents is not fully understood. The abuse of amphetamine, methamphetamine and MDMA has been related to neurotoxicity in human long-term abusers and to the risk of developing Parkinsons disease. However, whether such neurotoxicity occurs remain to be established. Systematic histological, immunohistochemical and morphometric investigations have shown profound morphological alterations in the brains of polydrug abusers. The major ndings comprise neuronal loss, neurodegenerative alterations, a reduction of glial brillary acidic proteinimmunopositive astrocytes, widespread axonal damage with concomitant microglial activation as well as reactive and degenerative changes of the cerebral microvasculature. These observations demonstrate that drugs of abuse initiate a cascade of interacting toxic, vascular and hypoxic factors, which nally result in widespread disturbances within the complex network of central nervous system cell-to-cell interactions.

Keywords: astrocytes, cerebral microvasculature, drug abuse, microglia, neurodegeneration

IntroductionDrug abuse represents a serious health issue worldwide. Drugs of abuse can be grouped as stimulants, analgesics and narcotics, hypnotics as well as antidepressants, nicotine and alcohol [13]. Besides the latter two substances, the predominant substances abused include cannabis, opiates, cocaine, amphetamine, methamphetamine and designer drugs [1,2]. Although individuals with a drug habit may favour one or other class of drug, depending in

Correspondence: Andreas Bttner, Institute of Forensic Medicine, University of Rostock, St.-Georg-Strasse 108, 18055 Rostock, Germany. Tel: +49 381 494 9900; Fax: +49 381 494 9902; E-mail: [email protected]

part on what is available, most perform polysubstance abuse [48]. The methodological problems in investigating the effects of drugs of abuse on the central nervous system (CNS) consist of distinguishing between substancespecic effects related to the properties of the drug itself, the inuence of adulterants, and of secondary effects related to the lifestyle of drug abusers, for example, malnutrition, infections and systemic diseases. Because polysubstance abuse is seen in the majority of cases, it is difcult to relate the observed ndings to a single substance. Therefore, in most cases the exact aetiology of the various CNS alterations remains unclear. Injecting drug abuse is also a risk factor for the acquisition of HIV-1 infection and there is evidence that

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HIV-1-associated CNS disorders are accentuated in drug abusers [9,10]. Infection of the brain with hepatitis viruses, especially with hepatitis C virus (HCV) is another potential confounding factor in the neuropathological appearances of the observed brain changes. Injection drug abusers are the largest group of persons infected with HCV, with a prevalence of 5090% [11]. The transmission of HCV is not the effect of the drug injected but of sharing contaminated equipment [11]. In contrast to HIV, HCV is detectable in high concentrations in other utensils for heroin injection, such as lters, spoons and rinsing liquids. Besides hepatic encephalopathy, there is also emerging evidence of neurocognitive impairment in HCV infection independently of drug abuse or HIV-1 infection [1215]. Research on the neurobiology of addiction has shown that the reinforcing properties of most drugs of abuse are mediated by activation of the mesolimbic dopaminergic system, the orbitofrontal cortex and the extended amygdala [1619]. Alterations of the intracellular messenger pathways, transcription factors and immediate early gene expression in these reward circuits are believed to be important for the development of addiction and chronic drug abuse [1620]. Possible genetic risk factors for drug addiction and changes in gene expression, associated with drug abuse, are still poorly understood [21,22]. Although a broad spectrum of alterations affecting the CNS has been described in drug abusers [1,2,23], there is no specic change that is characteristic and little is known about the fundamental neuropathological alterations of the cellular elements of the human brain. Therefore, despite a large body of literature on animal models, the following review will focus on the relevant human CNS ndings. The pharmacology and CNS alterations in alcohol and nicotine abuse are reviewed elsewhere [3,2427].

