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Official websites use. Share sensitive information only on official, secure websites. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author s and source are credited. This may be a factor in frequent criminal justice referrals and lengthy treatment required by METH users. MAP has largely been studied in Asian populations and risk factors have varied across studies. Duration, frequency and amount of use as well as sexual abuse, family history, other substance use, and co-occurring personality and mood disorders are risk factors for MAP. Seven candidate genes have been identified that may be associated with MAP. Six of these genes are also associated with susceptibility, symptoms, or treatment of schizophrenia and most are linked to glutamatergic neurotransmission. Animal studies of pre-pulse inhibition, attenuation of social interaction, and stereotypy and alterations in locomotion are used to study MAP in rodents. Employing various models, rodent studies have identified neuroanatomical and neurochemical changes associated with METH use. Throughout this review, we identify key gaps in our understanding of MAP and suggest potential directions for future research. Keywords: Candidate genes, Drug addiction, Methamphetamine, Psychotic symptoms, Schizophrenia, Substance use disorder. While this decrease from 6. For example, rural persons are more likely to use the drug than persons in either small or large metropolitan areas; and a recent analysis of the National Survey on Drug Use and Health noted that METH use increased as the setting became more rural Lambert et al. Of concern, young adults in rural areas were nearly twice as likely as their urban counterparts 2. Significantly, U. While amphetamines such as METH can precipitate and exacerbate psychotic symptoms in persons with schizophrenia Batki and Harris , it has long been recognized that such drug use can produce psychotic symptoms even in persons with no history of a primary psychotic disorder Chen et al. With these issues in mind, the goals of this review are to describe the risk factors, frequency, symptoms, and clinical implications of METH-associated psychosis MAP , discuss candidate genes with significant associations, and review preclinical animal research that aims to simulate an understanding of MAP. Within each of these areas, we will discuss gaps in our current knowledge and potential directions for future research. METH, cocaine, cannabis, alcohol, hallucinogens, sedatives, and heroin have all been implicated in substance-induced psychosis Caton et al. Historical features such as psychotic symptoms presenting before onset of substantial substance use or psychotic symptoms only occurring in the context of substance use are useful in establishing a diagnosis. However, in many clinical settings the history is less clear and discriminating between psychoses that are secondary to substance use such as METH and those that are primary psychotic illnesses in a substance-using individual can be diagnostically challenging. Additionally, persons with substance-induced psychosis had lower Positive and Negative Syndrome Scale PANSS scores, greater awareness of psychotic symptoms and were more likely to have suicidal ideation Caton et al. While these studies are useful in characterizing substance use-related psychosis, as will be discussed later in relation to METH, utilizing duration of psychotic symptoms as a key determinant in distinguishing primary psychosis from substance-induced psychosis may not be valid in all clinical settings. MAP has been most consistently described in Japanese populations typically associated with longstanding METH use and characterized as resembling paranoid schizophrenia. Nevertheless, a subset of METH users develops frank psychotic symptoms across a range from mild paranoia to hallucinations or unusual thought content. In , Chen characterized three groups of Taiwanese METH users who were either hospitalized or in a detention center: those with no history of any psychotic symptoms, those with brief psychosis less than 1 month after last METH use , and those with prolonged psychosis psychosis which persisted more than 1 month after last METH use. There was no difference in duration of METH use between the psychosis and non-psychosis group. In Japanese and Australian studies, method of METH administration injection versus smoking did not affect frequency of psychosis Matsumoto et al. In another U. However, those with frequent psychosis reported greater childhood attention deficit disorder ADHD and family history of psychiatric illness. In a small U. These studies did not identify factors which were consistently associated with MAP. However, the variability in the populations studied e. While METH psychosis has been discussed in the medical literature since the s, previous studies examining the frequency of MAP have employed varying definitions of the disorder. Additionally, not all of the studies used standardized