Synaptic Dopamine Levels Research Articles

Long-life triclosan exposure induces ADHD-like behavior in rats via prefrontal cortex dopaminergic deficiency

In recent years, exposure to triclosan (TCS) has been linked to an increase in psychiatric disorders. Nonetheless, the precise mechanisms of this occurrence remain elusive. Therefore, this study developed a long-life TCS-exposed rat model, an SH-SY5Y cell model, and an atomoxetine hydrochloride (ATX) treatment model to explore and validate the neurobehavioral mechanisms of TCS from multiple perspectives. In the long-life TCS-exposed model, pregnant rats received either 0 mg/kg (control) or 50 mg/kg TCS by oral gavage throughout pregnancy, lactation, and weaning of their offspring (up to 8 weeks old). In the ATX treatment model, weanling rats received daily injections of either 0 mg/kg (control) or 3 mg/kg ATX via intraperitoneal injection until they reached 8 weeks old. Unlike the TCS model, ATX exposure only occurred after the pups were weaned. The results indicated that long-life TCS exposure led to attention-deficit hyperactivity disorder (ADHD)-like behaviors in male offspring rats accompanied by dopamine-related mRNA and protein expression imbalances in the prefrontal cortex (PFC). Moreover, in vitro experiments also confirmed these findings. Mechanistically, TCS reduced dopamine (DA) synthesis, release, and transmission, and increased reuptake in PFC, thereby reducing synaptic gap DA levels and causing dopaminergic deficits. Additional experiments revealed that increased DA concentration in PFC by ATX effectively alleviated TCS-induced ADHD-like behavior in male offspring rats. These findings suggest that long-life TCS exposure causes ADHD-like behavior in male offspring rats through dopaminergic deficits. Furthermore, ATX treatment not only reduce symptoms in the rats, but also reveals valuable insights into the neurotoxic mechanisms induced by TCS.

Nicotine Abuse and Neurodegeneration: Novel Pharmacogenetic Targets to Aid Quitting and Reduce the Risk of Dementia.

Nicotine dependence has deleterious neurological impacts. Previous studies found an association between cigarette smoking and accelerating age-related thinning of the brain's cortex and subsequent cognitive decline. Smoking is considered the third most common risk factor for dementia, which prompted the inclusion of smoking cessation in dementia prevention strategies. Traditional pharmacologic options for smoking cessation include nicotine transdermal patches, bupropion and varenicline. However, based on smokers' genetic makeup, pharmacogenetics can be used to develop novel therapies to replace these traditional approaches. Genetic variability of cytochrome P450 2A6 has a major impact on smokers' behavior and their response to quitting therapies. Gene polymorphism in nicotinic acetylcholine receptor subunits also has a great influence on the ability to quit smoking. In addition, polymorphism of certain nicotinic acetylcholine receptors was found to affect the risk of dementia and the impact of tobacco smoking on the development of Alzheimer's disease. Nicotine dependence involves the activation of pleasure response through the stimulation of dopamine release. Central dopamine receptors, catechol-o-methyltransferase and the dopamine transporter protein, regulate synaptic dopamine levels. The genes of these molecules are potential targets for novel smoking cessation drugs. Pharmacogenetic studies of smoking cessation also investigated other molecules, such as ANKK1 and dopamine-beta-hydroxylase (DBH). In this perspective article, we aim to highlight the promising role of pharmacogenetics in the development of effective drugs for smoking cessation, which can increase the success rate of smoking quitting plans and ultimately reduce the incidence of neurodegeneration and dementia.

