Christian P. Müller

Drugs as instruments: a new framework for non-addictive psychoactive drug use.

Most people who are regular consumers of psychoactive drugs are not drug addicts, nor will they ever become addicts. In neurobiological theories, non-addictive drug consumption is acknowledged only as a necessary prerequisite for addiction, but not as a stable and widespread behavior in its own right. This target article proposes a new neurobiological framework theory for non-addictive psychoactive drug consumption, introducing the concept of drug instrumentalization. Psychoactive drugs are consumed for their effects on mental states. Humans are able to learn that mental states can be changed on purpose by drugs, in order to facilitate other, non-drug-related behaviors. We discuss specific instrumentalization goals and outline neurobiological mechanisms of how major classes of psychoactive drugs change mental states and serve non-drug-related behaviors. We argue that drug instrumentalization behavior may provide a functional adaptation to modern environments based on a historical selection for learning mechanisms that allow the dynamic modification of consummatory behavior. It is assumed that in order to effectively instrumentalize psychoactive drugs, the establishment of and retrieval from a drug memory is required. Here, we propose a new classification of different drug memory subtypes and discuss how they interact during drug instrumentalization learning and retrieval. Understanding the everyday utility and the learning mechanisms of non-addictive psychotropic drug use may help to prevent abuse and the transition to drug addiction in the future.

Brain membrane lipids in major depression and anxiety disorders

Major depression and anxiety disorders have high prevalence rates and are frequently comorbid. The neurobiological bases for these disorders are not fully understood, and available treatments are not always effective. Current models assume that dysfunctions in neuronal proteins and peptide activities are the primary causes of these disorders. Brain lipids determine the localization and function of proteins in the cell membrane and in doing so regulate synaptic throughput in neurons. Lipids may also leave the membrane as transmitters and relay signals from the membrane to intracellular compartments or to other cells. Here we review how membrane lipids, which play roles in the membranes function as a barrier and a signaling medium for classical transmitter signaling, contribute to depression and anxiety disorders and how this role may provide targets for lipid-based treatment approaches. Preclinical findings have suggested a crucial role for the membrane-forming n-3 polyunsaturated fatty acids, glycerolipids, glycerophospholipids, and sphingolipids in the induction of depression- and anxiety-related behaviors. These polyunsaturated fatty acids also offer new treatment options such as targeted dietary supplementation or pharmacological interference with lipid-regulating enzymes. While clinical trials support this view, effective lipid-based therapies may need more individualized approaches. Altogether, accumulating evidence suggests a crucial role for membrane lipids in the pathogenesis of depression and anxiety disorders; these lipids could be exploited for improved prevention and treatment. This article is part of a Special Issue entitled Brain Lipids.

Sex hormone activity in alcohol addiction: integrating organizational and activational effects.

There are well-known sex differences in the epidemiology and etiopathology of alcohol dependence. Male gender is a crucial risk factor for the onset of alcohol addiction. A directly modifying role of testosterone in alcohol addiction-related behavior is well established. Sex hormones exert both permanent (organizational) and transient (activational) effects on the human brain. The sensitive period for these effects lasts throughout life. In this article, we present a novel early sex hormone activity model of alcohol addiction. We propose that early exposure to sex hormones triggers structural (organizational) neuroadaptations. These neuroadaptations affect cellular and behavioral responses to adult sex hormones, sensitize the brains reward system to the reinforcing properties of alcohol and modulate alcohol addictive behavior later in life. This review outlines clinical findings related to the early sex hormone activity model of alcohol addiction (handedness, the second-to-fourth-finger length ratio, and the androgen receptor and aromatase) and includes clinical and preclinical literature regarding the activational effects of sex hormones in alcohol drinking behavior. Furthermore, we discuss the role of the hypothalamic-pituitary-adrenal and -gonadal axes and the opioid system in mediating the relationship between sex hormone activity and alcohol dependence. We conclude that a combination of exposure to sex hormones in utero and during early development contributes to the risk of alcohol addiction later in life. The early sex hormone activity model of alcohol addiction may prove to be a valuable tool in the development of preventive and therapeutic strategies.

Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users

BACKGROUNDnKratom (Mitragyna speciosa) preparations have been traditionally used in Southeast Asia for its medicinal properties. Lately, Kratom use has spread to Europe and the US, where abuse potential and health hazards increasingly emerge. This study is the first to measure systematically Kratom dependence, withdrawal symptoms, and drug craving in regular Kratom users in Malaysia.nnnMETHODSnA cross-sectional survey of 293 regular Kratom users was conducted in the community across three northern peninsular states of Malaysia. The Leeds Dependence Questionnaire, Marijuana Withdrawal Checklist, and Marijuana Craving Questionnaire-Short Form were used to measure Kratom dependence, withdrawal and craving.nnnRESULTSnMore than half of the regular users (>6 month of use) developed severe Kratom dependence problems, while 45% showed a moderate Kratom dependence. Physical withdrawal symptoms commonly experienced include muscle spasms and pain, sleeping difficulty, watery eyes/nose, hot flashes, fever, decreased appetite, and diarrhoea. Psychological withdrawal symptoms commonly reported were restlessness, tension, anger, sadness, and nervousness. The average amount of the psychoactive compound, mitragynine, in a single dose of a Kratom drink was 79mg, suggesting an average daily intake of 276.5mg. Regular users who consumed ≥3 glasses Kratom per day, had higher odds of developing severe Kratom dependence, withdrawal symptoms, and inability to control Kratom craving.nnnCONCLUSIONSnThe findings from this study show that regular Kratom use is associated with drug dependency, development of withdrawal symptoms, and craving. These symptoms become more severe with prolonged use and suggest a stronger control of the drug.

The ceramide system as a novel antidepressant target

Major depression is a systems disorder which impairs not only central nervous system aspects of mood and behavior but also peripheral organ systems. Current views on the pathogenesis and treatment of depression are predominantly based on proteins and transmitters and thus are difficult to reconcile central with peripheral pathomechanisms. Recent research showed that there is also a lipid-based pathway involved in the pathology of depression, which is activated by psychosocial stress, oxidative stress, or inflammation. Inducible dysfunction of the ceramide pathway, which is abundant in the brain as well as in peripheral organs, may account for mood disorder, behavioral symptoms, and further promote inflammation and oxidative stress in peripheral systems. As such, the lipid ceramide pathway may provide the missing link between brain dysfunction and somatic symptoms of depression. Pharmacological interventions that reduce ceramide abundance also show antidepressant action and may promise a better treatment of major depression.

To use or not to use: Expanding the view on non-addictive psychoactive drug consumption and its implications.

Proposing a change to the view on psychoactive drug use in non-addicts touches a sensitive issue because of its potential implications to addiction prevention, therapeutic practice, and drug policy. Commentators raised nine questions that ranged from clarifications, suggested extensions of the model to supporting data previously not regarded, to assumptions on the implications of the model. Here, we take up the suggestions of the commentators to expand the model to behavioral addictions, discuss additional instrumentalization goals, and review the evidence from laboratory animal studies on drug instrumentalization. We consider further the role of sociocultural factors and individual development in the establishment in drug instrumentalization and addiction. Finally, we clarify which implications we think this model may have. We conclude that drug instrumentalization theory can be further applied to other behaviors but will require a sensitive debate when used for drug and addiction policy that directly affects prevention and treatment.

A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression.

Major depressive disorder is a severe and chronic illness with high lifetime prevalence and a high incidence of suicide as the cause of death for patients with this diagnosis. Major depressive disorder is often treated with anti‐depressants. Although these drugs have been used for many years, their exact mode of action is still unknown. It has been suggested that many anti‐depressants act by increasing the concentrations of serotonergic transmitters in the synaptic space. However, recent studies have examined the effects of anti‐depressants on neurogenesis in the hippocampus, the restoration of hippocampal neuronal networks that may be affected by major depression, and the regulation of the hypothalamic–pituitary–adrenal axis by immature neurons in the hippocampus. Here, we present and discuss a novel hypothesis suggesting that these events are regulated by the concentrations of sphingolipids, in particular ceramide, in the hippocampus. These concepts suggest that the acid sphingomyelinase/ceramide system plays a central role in the pathogenesis of major depression and may be a novel target for anti‐depressants. Major depressive disorder is a severe and chronic illness with high lifetime prevalence and high incidence of suicide. Major depression is caused in part by an imbalance between factors that positively and negatively control neurogenesis. Anti‐depressants inhibit the acid sphingomyelinase/ceramide system and thereby reduce the sum of negative factors restoring neurogenesis, neuronal survival, and improved mood.

Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism

Significance Cognitive decline during aging impairs life quality and may lead to dementia. It is associated with a dysfunction of the brain acetylcholinergic system. Here we demonstrate that pharmacological stimulation of neurokinin3 receptors improves learning and memory in aged rats by enhancing acetylcholinergic function in the brain. In a human association study we show that a single-nucleotide polymorphism in the neurokinin3-receptor–coding gene TACR3 can predict learning and memory in elderly patients with cognitive impairments and their hippocampus volume. These findings suggest the neurokinin3 receptor as a potential biomarker and treatment target for cognitive enhancement in the elderly. Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R–coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism.

Use-Dependent Inhibition of Synaptic Transmission by the Secretion of Intravesicularly Accumulated Antipsychotic Drugs

Antipsychotic drugs are effective for the treatment of schizophrenia. However, the functional consequences and subcellular sites of their accumulation in nervous tissue have remained elusive. Here, we investigated the role of the weak-base antipsychotics haloperidol, chlorpromazine, clozapine, and risperidone in synaptic vesicle recycling. Using multiple live-cell microscopic approaches and electron microscopy of rat hippocampal neurons as well as in vivo microdialysis experiments in chronically treated rats, we demonstrate the accumulation of the antipsychotic drugs in synaptic vesicles and their release upon neuronal activity, leading to a significant increase in extracellular drug concentrations. The secreted drugs exerted an autoinhibitory effect on vesicular exocytosis, which was promoted by the inhibition of voltage-gated sodium channels and depended on the stimulation intensity. Taken together, these results indicate that accumulated antipsychotic drugs recycle with synaptic vesicles and have a use-dependent, autoinhibitory effect on synaptic transmission.

Adhesion molecule L1 binds to amyloid beta and reduces Alzheimer's disease pathology in mice

Alzheimers disease (AD) is a devastating neurodegenerative disorder and the most common cause of elderly dementia. In an effort to contribute to the potential of molecular approaches to reduce degenerative processes we have tested the possibility that the neural adhesion molecule L1 ameliorates some characteristic cellular and molecular parameters associated with the disease in a mouse model of AD. Three-month-old mice overexpressing mutated forms of amyloid precursor protein and presenilin-1 under the control of a neuron-specific promoter received an injection of adeno-associated virus encoding the neuronal isoform of full-length L1 (AAV-L1) or, as negative control, green fluorescent protein (AAV-GFP) into the hippocampus and occipital cortex. Four months after virus injection, the mice were analyzed for histological and biochemical parameters of AD. AAV-L1 injection decreased the Aβ plaque load, levels of Aβ42, Aβ42/40 ratio and astrogliosis compared with AAV-GFP controls. AAV-L1 injected mice also had increased densities of inhibitory synaptic terminals on pyramidal cells in the hippocampus when compared with AAV-GFP controls. Numbers of microglial cells/macrophages were similar in both groups, but numbers of microglial cells/macrophages per plaque were increased in AAV-L1 injected mice. To probe for a molecular mechanism that may underlie these effects, we analyzed whether L1 would directly and specifically interact with Aβ. In a label-free binding assay, concentration dependent binding of the extracellular domain of L1, but not of the close homolog of L1 to Aβ40 and Aβ42 was seen, with the fibronectin type III homologous repeats 1-3 of L1 mediating this effect. Aggregation of Aβ42 in vitro was reduced in the presence of the extracellular domain of L1. The combined observations indicate that L1, when overexpressed in neurons and glia, reduces several histopathological hallmarks of AD in mice, possibly by reduction of Aβ aggregation. L1 thus appears to be a candidate molecule to ameliorate the pathology of AD, when applied in therapeutically viable treatment schemes.