instruments to measure psychotic symptoms or described the time period e. Further, many of these studies written in Japanese are not accessible to all investigators. In a comparison of non-treatment seeking cocaine- and METH-dependent men and women, METH-dependent individuals were more likely to report psychotic symptoms than cocaine-dependent men and women Mahoney et al. While it has been difficult to identify factors consistently associated with MAP or to precisely determine the frequency of MAP, the characterization of MAP symptoms across populations has been quite consistent. Multiple studies in Japanese Akiyama , Taiwanese Chen et al. Other frequently reported symptoms were delusions of reference, visual hallucinations, and thought broadcasting Chen et al. Most episodes of substance-induced and MAP are of brief duration and resolve as substance levels diminish. However, Japanese investigators have reported that while MAP may be transient with recovery within 1 month of last METH use, METH psychosis may also be prolonged, persisting for longer than 6 months Ujike and Sato , and may persist despite drug abstinence Akiyama Western investigators have been more hesitant to attribute persistent psychotic symptoms solely to substance use and this is reflected in the diagnostic lexicon of the Diagnostic and Statistical Manual-IV which defines substance-induced psychosis as persisting for 1 month or less after last substance use APA In both studies, study participants were abstinent and had no history of schizophrenia or prior psychoses. Additionally, a previous neurological disorder head injury, ADHD, prematurity, learning disability may increase the risk of treatment-resistant psychosis in METH users Fujii In multiple prior studies, the presence of both psychiatric illness and substance use worsened SUD treatment outcome Rounsaville et al. In a study of METH dependent adults, individuals with any history of psychotic disorder at the 3-year follow-up were more than twice as likely to have been hospitalized in the previous 12 months, had more total hospitalizations, had greater severity of their psychiatric symptoms, and were more likely to have attempted suicide than participants with no history of psychosis. This study, however, did not distinguish between primary and substance-induced psychosis and those who required hospitalization were not eligible for study enrollment Glasner-Edwards et al. Only one randomized controlled trial evaluated anti-psychotics in persons with amphetamine-related psychosis. In this 4-week study, there was no significant difference in clinical efficacy between olanzapine and haloperidol Leelahanaj et al. It is unknown if findings from these large studies are generalizable to other populations such as those in the U. A single large study of U. However, there are no studies of factors such as perceived stress or cultural stress which have been identified in other populations as being factors in the development of psychoses. Similarly, there are no studies of any kind assessing protective factors for MAP, which may mitigate against risk factors. Of note, none of the above studies examined sleep deprivation as a factor in the genesis of MAP, a factor that is well-described as a stressor which can result in psychosis. Additionally, there are no studies examining what role preexisting conditions, socio-environmental stressors or protective factors play in the severity, persistence or relapse of MAP. Lastly, little is known about the prevention of persistent and recurrent MAP. MAP is likely a complex genetic disease in which environmental factors interact with multiple polymorphic genes to influence susceptibility. The candidate genes listed in Table 2 were selected based on a wide range of evidence, such as biological function, differential expression in disease, involvement in schizophrenia, which is considered pharmacologically similar to MAP, and findings from animal models. In these studies, allele frequencies were compared in unaffected and affected individuals. Unaffected individuals were generally healthy individuals without a history of psychosis-related disorders. Of note, several studies consisted of heterogeneous populations that included individuals with and without psychosis. These populations are annotated as such in Table 2. Another phenotype often considered in these studies was the clinical course of MAP. Accordingly, the individuals were categorized based on the duration of the psychotic state after METH discontinuation. Transient psychosis was defined as symptoms that improved within 1 month of METH discontinuation and the start of treatment with neuroleptics; whereas, the prolonged type was defined as psychotic symptoms continuing for more than 1 month after METH discontinuation and the treatment of neuroleptics. The hypothesis-driven studies investigating putative candidate genes and their association with psychosis among METH-dependent individuals are summarized in Table 2. Recognizing the high probability