tions and hyperintense lesions have been demonstrated in the white matter, which were attributed to ischaemic lesion [34,3840]. Single photon emission computed tomography showed focal perfusions decits in various brain regions [4145]. On positron emission tomography a reduction of the global glucose metabolism has been demonstrated [46,47]. Studies using proton magnetic resonance spectroscopy have identied several biochemical changes in the brain that may underlie the neuropathology that subsequently gives rise to the cognitive and behavioural impairments associated with drug addiction [48]. Some neurochemical abnormalities have been attributed to alterations in nonneuronal brain tissue [48]. Diffusion tensor imaging revealed microstructural abnormalities in the white matter and the corpus callosum, suggestive of axonal injury [4954]. Despite these numerous neuroimaging studies, the cause or possible morphological correlates of these alterations are still not fully resolved.

CNS effects of the major drugs of abuseDepending of the frequency and types of drugs abused, the predominant neurologic-psychiatric complications of drug abuse include a high prevalence of depression, memory loss and cognitive decline, and the possible predisposition to schizophrenia.

CannabisCannabis is the most commonly used illicit drug worldwide [2,5559]. Cannabis preparations (marihuana, hashish) are usually mixed with tobacco and smoked. Oral ingestion as tea or addition to pastries is also widespread. Cannabis is unsuitable for intravenous use as it is relatively waterinsoluble. The concentration of the major psychoactive component of cannabis, D9-tetrahydrocannabinol (THC), varies according to the preparation and the origin of the plant from 1% to 7% in marihuana, 2% to 10% in hashish and 10% to 60% in hash oil [55,57]. Cannabis combines many of the properties of alcohol, tranquillizers, opiates and hallucinogens; it is anxiolytic, sedative, analgesic and psychedelic [55]. The psychotropic action of cannabis starts after several minutes reaches a maximum by 2030 min and persists for 24 h. However,

Neuroimaging ndingsNeuroimaging studies revealed widespread alterations in the brains of drug abusers [28]: Computed tomography studies have shown diffuse brain atrophy [2931]. On magnetic resonance imaging decreased grey and white matter volume has been demonstrated in particular areas of the brain [3237]. Moreover, focal demyelina-

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the action of cannabis is of highly individual variability. Furthermore, there is a dose-related impairment of cognitive and psychomotor performance. Acute effects include euphoria and relaxation with perceptual changes. However, dysphoric reactions, including anxiety and panic, depression, paranoia and psychosis can also occur. Systemic effects include a dose-related tachycardia, vasodilation and postural hypotension [5559]. THC is a lipid-soluble substance that is distributed heterogeneously within the brain, with its highest concentrations in neocortical, limbic, sensory and motor areas [5558]. THC and other cannabinoids exert their effects by the interaction with specic cannabinoid receptors, which are distributed heterogeneously within the brain [5964]. Two cannabinoid receptors, CB1 and CB2, have been pharmacologically characterized and anatomically localized. CB1 receptors are found predominantly in the central and peripheral nervous system, where they have been implicated in presynaptic inhibition of neurotransmitter release. CB2 receptors are present on immune cells, where they may be involved in cytokine release [5965]. The highest density of CB1 receptors is found in the substantia nigra, the basal ganglia, the hippocampus and the cerebellum [63,66,67]. Within the neocortex they are present with the highest density in the frontal cortex, the dentate gyrus, the mesolimbic dopaminergic system and the temporal lobe [63,66,67]. This specic distribution of CB1 receptors correlates well with the effects of cannabinoids on memory, perception and movement control. The very low density of CB1 receptors in the brain stem and medulla oblongata explains the low acute toxicity and lack of lethality of cannabis [55,59,66]. Nevertheless, the CNS toxicity of cannabis seems to have been underestimated for a long time [68], as recent ndings revealed THC-induced neuronal death in cultured rat neurones [6971]. The discovery of specic endogenous cannabinoid receptor ligands (endocannabinoids), and the distribution of their receptors, strongly suggests that these lipid neurotransmitter systems play an important role in higher cortical-emotional functions, memory storage, movement coordination and several pathological conditions [59,6265,72,73]. Despite its widespread abuse, cannabis-related cerebrovascular events are infrequently reported. They are believed to be due to a cannabis-induced vasospasm or a

cannabis-induced hypotension [7478]. However, due to the widespread use of this drug, it is difcult and often impossible to establish whether these strokes are truly associated with cannabis, other ingested drugs, or purely coincidental. The important question whether cannabis can cause irreversible brain damage, particularly to adolescents, or lead to increased risk for schizophrenia, persisting beyond transient intoxication, is still a matter of debate [79,80].