Dopamine antinociceptive system

The article presents modern views on structure and functioning of dopaminergic structures of the brain and spinal cord and their role in mechanisms of antinociception, formation, and chronification of different pain syndrome types. The paper provides a detailed description of analgesic effects of various dopamine receptors in the structures of the CNS (the spinal cord, ventral tegmental area, periaqueductal gray, corpus striatum, nucleus accumbens, hypothalamus, and medial prefrontal cortex) which function as the dopaminergic antinociceptive system. The results of numerous investigations carried out on models of neuropathic pain syndrome have shown that D2 dopamine receptors possess the greatest analgesic activity. Their antinociceptive mechanism of action is effectuated at the level of substantia gelatinosa of the spinal cord and cerebral dopaminergic structures. D1‑like receptors have lower analgesic activity and different mechanisms of action depending on localization within the brain. High availability of D2/D3 receptors in corpus striatum is indicative of a low synaptic level of endogenous dopamine and leads to reduction of pain perception threshold. On the contrary, low availability of D2/D3 receptors results in the increase of pain perception threshold. The dopaminergic antinociceptive system is characterized by a modulating effect on other neurotransmitter systems participating in nociception and antinociception. An important mechanism of antinociception of dopaminergic structures is connected with superadditivity and synergism of D2 receptors with opioid receptors. Proven participation of dopaminergic structures in pain perception and analgesia demonstrates a potential possible application of D2‑receptors agonists as an adjuvant method for achieving a greater effect in therapeutic multimodal schemes of analgesia.

A hypothalamus-habenula circuit regulates psychomotor responses induced by cocaine.

Administration of cocaine increases synaptic dopamine levels by blocking dopamine reuptake and leads to increased locomotor activity and compulsive drug-seeking behaviour. It has been suggested that the lateral hypothalamus (LH) or lateral habenula (LHb) is involved in drug-seeking behaviours. To explore the role of the LH and the LHb in cocaine-induced psychomotor responses, we tested whether modulation of the LH or the LH-LHb circuit affects cocaine-induced locomotion. Cocaine-induced locomotor activity and dopamine release were suppressed by the activation of the LH with 2-[2,6-difluoro-4-[[2-[(phenylsulfonyl)amino]ethyl]thio]phenoxy]acetamide (PEPA), an AMPA receptor agonist. When the LH was inhibited by microinjection of a GABA receptor agonists mixture prior to cocaine injection, the cocaine's effects were enhanced. Furthermore, optogenetic activation of the LH-LHb circuit attenuated the cocaine-induced locomotion, while optogenetic inhibition of the LH-LHb circuit increased it. In vivo extracellular recording found that the LH sent a glutamatergic projection to the LHb. These findings suggest that the LH glutamatergic projection to the LHb plays an active role in the modulation of cocaine-induced psychomotor responses.

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors.

Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

Selective antagonists of calcium-permeable GluA1 AMPA-receptors as potential antiaddictive agents

An increase in synaptic dopamine levels, particularly in the nucleus accumbens sheath, is a critical initial response for encoding a drugs positive effect and the development of associative learning, which is crucial for finding drugs in response to their rewarding effects.
 This study aims to review current data describing the role of AMPA glutamate receptors in the pathological drug search that occurs during the transition from drug use to drug abuse.
 Publications reviewed and analyzed the journal publications in international databases (PubMed, Web of Science, Scopus, RSCI) on the mechanisms of interaction between dopamine and AMPA glutamate receptors in drug addiction pathogenesis are reviewed and analyzed.
 After repeated exposure to psychostimulant drugs, the dopamine response to narcogen administration becomes sensitized, which is responsible for drugs of abuse over other natural reinforcers. The nucleus accumbens contains convergent inputs of dopamine and glutamate, which modulate the response to psychostimulant drugs. Simultaneously, a constant increase in AMPA-receptors lacking the GluA2 subunit was observed, which leads to an increase in conductivity and initiates a cascade of calcium-dependent signaling. With the development of compulsive drug seeking, the expression of AMPA-receptors in the nucleus accumbens increases.
 Based on this hypothesis, it is reasonable to propose drugs for the treatment of drug dependence that counteract the neuroplastic changes in AMPA-receptors caused by repeated drug exposure and leading to addiction. IEM-1460 and IEM-2131, which are two GluA1 AMPA blockers, have been proposed as potential therapeutic agents against addiction and other CNS diseases.

Methamphetamine induces a low dopamine transporter expressing state without altering the total number of peripheral immune cells.