of false-positive associations due to multiple comparisons, we chose to focus on candidate genes with significant associations, i. DAOA is the gene encoding the d-amino acid oxidase activator. DAOA is expressed in multiple tissues including the amygdala, caudate nucleus, spinal cord and testes Chumakov et al. D-serine levels are low in schizophrenic patients and administration of D-serine has been shown to reduce some of the symptoms of this disease Kantrowitz et al. This provides a potential link between DAOA and the glutamate hypo-function hypothesis of schizophrenia, which integrates environmental influences and causative genes, is based on clinical and neuropathological evidence of the hypo-function of glutamatergic signaling via NMDA receptors. The DAOA gene is located on chromosome 13q and has been found to be a susceptibility locus for schizophrenia Badner and Gershon , and many studies have found an association between genetic variants in DAOA and schizophrenia Chumakov et al. In a case-controlled study, Kotaka et al. This polymorphism was previously shown to be associated with schizophrenia; however, its functionality is unknown. DTNBP1 encodes dystrobrevin-binding protein 1 also referred to as dysbindin. This ubiquitously expressed, coiled-coil-containing protein is a subunit of the biogenesis of lysosome-related organelles complex 1 BLOC-1 , which regulates trafficking to lysosome-related organelles Li et al. In muscle, the DPC is required for the maintenance of muscle integrity and normal muscle function. In the brain, dysbindin is most prevalent in axons, particularly those with large synaptic terminals such as the mossy fiber synaptic terminals in the cerebellum and hippocampus Benson et al. In a case controlled study, Kishimoto et al. Consistent with this, reduced levels of dysbindin expression have been associated with the pathogenesis of schizophrenia Talbot et al. In schizophrenic patients, dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampus which is inversely correlated with increased vesicular glutamate transporter Talbot et al. As evidence is mounting that glutamate hypo-function may be related to the etiology of schizophrenia Konradi and Heckers , it is postulated that DTNBP1 variants may contribute to MAP through pathways involving glutamatergic neurotransmission. Despite the many genetic studies of this gene, the link between functionality of these polymorphisms and dysbindin expression has not been investigated. Frizzled proteins are cell surface receptors for secreted Wnt proteins Wang et al. Both frizzled and Wnt proteins are thought to be important in central nervous system CNS development. FZD3, the human Frizzled-3 gene, is widely expressed in the developing nervous system and is involved in axonal growth and guidance Wang et al. Wnt signaling plays a role in axonal remodeling and synaptic differentiation in the cerebellum Cadet and Krasnova ; Lucas and Salinas and abnormal Wnt signaling has been linked to schizophrenia Cotter et al. FZD3 maps to chromosome 8p21 and consists of eight exons. The 8p region has been identified as a susceptibility locus for schizophrenia in several studies Blouin et al. However, genetic studies with the Frizzled-3 gene and schizophrenia have been contradictory, with both positive and negative associations among Han Chinese Yang et al. GRM2 is another gene involved in glutamatergic neurotransmission and found to be significantly associated with MAP Tsunoka et al. GRM2 is located on chromosome 3p in a region linked to schizophrenia in several studies Badner and Gershon ; Pulver et al. Although another group II metabotropic glutamate receptor, glutamate receptor 3 mGlu3 , has been implicated in etiological, pathophysiological and pharmacotherapeutic aspects of schizophrenia Harrison et al. Through serotonin 5-HT binding, this receptor mediates inhibitory neurotransmission. The serotonin system has been shown to be important in the neural processing of anxiety and the neurobiological control of learning and memory. Similar to the glutamatergic pathway, altered serotonergic neurotransmission is speculated to contribute to schizophrenia susceptibility. Evidence suggests that METH, which acts as a substrate for the 5-HT transporter, elevates extracellular 5-HT levels by both promoting the efflux via transporter-mediated exchange and by increasing cytoplasmic levels by disrupting storage of 5-HT in vesicles Cadet and Krasnova ; Rothman and Baumann Although studies have explored whether there is an association between several of the genes involved in 5-HT regulation and MAP, only the rs polymorphism in the 5-HT1A receptor was significantly associated using an alpha level of 0. Polymorphisms in the 5-HT1A receptor have been associated with schizophrenia in several studies Huang et al. Prokineticins and their receptors are involved in a wide range of biological functions in multiple organ systems. In the CNS, prokineticin 2 modulates neurogenesis, circadian rhythms, and migration of the