Opioids and derivativesOpioids, especially heroin, are the leading substances that cause death in drug abusers. Derivatives include morphine, hydrocodone, oxycodone, hydromorphine, codeine and other narcotics such as fentanyl, meperidene, methadone and opium [2,3]. Heroin is made from opium and crosses the bloodbrain barrier (BBB) faster than morphine [81]. Heroin is usually administered intravenously. Intranasal and subcutaneous administration is also possible. Heroin alkaloid may be prepared for inhalation by heating on metallic foil (chasing the dragon) that results in a higher bioavailability of heroin compared with smoking in a cigarette [3]. Intravenous heroin induces an extreme euphoria lasting for several minutes. Subsequently, there is a pleasant dream-like state with drowsiness and analgesia [81]. However, marked tolerance develops to euphoria. Opiate overdose produces the triad of coma, respiratory depression and miosis [81]. Between 50% and 70% of intravenous heroin abusers have experienced a non-fatal overdose at some time in their lives [4]. Medical complications of long-term heroin abuse include thrombophlebitis, endocarditis, hepatitis, pneumonia, nephropathy and immunodepression [2,81]. Due to the practise of needlesharing, there is a high risk for infections [11]. Risk factors for opioid-induced deaths include overdose, concomitant use of other CNS depressants and loss of tolerance after a period of abstinence [48]. At necropsy, up to 90% of all cases of persons dying of heroin overdose show brain oedema with prominent tonsillar herniation and uncal grooving. However, rapid death after heroin intake will not lead to any morphological evidence of neuronal cell injury. In cases of delayed death after a survival period of 5 h or longer, hypoxicischaemic leukoencephalopathy with loss of neurones in



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the hippocampal formation, the Purkinje cell layer and/or the olivary nucleus, as well as vascular congestion, will become apparent [8286]. In the globus pallidus, neuronal loss and bilateral, symmetrical ischaemic lesions/ necrosis have been described in 510% of cases [85,87]. All the above mentioned alterations are assumed to be caused rather by recurrent episodes of hypoxia during the intoxicated state than to be related to direct neurotoxic effects of the opioid drugs [8287]. Stroke in heroin abusers, occurring in the absence of endocarditis or mycotic aneurysms, has rarely been observed [84,8893]. Within the hippocampus of heroin deaths, enhanced expression of glial brillary acidic protein (GFAP) by astrocytes and/or a proliferation of microglia have been found [84]. However, an increased GFAP expression could not be conrmed by other authors [23]. An increase in polysialic acid neural cell adhesion molecule positive hippocampal neurones and astrocytes is assumed to reect an attempt to repair cell damage [94]. Perivascular pigment-laden macrophages and pigment depositions are sometimes observed and are attributed to repeated intravenous injections of impure heroin [95], or to BBB breakdown [23,96]. Infections in heroin abusers result from unsterile injection techniques and from immunosuppression, caused by chronic opiate abuse [1,2,11,85,97]. Endocarditis might lead to septic foci in the brain or to intracranial mycotic aneurysms [1,2,85,97]. Transverse myelitis/myelopathy is an exceptionally rare lesion described in heroin abusers [1,2,85,98,99]. The aetiology is still unclear and neither the clinical picture nor the pathological changes correspond to any particular pattern. A distinct entity, spongiform leukoencephalopathy, has been reported to occur almost exclusively after inhalation of heroin pyrolysate vapours (chasing the dragon) [1,2,100102]. The most characteristic nding is the selective involvement of the posterior limb of the internal capsule and sparing of subcortical U-bres. Neuropathological examination reveals spongiform degeneration of the deep white matter with vacuolation of the myelin sheath, loss of oligodendrocytes, axonal reduction and astrogliosis. The grey matter is usually unremarkable and the brainstem, spinal cord and peripheral nerves are spared [100102]. A lipophilic toxin-induced process was considered to be due to contaminants, but a denite toxin could not yet be identied.