Methamphetamine is a widely abused psychostimulant and one of the main targets of dopamine transporter (DAT). Methamphetamine reduces DAT-mediated dopamine uptake and stimulates dopamine efflux leading to increased synaptic dopamine levels many folds above baseline. Methamphetamine also targets DAT-expressing peripheral immune cells, reduces wound healing and increases infection susceptibility. Peripheral immune cells such as myeloid cells, B cells and T cells express DAT. DAT activity on monocytes and macrophages exhibits immune suppressive properties via an autocrine paracrine mechanism, where deletion or inhibition of DAT activity increases inflammatory responses. In this study, utilizing a mouse model of daily single dose of methamphetamine administration, we investigated the impact of the drug on DAT expression in peripheral immune cells. We found in methamphetamine-treated mice that DAT expression was down-regulated in most of the innate and adaptive immune cells. Methamphetamine did not increase or decrease the total number of innate and adaptive immune cells but changed their immunophenotype to low-DAT-expressing phenotype. Moreover, serum cytokine distributions were altered in methamphetamine-treated mice. Therefore, resembling its effect in the CNS, in the periphery, methamphetamine regulates DAT expression on peripheral immune cell subsets, potentially describing methamphetamine regulation of peripheral immunity.

Effective Management of "OFF" Episodes in Parkinson's Disease: Emerging Treatment Strategies and Unmet Clinical Needs.

Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available.In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.

Plasma membrane calcium ATPase downregulation in dopaminergic neurons alters cellular physiology and motor behaviour in Drosophila melanogaster.

The accumulation of Ca2+ and its subsequent increase in oxidative stress is proposed to be involved in selective dysfunctionality of dopaminergic neurons, the main cell type affected in Parkinson's disease. To test the in vivo impact of Ca2+ increment in dopaminergic neurons physiology, we downregulated the plasma membrane Ca2+ ATPase (PMCA), a pump that extrudes cytosolic Ca2+ , by expressing PMCARNAi in Drosophila melanogaster dopaminergic neurons. In these animals, we observed major locomotor alterations paralleled to higher cytosolic Ca2+ and increased levels of oxidative stress in mitochondria. Interestingly, although no overt degeneration of dopaminergic neurons was observed, evidences of neuronal dysfunctionality were detected such as increases in presynaptic vesicles in dopaminergic neurons and in the levels of dopamine in the brain, as well as presence of toxic effects when PMCA was downregulated in the eye. Moreover, reduced PMCA levels were found in a Drosophila model of Parkinson's disease, Parkin knock-out, expanding the functional relevance of PMCA reduction to other Parkinson's disease-related models. In all, we have generated a new model to study motor abnormalities caused by increments in Ca2+ that lead to augmented oxidative stress in a dopaminergic environment, added to a rise in synaptic vesicles and dopamine levels.

Computational neuronal correlation with enhanced synchronized activity in the basal ganglia and the slowing of thalamic theta and alpha rhythms in Parkinson's disease.

The aim of this work is computationally to correlate the synchronized neuronal activity of basal ganglia and slowing in theta and alpha rhythms in electroencephalogram (EEG) signal in thalamic region in case of dopamine depletion and decrease of synaptic connections. The used network topology is a scale-free network with constant node degree. The dopamine-modulated type Izikhevich neuron model is used for modeling the striatal region, consisting of fast-spiking interneurons, D1 and D2 type dopamine expressing medium spiny neurons. On the other hand, the ordinary Izikhevich neuron model is used in the modeling of extrastriatal basal ganglia (BG) regions where globus pallidus (GP) subregion neurons have also dopamine-dependent parameters. The thalamic region of the network is mass modeled including inhibitory input from basal ganglia. Depending on the decrease of synaptic connections and dopamine level, the synchronization among basal ganglia neuron populations is investigated. The effect of synaptic delay on synchronization is also considered. It is observed that the decrease of dopamine neurotransmitter and decrease in the number of synaptic connections cause an increased synchronous activity in BG. Also, slowing in theta and alpha bands in thalamus EEG signals is observed. This shows the causal relation between synchronization and power shifting to lower frequency components in the case of neurodegenerative diseases such as Parkinson's disease (PD).