subventricular zone-derived neuronal progenitors Cheng et al. The involvement of PK-R2 in circadian rhythm raises the question of whether this gene may be associated with mood disorders, a phenotype often observed in patients with drug addiction. Several animal studies have shown that METH increases expression of circadian genes in the brain Iijima et al. An association between PROKR2 gene variants and major depressive disorder and bipolar disorder was reported in a Japanese population Kishi et al. It is currently believed that termination of the different synaptic actions of glycine is produced by rapid re-uptake through two sodium- and chloride-coupled transporters, GLYT1 located in the plasma membrane of glial cells and GLYT2 located in pre-synaptic terminals. GLYT1 regulates both glycinergic and glutamatergic neurotransmission by controlling the reuptake of glycine at synapses. Competitive antagonists of NMDA receptors produce a psychotic state in healthy subjects and exacerbate symptoms in schizophrenics. SLC6A9 has emerged as a key novel target for the treatment of schizophrenia. Morita et al. In summary, there is reasonably strong evidence that genetic variation in neurotransmitter systems and in neural development or growth is associated with risk for MAP. Potential epistatic i. Polymorphism in a key gene in serotonin system regulation and signaling HTR1A is also associated with risk for MAP, which suggests that other 5-HT system genes may also be good candidates. These studies reviewed in relation to MAP have examined candidate genes selected based on current concepts of neurobiology. Priorities for future genetic research on MAP include: replicate genetic associations within and across ethnically diverse populations; adjust for multiple comparisons to minimize false-positive associations; utilize linkage disequilibrium and tagSNP information to capture the polymorphic structure of candidate genes; increase statistical power by using larger population cohorts to minimize false-negative associations; improve phenotyping of MAP by use of a continuum versus a categorical classification and account for trajectory of cessation, treatment response and relapse; identification of allele-specific in vivo activity in humans and non-human animals. The neuropsychological events noted show deficits in attention, working memory, and decision making in METH addicts. Bioimaging and histopathologic evaluations show that the clinical findings parallel composite damage to dopamine and serotonin axons, loss of gray matter with linked hypertrophy of the white matter and microgliosis in different brain areas Kuhn et al. Such neurotoxicity and inevitable neurodegeneration parallels the presence of oxidative stress, excitotoxicity, neuroinflammation, mitochondrial dysfunction, decreased antioxidants and stress patterns Cadet and Krasnova These effects a host of intracellular organelle functions and suggests that a range of therapeutic strategies can be developed that would slow or reverse adverse neuronal events Kosloski et al. In this section, we review the published preclinical animal research that aims to simulate or directly understand some facet of METH-related psychosis. We will not attempt to survey the vast literature on neurobiologic and neurotoxic effects of METH exposure as it is beyond the scope and the focus of the present paper. The interested reader is referred to the following reviews on these topics Cadet and Krasnova ; Fleckenstein et al. This section of the review, however, will have an eye toward the validity of the animal models that have been used to date, as well as identifying key gaps in the methods and research that need to be filled. Given the paucity of animal research directly focused on questions related to MAP, an important goal of this section is to make recommendations for future research that involves the development of translationally-relevant models that are reliable i. Clearly, establishing animal models that are predictive of the human phenomenon of interest MAP in this case will not happen without experimental situations and associated manipulations that are reproducible and consistent within and across laboratories. We agree with writers that espouse the best way to this broad form of predictive validity and to strong translational animal models is to work toward improving construct and etiological validity Geyer and Markou ; Markou et al. For construct validity, attention to continually improving the match between what is measured at the behavioral psychological and neural levels in the animal models of MAP with what is believed to be the behavioral and neural processes underlying this psychosis in humans Markou et al. As an example, if the current state of knowledge suggests that individuals with MAP have impaired sensorimotor gating that leads to sensory flooding and cognitive fragmentation, then some insight regarding the human condition may come from a better understanding of a similar attentional process in animal models. In