Alterations of neurotransmitters and receptorsLong-term heroin abuse seems not to be related with a reduced density of CNS m- and d-opioid receptors [103 106]. Instead, the molecular mechanisms underlying opiate addiction seem to involve the second messenger signalling system [16,18,19,104,107114]. Necropsy studies revealed that long-term heroin abuse causes an increase in certain G proteins in different regions of the brain [105,107,110]. Others have shown a decreased level of Ca2+-dependent protein kinase C-a [104] and an increased level of a membrane-associated G proteincoupled receptor kinase [113]. Further ndings include the downregulation of the adenylyl-cyclase subtype I [109,111], a decrease in the density of alpha 2-adrenoreceptors [103], a decrease in the immunoreactivity of protein kinase C-ab [114], and decreased levels of neurolament proteins [115]. Within the dopaminergic system the levels of tyrosine hydroxylase protein and those of the dopamine (DA) metabolite homovanillic acid were reduced in the nucleus accumbens [116]. Striatal levels of serotonin (5-hydroxytryptamine or 5-HT) were either normal or elevated, whereas the concentration of the 5-HT metabolite 5-hydroxyindoleacetic acid was decreased [116]. According to the authors, chronic heroin abuse might produce a modest reduction in dopaminergic and serotonergic activity that could affect motivational state and impulse control. Maintenance therapy for heroin addiction includes codeine, dihydrocodeine, methadone and buprenorphine [117120]. In the majority of deaths related to these substances, additional CNS depressant drugs, mainly alcohol and benzodiazepines, can be detected. The neuropathological ndings are similar to those encountered in heroin deaths.

CocaineCocaine is derived from the leaves of the coca plant. Cocaine hydrochloride is a water-soluble white salt and the most frequent preparation of the drug that is available in form of cystals, granules or a white powder. It can be administered intranasally (snorting) or injected [2,3]. The free alkaloid form (free base) that had been extracted with volatile solvents is usually smoked. Crack cocaine is produced by rst dissolving the hydrochloride salt in water, then mixing with baking soda and heating. The


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cracking sound made by the crystals when they are heated provides the name [2]. Cocaine initially induces profound subjective well-being together with alertness and increased self-condence. Subsequently, there is a mild euphoria followed by fatigue. Acute psychiatric disturbances include dysphoria, agitation, aggressive behaviour, depression, paranoia, psychosis and hallucinations. Medical complications include vasoconstriction, tachycardia, hypertension and sudden cardiac death [3,25,31]. Cocaine is a potent CNS stimulant. It crosses the BBB rapidly due to its highly lipophilic properties [121,122]. Throughout the brain, cocaine and its major metabolites are widely distributed and receptors with varying afnities are found [123,124]. Cocaine acts by binding to specic receptors at presynaptic sites preventing the reuptake of neurotransmitters [2,3,122]. The major synaptic effect of cocaine is the release of dopamine (DA) from the synaptic vesicles and the blocking of DA reuptake resulting in an enhanced dopaminergic neurotransmission [2,3,122]. Cocaine is the most frequent drug of abuse associated with fatal and non-fatal cerebrovascular events, with either haemorrhagic or ischaemic strokes [89,91 93,125135]. In contrast to the non-drug-using population, cocaine-related stroke occurs primarily in young adults [1,125128]. Cocaine-related ischaemic infarctions can occur in every brain region [2,128,130]. The underlying cause is attributed to cerebral vasospasm either by cocaine or its metabolites [92,128,131,136138]. Other mechanisms include cocaine-induced cardiac arrhythmia with secondary cerebral ischaemia, or the direct effects of cocaine on haemostasis with increased platelet aggregation [89,128,131,135,139,140]. In cocaine-related intracerebral (ICH) and subarachnoidal (SAH) haemorrhage, underlying arteriovenous malformations or aneurysms are frequently observed [93,125,127130,132,141,142]. Cocaine abuse has been shown to predispose to aneurysmal rupture at a signicantly earlier age, and in much smaller aneurysms, compared with non-drug-using persons [125,143]. Cocaine-related ICH is associated more frequently with subcortical locations, a higher risk of intraventricular haemorrhage, and poor prognosis compared with nondrug-abusing patients with spontaneous ICH [144]. Rupture of an arteriovenous malformation, or aneurysm, are most likely related to the sudden elevation of blood