Central Insulin Modulates Dopamine Signaling in the Human Striatum.

Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive. We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial. In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin. This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.

Binding Mode of Human Norepinephrine Transporter Interacting with HIV-1 Tat.

The increase of HIV infection in macrophages results in HIV proteins being released, like HIV Tat which impairs the function of monoamine transporters. HIV-infected patients have displayed increased synaptic levels of dopamine (DA) due to reduced binding and function of monoamine transporters such as the norepinephrine transporter (NET) and the dopamine transporter (DAT). Development of a three-dimensional model of the HIV-1 Tat-human NET (hNET) binding complex would help reveal how HIV-1 Tat causes toxicity in the neuron by affecting DA uptake. Here we use computational techniques such as molecular modeling to study microscopic properties and molecular dynamics of the HIV-1 Tat-hNET binding. These modeling techniques allow us to analyze noncovalent interactions and observe residue-residue contacts to verify a model structure. The modeling results studied here show that HIV-1 Tat-hNET binding is highly dynamic and that HIV-1 Tat preferentially binds to hNET in its outward-open state. In particular, HIV-1 Tat forms hydrogen bond interactions with side chains of hNET residues Y84, K88, and T544. The favorable hydrogen bonding interactions of HIV-1 Tat with the hNET side chain residues Y84 and T544 have been validated by our subsequently performed DA uptake activity assays and site-directed mutagenesis, suggesting that the modeled HIV-1 Tat-hNET binding mode is reasonable. These mechanistic and structural insights gained through homology models discussed in this study are expected to encourage the pursuit of pharmacological and biochemical studies on HIV-1 Tat interacting with hNET mechanisms and detailed structures.

Triadimefon triggers circling behavior and conditioned place preference/aversion in zebrafish in a dose dependent manner

Triadimefon (TDF) is a pesticide used in agricultural crops to control powdery mildews, rusts and other fungal pests. It exerts its fungicidal activity through the inhibition of ergosterol biosynthesis, impairing the formation of the cell membrane. For vertebrates, one of its side effects is the binding to the dopamine transporter increasing the levels of synaptic dopamine, similarly to cocaine. In addition, it has been demonstrated that TDF affects the abundance of other monoamines in the brain, specifically serotonin. It is well known that drugs which alter the dopaminergic and serotonergic systems produce behavioral changes and participate in the development of addictions in mammals. In this work we have used the conditioned place preference paradigm to assess, for the first time, the rewarding properties of TDF in zebrafish. We found out that TDF triggers both, preference and aversion depending on the dosage used during conditioning. We observed that 5 mg/L produced aversion to the pattern previously paired with TDF. However, 15 mg/L induced the opposite behavior, showing that zebrafish seek out those environments which had previously been paired with the higher dose of TDF. These results are congruent with our previous findings, where we showed that 5 mg/L reduced the levels of serotonin, usually linked to anxious behaviors (a negative cue), whereas higher concentrations of TDF increased extracellular dopamine, the main currency of the reward system. Interestingly, both doses of TDF induced circling behavior, a feature usually seen in glutamatergic antagonists.

Effects of benztropine analogs on delay discounting in rats.

Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability. The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD. Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control. d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding. AHN 1-055 may be of clinical utility in the treatment of ADHD.