this example, pre-pulse inhibition PPI may be of particular import. Pre-pulse inhibition refers to the decrease in startle response evoked by an auditory stimulus that is preceded by a pre-pulse stimulus usually the startle stimulus at lower intensity and shorter duration. The strategy of searching for and establishing construct validity likely means that no single animal model will be sufficient to capture all processes relevant to the disorder of interest in humans. Also, this strategy is inherently translational. Working toward etiologic validity further encourages the communication and sharing of ideas, theories, and methods necessary for successful translational research Markou et al. Etiologic validity refers to the matching of environmental and physiological precursors presumably responsible for the onset of the disorder. There is ongoing debate as to the extent that METH induces psychotic symptoms versus exacerbating pre-existing symptoms see earlier. This is one of many unique instances in which animal models could serve to inform this important clinical issue. For instance, will rats intravenously self-administer enough METH to alter those behavioral and neural processes altered in humans diagnosed with MAP? Are the predisposing factors, whether environmental, neural, or genetic, thought to be relevant in human MAP contributing to such effects in the animal models? Prior research has demonstrated that under some conditions rats self-administering METH will show deficits in object recognition memory Reichel et al. Unfortunately, this research is quite limited within the context of greater understanding of MAP in humans. Given that METH psychosis is associated with severe behavioral and neuropsychiatric complications see earlier , there is a pressing need to definitively and precisely identify the behavioral and neurobiological mechanisms underlying the development of METH psychosis. As a result of this identification, behavioral interventions and psychopharmacological treatment strategies can then be developed. Despite the limited work, animal studies have consistently shown that many psychological processes underlying clinical features of METH psychosis can be reproduced in a variety of animal species, including mice, rats, guinea pigs, cats and non-human primates e. Like METH addicts, animals that are chronically treated with a low non-toxic dose of METH gradually develop psychotic-like symptoms, such as a decrease in motor activity, an increase in stereotypies, decreased interest to external stimuli and surroundings, and decreased social functioning Kuczenski et al. Also, some of the changed behavioral patterns e. Furthermore, concurrent antipsychotic drug treatment can prevent recurrence triggered by METH use Misra et al. These results strongly suggests that animal models of METH psychosis have high face e. Most of this work has been carried out by Japanese researchers since the early s beginning during the decade immediately after World War II when METH abuse occurred in epidemic proportions in Japan Ujike and Sato Japanese psychiatrists had observed an increased number of cases of MAP in chronic METH users and began to investigate the behavioral characteristics of the psychosis and associated biochemical mechanisms in animals. Nonhuman primate models are thought to be better than other species models in capturing complex and fine-grained behavioral abnormalities resembling human MAP, especially aspects of perceptual aberrations, social interaction, and interpersonal relationship. This is because monkeys, especially Japanese monkeys Macaca fuscata are well known to form a stable and intricate hierarchical society in which each member follows a certain rank order appropriate in interacting with others. An early study provided a vivid description of acute and chronic effects of METH treatment on a group of Japanese monkeys Machiyama They gave monkeys intramuscular METH injection at 1. At the same time, physiological saline was given by intramuscular injection to the other animals that served as controls. Upon acute treatment, some monkeys showed motor excitation, whereas other showed motor suppression. They identified that this marked individual difference was due to the different behavioral traits of monkeys in the group. Active monkeys that showed enhanced repetitive motor activity to acute METH were those aggressive individuals occupying higher ranks while non-active monkeys, at the bottom in the ranking order, demonstrated a decrease in motor activity to acute METH treatment. Over the course of repeated drug treatment, some monkeys developed behavioral abnormalities in a variety of psychological domains. In the sensorimotor domain, after about 1 month treatment, some monkeys displayed a stereotypical body-fingering behavior which entailed continuous fingering and investigating certain parts of the body, such as the wrist, thigh, abdomen, penis, or scrotum Machiyama In the perception domain, after about 2 months of repeated