pressure and heart rate from the sympathomimetic effect of the drug [92,128130,132,141,145]. A cocaine-induced cerebral vasculitis as a cause for cerebrovascular events could only be demonstrated in rare cases [89,146,147]. In experimental models, cocaine enhances leucocyte migration across the cerebral vessel wall and opens the BBB to HIV-1 invasion by a direct effect on brain endothelial cells and by the induction of pro-inammatory cytokines and chemokines [148,149].

Alterations of neurotransmitters and receptorsIn the striatum of cocaine-related deaths, reductions in the levels of enkephalin mRNA, m-opioid receptor binding and DA uptake site binding, along with elevation in levels of dynorphin mRNA and k-opioid receptor binding have been described [150]. In chronic cocaine abusers, a decreased level of DA was identied in the caudate nucleus and frontal cortex, but not in the putamen, nucleus accumbens and cerebral cortex [151155]. This decrease was not paralleled by an increase of DA D1 and D2 gene expression [156]. Simultaneously, there was an increase of cocaine binding sites on the DA transporter with a decrease of the DA D1 receptor density in the striatum and of DA D1 and DA D3 receptor density in the nucleus accumbens [152154,157159]. A marked reduction in immunoreactivity of the vesicular monoamine transporter-2 [151] and of the transcription factor NURR1 [160] in necropsy samples of human cocaine abusers might reect damage to the dopaminergic system. An overexpression of a-synuclein in midbrain DA neurones in chronic cocaine abusers may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse [161]. This accumulation of a-synuclein protein in long-term cocaine abuse might increase the risk of developing Parkinsonism [161]. Further necropsy ndings include an upregulation of k2-opioid receptors in the limbic system [162] and of cAMP response element-binding protein in the ventral tegmental area [163]. In the serotonergic system an increase of the 5-HT transporter in the striatum, substantia nigra and limbic system has been demonstrated [164]. In the putamen, a DA-rich brain area, the activity of phospholipase A2 and phosphocholine cytidylyltransferase was selectively decreased [165].



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Amphetamines and methamphetamineAmphetamines and methamphetamine are widely used psychostimulants that act on monoamine transporters [2,3]. These substances are available as powder, capsules, tablets or uids. Therefore, they can be swallowed, snorted, injected intravenously or smoked. The composition, purity and dose are highly variable [2]. Their potent sympathomimetic effects include an elevation of pulse rate, blood pressure and an increased level of alertness. Adverse effects include insomnia, excitability, seizures, panic attacks, psychosis and aggressive behaviour [2,3,25]. Throughout the brain, methamphetamine is heterogeneously distributed [166]. Amphetamines and methamphetamine are the second most common cause (after cocaine) of strokes occurring largely in persons younger than 45 years [127]. Furthermore, SAH and ICH have been described [2,3,91,92,125,126,129,167172]. Similar to cocaine, a sudden elevation in blood pressure [167,169,171] is postulated as a major mechanism. The vasoconstrictive effect of both substances may also lead to the development of ischaemic infarction [167,171]. Methamphetamine has been shown to induce inammatory genes in human brain endothelial cells [173].