The rate of dasotraline brain entry is slow following intravenous administration

RationaleDrugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration would facilitate the rapid elevation of dopamine levels associated with stimulant drugs.ObjectiveTo assess the kinetics of DAS across the blood-brain barrier and time to onset of dopamine transporters (DAT) inhibition.MethodsWe compared the onset of DAT occupancy and the associated elevation of synaptic dopamine levels in rhesus monkey following i.v. administration of DAS or methylphenidate (MPH) using positron emission tomography (PET). Brain entry times were estimated by reductions in [18F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [11C]-Raclopride binding to D2 receptors.ResultsIntravenous administration of DAS (0.1 and 0.2 mg/kg) resulted in striatal DAT occupancies of 54% and 68%, respectively; i.v. administered MPH (0.1 and 0.5 mg/kg) achieved occupancies of 69% and 88% respectively. Brain entry times of DAS (22 and 15 min, respectively) were longer than for MPH (3 and 2 min). Elevations in synaptic dopamine were similar for both DAS and MPH however the time for half-maximal displacement by MPH (t = 23 min) was 4-fold more rapid than for DAS (t = 88 min).ConclusionsThese results demonstrate that the pharmacodynamics effects of DAS on DAT occupancy and synaptic dopamine levels are more gradual in onset than those of MPH even with i.v. administration that is favored by recreational drug abusers.

Interaction of Catechol-O-methyltransferase Val158 Met polymorphism and sex influences association of parietal intrinsic functional connectivity and immediate verbal memory.

IntroductionSex differences modulate catechol‐O‐methyltransferase (COMT) genotype effect at a synaptic dopamine level, which influences brain function as well as cognitive performance. In this study, we investigated how COMT Val158Met polymorphism and sex affect intrinsic functional connectivity and memory.MethodsIntrinsic functional networks were extracted using independent component analysis of resting‐state functional magnetic resonance imaging data from 186 healthy young COMT‐genotyped participants. The association of these functional networks and memory function was tested to investigate whether the effect of COMT × sex interaction influences the association of intrinsic functional connectivity and memory performance. Quadratic curve fit estimation was used to examine the relationship between functional connectivity and speculative dopamine level among groups.ResultsCOMT MM/MV carriers, relative to VV carriers, showed increased functional connectivity in left superior parietal lobule and right inferior frontal gyrus. Further, male MM/MV carriers showed significant higher mean functional connectivity in left inferior parietal lobule relative to male VV carriers and female MM/MV carriers, which was associated with worse immediate verbal recall performance. Additionally, the relationship between inferior parietal lobule functional connectivity and speculative dopamine level among groups fits the quadratic curve.ConclusionsThese findings suggest that the interaction of COMT genotype and sex might regulate synaptic dopaminergic concentrations and influence the association of intrinsic functional connectivity and immediate verbal memory in left inferior parietal lobule.

Identification of a New Allosteric Binding Site for Cocaine in Dopamine Transporter.

Dopamine (DA) transporter (DAT) is a major target for psychostimulant drugs of abuse such as cocaine that competitively binds to DAT, inhibits DA reuptake, and consequently increases synaptic DA levels. In addition to the central binding site inside DAT, the available experimental evidence suggests the existence of alternative binding sites on DAT, but detection and characterization of these sites are challenging by experiments alone. Here, we integrate multiple computational approaches to probe the potential binding sites on the wild-type Drosophila melanogaster DAT and identify a new allosteric site that displays high affinity for cocaine. This site is located on the surface of DAT, and binding of cocaine is primarily dominated by interactions with hydrophobic residues surrounding the site. We show that cocaine binding to this new site allosterically reduces the binding of DA/cocaine to the central binding pocket, and simultaneous binding of two cocaine molecules to a single DAT seems infeasible. Furthermore, we find that binding of cocaine to this site stabilizes the conformation of DAT but alters the conformational population and thereby reduces the accessibility by DA, providing molecular insights into the inhibitory mechanism of cocaine. In addition, our results indicate that the conformations induced by cocaine binding to this site may be relevant to the oligomerization of DAT, highlighting a potential role of this new site in modulating the function of DAT.

Crosstalk Between Kappa Opioid and Dopamine Systems in Compulsive Behaviors.