treatment, some monkey displayed hallucination-like perceptual distortions e. In the social behavior domain, some monkeys gradually lost interest in social interaction e. There were also marked individual differences. Monkeys, with middle and high ranks that responded actively to acute METH injection, demonstrated the most severe behavioral abnormalities in response to chronic METH treatment. Monkeys with lower ranks fared better and only exhibited mild changes. Two high ranked monkeys even died before the entire experiment was completed. After the termination of daily injections, some behavioral abnormalities disappeared, while others persisted for an extended period. In general, perceptual aberrations e. Also, some monkeys who exhibited persistent behavioral changes that were easily identifiable by uninformed observers recovered better than others. Most interestingly, the psychotic behaviors of chronically treated monkeys could be re-triggered by a saline injection or a METH injection, mimicking clinical phenomena of stress and drug priming-induced relapse of METH psychosis. One of the issues with these observational studies is the lack of formal assessments of psychological functions. Therefore, it is unclear what psychological function s e. The second issue is that the experimenter-controlled METH administration regimen did not mimic human METH use via self-administration and the constant dosing regimen used in the monkey studies also did not reflect the typical pattern of human METH use. Most METH abusers start with very low doses of the drug and have had a long history of progressively escalating their doses. Thus, human METH psychosis often appears during the course of escalating dosage of drug administration i. This aspect of METH use pattern was not mimicked in these early studies. There are several issues that may hinder the effort to delineate the neurobiological underpinnings of METH psychosis. The first is the lack of validated rodent behavioral models of METH psychosis. Unlike non-human primate models, which provide richer behavioral repertoires sensitive to the psychotomimetic effect of METH, most rodent studies focus on motor activity and stereotypy. One issue with psychomotor sensitization and stereotypy as behavioral indices of METH psychosis is that they do not seem to capture the emotional, cognitive, and perceptual disturbances that characterize human METH psychosis disorders. Other behavioral abnormalities induced by repeated METH treatment, such as disruption of PPI of acoustic startle response, may provide a better model Braff et al. The following section discusses this rodent research in more detail. The following narrative will provide an overview of this research and highlight some key findings that indicate their possible utility for understanding aspects of MAP in humans. Rodents will startle to a sudden loud sound such as a 40 ms, dB white noise. Under typical conditions, this startle reaction is reduced if this startle stimulus is preceded by a shorter and less intense pre-pulse stimulus e. This inhibition of the startle is thought to measure sensorimotor gating Braff and Geyer Individuals diagnosed with schizophrenia show deficits in PPI; an effect that can be simulated by acute and repeated treatment with METH. However, in that same report by Arai et al. More recently, Hadamitzky et al. This research reflects an important advance in developing a translational model to study aspects of MAP. That is, like humans, this alteration in sensorimotor gating was self-induced by the rat. Behavioral pharmacology research investigating the mechanism of the METH-induced deficits in PPI have focused either on the effects of established antipsychotic medications or on the effects of ligands thought to act on receptor processes involved in aspects of the psychosis. Along the former lines, the typical antipsychotic medication haloperidol has been shown to alleviate PPI deficits induced by acute treatment with METH Maehara et al. In this same report, the investigators did not find an effect of the nicotinic agonist nicotine. This result contrasts with Mizoguchi et al. The most notable difference in protocol between these discrepant reports was that Maehara et al. Regardless, the comorbidity between METH and tobacco use, as well as schizophrenia and tobacco use, makes this an important area for future research. When a rat is paired with a conspecific, they show a variety of species-specific behaviors. These behaviors include sniffing, grooming, crawling over or under, and nosing Barnett Some researchers have suggested that alternations in social interaction resulting from METH exposure may be a useful model to study the paranoid and social anxiety symptoms of humans with MAP Clemens et al. Previous research has shown that acute METH treatment can alter social interaction. For example, Shinba et al. METH increased general activity in the chamber across the entire 7. Acute high dose METH increased activity and head-weaving. Albeit interesting, the