dopaminergic system markers [181,184], the evidence is inconclusive in regard to dopaminergic system degeneration. To dene methamphetamine abuse as a risk factor in Parkinson disease, it would be important to know whether these alterations represent neurodegenerative changes or a drug-induced compensatory response to the disruption of neurochemical homeostasis [182,183]. The mechanisms of methamphetamine-induced neurotoxicity are thought to be mediated by multiple mechanisms including the generation of free radicals and nitric oxide, excitotoxicity, mitochondrial dysfunction, and the induction of immediate early genes as well as transcription factors [175177,182185]. However, whether neurotoxicity occurs in human methamphetamine and amphetamine abusers remains to be established.

Amphetamine and methamphetamine derivativesAmphetamine and methamphetamine derivatives (designer drugs) comprise a broad spectrum of substances [2,186]. The street name ecstasy subsumes different hallucinogenic amphetamine derivatives with MDMA (3,4-methylenedioxymethamphetamine) and MDE (3,4-methylenedioxyethylamphetamine) being the main components [187]. These drugs are taken orally in form of tablets that are usually embossed with a logo [2]. The effects of MDMA and MDEA last about 35 h and include relaxation, euphoria, sensual enhancement, reduction of anxiety and emotional closeness to others. This psychological prole has been called entactogenic and has the connotation of inducing a feeling of touch with the world within. In addition, these substances also have stimulant-like and hallucinogenic effects [2,188 191]. The effects of MDMA vary according to the dose and the frequency and duration of use [190]. Adverse effects include headache, nausea, tooth grinding (bruxism), tachycardia and an increase in body temperature. Furthermore, hyperactivity, ight of ideas, depersonalization, panic attacks, anxiety, depression, agitation, delirium, and insomnia may occur [190]. MDMA interacts with various neurotransmitter circuits but predominantly affects the dopaminergic and serotonergic system [186,188191]. In human post mortem tissue, a distinct immunopositive reaction for MDMA and MDA was observed in the white matter in all cortical regions and in neurones of the basal ganglia, the hypo-

Alterations of neurotransmitters and receptorsThe neurotoxic effects of amphetamines and methamphetamine on the dopaminergic system have been described in various animal species and in humans. These effects are characterized by desensitization of DA receptor function, marked reduction of DA transporters and of DA levels as well as other dopaminergic axonal markers [174 181]. Similar alterations have been observed in the serotonergic system [175]. However, the irreversibility of these changes has not been established [175]. Although these alterations have been attributed to neurodegeneration, direct evidence for the loss of nerve terminals and/or their corresponding substantia nigra cell bodies have not been provided unequivocally [175,177]. Nevertheless, based on animal studies, there is concern that the alterations in the dopaminergic system may predispose methamphetamine abusers to develop Parkinsonism as they age [175,182,183]. Because neuroimaging and necropsy studies of human methamphetamine abusers suggest changes in only some


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thalamus, the hippocampus and the cerebellar vermis, but relatively weak staining of neurones in the brainstem was seen [192]. In reports on human fatalities following MDMA consumption, detailed neuropathological examinations were mostly not performed [193196]. Cerebrovascular complications after ecstasy consumption have been described only occasionally [197203]. In the globus pallidus bilateral hyperintense lesions have been found [204,205]. On neuropathological examination necrosis of the globus pallidus, diffuse astrogliosis and spongiform changes of the white matter have been described [205]. Other neuropathological ndings in deaths after ecstasy abuse were mainly due to the complications of hyperthermia with disseminated intravascular coagulopathy and consisted of cerebral oedema, focal haemorrhages and nerve cell loss [196].

ations have been attributed to drug-induced respiratory failure and were therefore considered to be non-specic [84,220]. However, in most of these studies, there was no control group and systematic data on frequency or topography of the lesions are lacking. Subsequent systematic neuropathological studies of polydrug abusers revealed ischaemia-independent widespread neuronal loss, a reduction of GFAP-positive astrocytes, an axonal damage with concomitant microglia activation as well as reactive and degenerative vascular changes [23].