The strength of goal-oriented behaviors is regulated by midbrain dopamine neurons. Dysfunctions of dopaminergic circuits are observed in drug addiction and obsessive-compulsive disorder. Compulsive behavior is a feature that both disorders share, which is associated to a heightened dopamine neurotransmission. The activity of midbrain dopamine neurons is principally regulated by the homeostatic action of dopamine through D2 receptors (D2R) that decrease the firing of neurons as well as dopamine synthesis and release. Dopamine transmission is also regulated by heterologous neurotransmitter systems such as the kappa opioid system, among others. Much of our current knowledge of the kappa opioid system and its influence on dopamine transmission comes from preclinical animal models of brain diseases. In 1988, using cerebral microdialysis, it was shown that the acute activation of the Kappa Opioid Receptors (KOR) decreases synaptic levels of dopamine in the striatum. This inhibitory effect of KOR opposes to the facilitating influence of drugs of abuse on dopamine release, leading to the proposition of the use of KOR agonists as pharmacological therapy for compulsive drug intake. Surprisingly, 30 years later, KOR antagonists are instead proposed to treat drug addiction. What may have happened during these years that generated this drastic change of paradigm? The collected evidence suggested that the effect of KOR on synaptic dopamine levels is complex, depending on the frequency of KOR activation and timing with other incoming stimuli to dopamine neurons, as well as sex and species differences. Conversely to its acute effect, chronic KOR activation seems to facilitate dopamine neurotransmission and dopamine-mediated behaviors. The opposing actions exerted by acute versus chronic KOR activation have been associated with an initial aversive and a delayed rewarding effect, during the exposure to drugs of abuse. Compulsive behaviors induced by repeated activation of D2R are also potentiated by the sustained co-activation of KOR, which correlates with decreased synaptic levels of dopamine and sensitized D2R. Thus, the time-dependent activation of KOR impacts directly on dopamine levels affecting the tuning of motivated behaviors. This review analyzes the contribution of the kappa opioid system to the dopaminergic correlates of compulsive behaviors.

The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [11C]-(+)-PHNO PET study

Childhood trauma is a risk factor for psychosis. Amphetamine increases synaptic striatal dopamine levels and can induce positive psychotic symptoms in healthy individuals and patients with schizophrenia. Socio-developmental hypotheses of psychosis propose that childhood trauma and other environmental risk factors sensitize the dopamine system to increase the risk of psychotic symptoms, but this remains to be tested in humans. We used [11C]-(+)-PHNO positron emission tomography to measure striatal dopamine-2/3 receptor (D2/3R) availability and ventral striatal dexamphetamine-induced dopamine release in healthy participants (n = 24). The relationships between dexamphetamine-induced dopamine release, dexamphetamine-induced positive psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS), and childhood trauma using the Childhood Trauma Questionnaire (CTQ) were assessed using linear regression and mediation analyses, with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced symptoms as the dependent variable. There was a significant interaction between childhood trauma and ventral striatal dopamine release in predicting dexamphetamine-induced positive psychotic symptoms (standardized β = 1.83, p = 0.003), but a mediation analysis was not significant (standardized β = −0.18, p = 0.158). There were no significant effects of dopamine release and childhood trauma on change in negative (p = 0.280) or general PANSS symptoms (p = 0.061), and there was no relationship between ventral striatal baseline D2/3R availability and positive symptoms (p = 0.368). This indicates childhood trauma and dopamine release interact to influence the induction of positive psychotic symptoms. This is not consistent with a simple sensitization hypothesis, but suggests that childhood trauma moderates the cognitive response to dopamine release to make psychotic experiences more likely.

Catechol-O-methyltransferase polymorphism Val158Met is associated with distal neuropathic pain in HIV-associated sensory neuropathy.

Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of the catechol-O-methyltransferase (COMT), ValMet. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of ValMet as a predictor of DNP in HIV-SN. In 1044 HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between ValMet and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background. Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, ValMet was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNP: lifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4. Stratified by genetic ancestry, the association between ValMet and DNP was significant in European and African genetic ancestry. ValMet may be a genetic marker for susceptibility to DNP in HIV-SN. Our findings support the notion that differences in pain processing mediated by COMT-related dopamine signaling play a role in susceptibility to DNP in HIV-SN. Because prior studies suggest that the COMT allele may influence dose-response relationships with opioid treatment, knowing COMT genotype could influence management.