most notable finding from the perspective of this report is that following 4 weeks of abstinence from METH these rats had significantly lower social interaction score than controls. In fact, the alterations in social interaction were seen after 7 weeks of abstinence. As the acute dose of METH increases, its behavioral effect in rats and mice generally shifts from inducing hyperactivity to inducing stereotypy. These effects of METH can become exaggerated i. Further, a handful of papers published in the s showed that spontaneous wheel running, activity, and reactivity to external stimuli are blunted long after e. The presentation of such behavioral alterations that sensitize with repeated treatment and persist with abstinence has been considered a model for some of the symptoms of psychosis Machiyama ; Takigawa et al. Converging support for this notion comes from the overlap in the neurobiological processes underlying these motor effects of METH and that of psychosis in humans, as well as behavioral pharmacologic work indicating the effectiveness of antipsychotic medications. For instance, METH-induced locomotor stimulation is blocked by clozapine, haloperidol, and chlorpromazine Maehara et al. Additional pharmacologic research has implicated the serotonergic, dopaminergic, and muscarinic systems in these effects Balsara et al. For instance, Ujike et al. Notably, a recent study by Kuczenski et al. Their findings confirm and extend earlier research describing the development of stereotypy, as well as disruption of sleep, in what seems to be a more translationally relevant model of MAP. Whether this is the case or not will need to await further research. However, one limitation of this model that will need to be overcome, if this model is to be more widely adopted, is the high mortality rate of the rats in the escalating METH exposure phase. This approach makes sense given that METH is known to cause both acute and chronic neurotoxic changes in dopaminergic and serotonergic neurons in animals and humans and that psychosis in schizophrenia is thought to result from hyperactivity of the mesolimbic dopaminergic system. Some structural changes enlarged lateral ventricle, enlarged basal ganglia, reduced hippocampal volume , that have been reported in patients with schizophrenia, have also been found in people who were chronic METH users, strongly indicating that these structural changes and their underlying mechanisms may be responsible for METH psychosis Chang et al. Human postmortem and imaging studies have consistently shown that chronic METH use causes a reduction of dopamine transporter DAT density in the various dopaminergic systems, including the dorsal striatum, nucleus accumbens, and prefrontal cortex. However, this pronounced effect persists long after cessation of drug administration Sekine et al. The striatal dopamine D2 density is generally not affected. However, lower level of D2 receptor availability in the orbitofrontal cortex has been reported Volkow et al. Furthermore, there seem to be a significant negative correlation between the clinical severity of psychotic symptoms and DAT density, and a positive correlation between the duration of METH use and the severity of psychotic symptoms, suggesting that chronic METH use causes the reduction in DAT density, which may directly contribute to the development of METH psychosis Iyo et al. Volkow et al. They found that there was a negative correlation between the DAT reductions and the impaired motor performance, and a positive correlation between the levels of DAT reductions and verbal memory performance: the lower the dopamine DA transporter level, the slower the motor responses, and the greater worsening of memory performance. It is possible that other permanent neuroadaptions caused by DAT reduction also play a role. In contrast to limited research on human subjects, there are many studies that have examined METH-induced brain changes in rodents. To ensure that the neurochemical changes discussed here are potentially relevant to the underpinnings of MAP, in this section, we will narrow our discussion to research that has demonstrated behavioral sensitization following human patterns of METH abuse e. Behavioral sensitization refers to a progressive increase in motor and stereotypical responses to repeated drug treatment Martinez et al. Thus, the acute effect of METH use is not covered here. The rationale behind this approach is that endogenous sensitized dopaminergic function e. Thus, studies utilizing this approach will be emphasized. Chronic treatment of METH causes an increase of dopaminergic neurotransmission in the striatum. For example, Nishikawa et al. Kazahaya et al. Segal and Kuczenski found that multiple short-interval METH injections four daily injections at 2-hr intervals at 4. These findings, coupled with the findings that repeated METH treatment directly sensitizes DA receptors in the nucleus accumbens and ventral tegmental area Amano et al. As discussed earlier, pharmacologic