NeuronesThe neuronal loss has been ascribed to be due to a direct impairment of neurones by drugs of abuse and, indirectly, to drug-induced damage of astrocytes, axons and the cerebral vasculature [23]. In support of this nding is the observation in animal models that drugs of abuse can induce apoptotic neuronal cell death [69,175,221225]. In human studies drug-induced alterations of neurolament proteins [115,226,227], of neuronal TUNEL positivity [96] or of transcription factors, for example, cAMP response element-binding protein [112] and c-fos [20] is thought to be an alternative pathway for neuronal loss. In young opiate abusers an increase in the number and distribution of hyperphosphorylated tau-positive neurobrillary pretangles, fully formed tangles and neuritic threads has been reported [228]. This, together with reports of occasional ubiquitin-positive inclusions in neurones of drug abusers [96], indicates drug-related neurodegeneration. Whether these changes are potentially reversible is still unclear. Within the substantia nigra there was a decrease of the numerical density of the pigmented neurones, whereas the density of the non-pigmented neurones was unchanged [23]. The presence of eosinophilic ubiquitinated cytoplasmic inclusions, which did not resemble classic Lewy bodies, and which are negative for a-synuclein, indicates abnormal cytoplasmic protein sequestration [96]. To date it is not clear whether this nding represents a transient neuronal abnormality or commitment to an irreversible neurodegenerative pathway [96].

Alterations of neurotransmitters and receptorsIn the brains of laboratory animals, including nonhuman primates, exposure to MDMA has been associated with dopaminergic and especially serotonergic neurotoxicity [176,188191,206209]. There is strong evidence for neurodegeneration and axonal loss, although the exact mechanism is still unclear [189191,206209]. Current hypotheses include the formation of toxic MDMA metabolites with generation of free radicals as well as oxidative stress, excitotoxicity, apoptosis and mitochondrial dysfunction [176,209212]. Although in recent years, the question of ecstasyinduced neurotoxicity and possible functional sequelae has been addressed in several studies, the extent to which these animal and non-human primate data are applicable to humans and whether persistent neurotoxicity occurs in humans is still controversial [42,207209,213219]. To date, the most consistent ndings associate subtle cognitive, particularly memory, impairments with heavy ecstasy abuse [213,218,219].

Neuropathological studiesThe consequences of drugs of abuse on the cellular elements of the human brain have not been studied systematically. There are only few reports on histopathological alterations in the brains of human drug abusers describing oedema, vascular congestion, ischaemic nerve cell damage and neuronal loss [8385,96,220]. These alter-

White matterIn the white matter of polydrug abusers a widespread axonal damage has been demonstrated by using b-APP



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Figure 1. Immunohistochemistry demonstrating b-APP-immunopositive bundles and b-APP-immunopositive globular deposits in the pons of polydrug abusers, counterstained with haematoxylin, original magnication 100.

negative drug abusers and non-drug using controls there was no statistical difference between these groups in relation to astrocytes [231,234]. In the brains of polydrug abusers the numerical density of GFAP-positive astrocytes has been shown to be reduced [23]. This reduction of GFAP-positive astrocytes is believed to be due to the interference of drugs with the GFAP gene transcription, inducing an altered GFAP phosphorylation [235], as well as the generation of free radicals by induction of a cytochrome P450 isoform [236]. I2-imidazoline receptors are involved in the regulation of the GFAP expression [226]. In the frontal cortex of heroin deaths the density of I2-imidazoline receptors and the immunoreactivity of the related imidazoline receptor protein were decreased [237].