evidence is consistent with this finding. Ujike et al. Chronic METH users often take the drug continuously, and the plasma drug concentrations are elevated and maintained throughout a 2—3 day binge. Kuczenski et al. Using this drug administration procedure, they still found a prolonged elevation in caudate extracellular DA and behavioral sensitization. Rats receiving single daily injections of METH, followed by multiple runs four daily injections at 2-hr intervals showed a decrease in serotonin response in the striatum during runs Segal and Kuczenski Other neurotransmitters implicated in METH sensitization include substance P and sigma receptors, as evidenced by the findings that repeated METH treatment decreased the substance P receptor binding Ujike et al. There is great need for increased research to further understand factors related to MAP and how this psychosis affects METH use, dependence, and treatment outcomes. The current state of knowledge suggests that these factors, and their interaction, will span genetic to socioenvironmental influences. As such, research directed at the better understanding of MAP, by necessity, will need to be translational. This review identifies some gaps in our understanding and outlined potential future avenues of research that could help realize this goal of better treatment efficacy for METH-dependent individuals with MAP. For instance, there are no studies assessing protective factors for MAP, which may mitigate against risk factors for psychosis. Along these lines, there is a solid foundation of genetics work that has identified several candidate genes that may play a role in MAP development. However, larger studies of more ethnically diverse populations that likely have unique risk and protective factors are needed. Finally, advances in the development of animal models that show etiological and predictive validity are needed for a more complete understanding of the causes of MAP. These models would likely assist in drug development and behavioral interventions. As a library, NLM provides access to scientific literature. J Neuroimmune Pharmacol. Find articles by Kathleen M Grant. Find articles by Tricia D LeVan. Find articles by Sandra M Wells. Find articles by Ming Li. Find articles by Scott F Stoltenberg. Find articles by Howard E Gendelman. Find articles by Gustavo Carlo. Find articles by Rick A Bevins. Received May 6; Accepted Jun 21; Issue date Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Shoptaw et al. McKetin et al. Yen and Chong Grant et al. Glasner-Edwards et al. Wallace et al. Leamon et al. Ikeda et al. Itoh et al. Morio et al. Li et al. Suzuki et al. Kotaka et al. Liu et al. Chen et al. Kishimoto et al. Kishi et al. Nishiyama et al. Tsunoka et al. Koizumi et al. Hashimoto et al. Ezaki et al. Nakamura et al. Okahisa et al. Ohgake et al. Okochi et al. Kobayashi et al. Ide et al. Iwata et al. Matsuzawa et al. Kanahara et al. Kinoshita et al. Inada et al. Aoyama et al. Yoshikawa et al.

Lithuanian Customs busted a huge shipment of cocaine

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Lithuanian officers had doubts about the character and the route of the freight when the alleged casting moulds for plastic lids and covers came from Ecuador, in April, with a stopover in Colombia and the German port of Hamburg. Cargo received from the two South American countries contained a number of drug shipments in past few years. However, a Vilnius-registered company, headed by a Russian citizen with a residence permit, constantly raised legal obstacles in order to avoid checking. Only when officers managed to prove that the check would not damage the equipment, a check had been conducted and inside the casting moulds and cooling chambers tight packages of cocaine covered in silicone were discovered. A total weight of the busted cocaine is over kg, its approximate value on the black market is nearly 49 million euros. Lithuanian prosecutors believe the cocaine was intended for European Union countries. They said that there was a threat if we would try to drill mechanically in order to check. They said we would damage equipment. Later they wrote letters to Customs that they totally reject any drilling, because equipment would be damaged. Sound bite Lithuanian. But again… makes a pause most likely these drugs would have stayed within the EU. To send it to Russia through Lithuania is not very handy, when there are states with much easier transit. Non-EU states without any of our bureaucratic and other obstacles, and it gets into Russia by much easier ways. So by looking from this analytical perspective, the most likely is that the drugs, at least most of them, would have stayed within the EU. News 1 h ago. News 3 h ago. News 4 h ago. News 5 h ago. News 7 h ago. News 8 h ago. News 9 h ago. News 11 h ago. News 1 d ago. News 2 d ago. News 3 d ago. News Lithuanian Customs busted a huge shipment of cocaine. Algirdas Acus Newest, Most read Newest Most read.

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