immunohistochemistry [23,229]. The alterations consisted of b-APP-immunopositive bundles and globular depositions (Figure 1), but they never showed the extensive pattern seen in traumatic brain injury [23,229]. Furthermore, there is a concomitant activation of microglia predominantly in the white matter and in most subcortical regions [23,83,220,229]. This upregulation of microglia has also been shown in drug abusers with and without pre-symptomatic HIV-1 infection [230,231]. Activated microglial cells are a source of proinammatory cytokines, which are linked to neuronal damage and loss [10]. The axonal injury suggests a toxicmetabolic drug effect, as there were no sufcient ndings for a secondary phenomenon in these cases, neither due to a generalized hypoxic-ischaemic condition, nor to a brain oedema and the concomitant activation of microglia is indicative of a long-standing progressive process [23,229]. These alterations might be the morphological correlate of the observed demyelination and hyperintense areas seen on magnetic resonance imaging.

Vascular changesIn AIDS patients concentric small-vessel wall thickening, perivascular space dilatation, pigment deposition, vessel wall mineralization and perivascular inammatory cell inltrates were seen in 50% of the former drug abusers [238]. Similar vascular alterations can be observed in HIV-1-negative polydrug abusers (Figure 2A) [23,96]. The presence of acute and chronic BBB breakdown in drug abusers, suggests that the brain parenchyma is exposed to unusual quantities of serum proteins, including immunoglobulins, as well as other blood-borne factors, including HIV [96]. It may further be the stimulus for the occasional perivascular lymphocytic aggregates that are seen in the brains of HIV-1-negative drug abusers (Figure 2B) [10]. Furthermore, reactive endothelial cell proliferation, degenerative hyalinotic thickening, marked endothelial swelling and endothelial cell hyperplasia are present in the brains of polydrug abusers (Figure 2C,D) [23]. In addition, a decrease of the collagen type IV content of the vascular basal lamina [239] and a disruption of the BBB tight junctions [10] have been observed. This non-inammatory vasculopathy has been interpreted as the morphological substrate of a disturbed BBB and might be the morphological substrate of the alterations seen on neuroimaging [23,240]. In conclusion, drugs of abuse initiate a cascade of interacting toxic, vascular and hypoxic factors that nally result in widespread disturbances within the complex network of CNS cell interactions (Figure 3). However, much work will need to be done to clarify the yet

AstrocytesAlthough astrocytes play an essential role, for example, in the maintenance of BBB, regulation of glutamatergic neurotransmission and neurotransmitter metabolism, little is known about alterations of these cells in human drug abusers [232,233]. In an older study widespread fragmentation and a numerical depletion of astrocytes in the white matter have been reported in the brains of drug deaths [85]. In HIV-1-positive opiate abusers, HIV-1-


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A

B

C

D

Figure 2. Photomicrographs illustrating the spectrum of cerebral vascular changes in polydrug abusers. (A) Small artery in occipital white matter showing concentric wall thickening. The surrounding perivascular space contains occasional macrophages and pigment deposition. H&E, original magnication 200. (B) Small vessel in the orbital white matter with perivascular lymphocytic aggregates. H&E, original magnication 200. (C) Endothelial proliferation in the dentate nucleus, H&E, original magnication 200. (D) Endothelial hyperplasia in the parietal white matter, H&E, original magnication 200.

unresolved questions of the disastrous role of drugs of abuse on the CNS.

AcknowledgementsThe help of Claire Delbridge in correcting the manuscript is highly appreciated. I thank Jeanne Bell, Institute of Neuropathology, University of Edinburgh for critical discussions and Serge Weis, Laboratory of Neuropathology, Neuropsychiatric Hospital Wagner-Jauregg, Linz, Austria for his long-standing support and friendship.

ReferencesFigure 3. The consequences of drugs of abuse on the cellular elements of the CNS.

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Received 26 July 2010 Accepted after revision 30 September 2010 Published online Article Accepted on 6 October 2010


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