Dopamine System Research Articles

Toward an Etiology of Spaceflight Neuroplastic Syndrome: Evolutionary Science Leads to New Hypotheses and Program Priorities.

Evolutionary theory is applied to recent neuroscientific findings on factors associated with risk-and-reward systems, and consequently, aspects of human decision making in spaceflight. Factors include enzymes aiding metabolic pathways of dopamine and serotonin; neurotrophic factors supporting neuronal functioning and plasticity; and genes associated with serotonin and dopamine systems. Not all factors are at risk in spaceflight. Some remain stable. It is hypothesized that neural deconditioning in spaceflight arises from faulty signals sent to the brain and gut in attempting to adapt phenotypically to a novel space environment. There is a mismatch between terrestrial selection pressures during human evolution and conditions of cosmic radiation, microgravity, and higher CO2, which together cause scattered results. A contrary question is broached: Given these findings, why are human sequelae not worse? Discussion of programmatic issues then focuses on methodologies to determine the suitability of civilians for spaceflight, an issue that grows more pressing while more varied populations prepare for spaceflight in LEO and on, and in orbit around the Moon.

Two-Step Actions of Testicular Androgens in the Organization of a Male-Specific Neural Pathway from the Medial Preoptic Area to the Ventral Tegmental Area for Modulating Sexually Motivated Behavior.

The medial preoptic area (MPOA) is a sexually dimorphic region of the brain that regulates social behaviors. The sexually dimorphic nucleus (SDN) of the MPOA has been studied to understand sexual dimorphism, although the anatomy and physiology of the SDN is not fully understood. Here, we characterized SDN neurons that contribute to sexual dimorphism and investigated the mechanisms underlying the emergence of such neurons and their roles in social behaviors. A target-specific neuroanatomical study using transgenic mice expressing Cre recombinase under the control of Calb1, a gene expressed abundantly in the SDN, revealed that SDN neurons are divided into two subpopulations, GABA neurons projecting to the ventral tegmental area (VTA), where they link to the dopamine system (CalbVTA neurons), and GABA neurons that extend axons in the MPOA or project to neighboring regions (CalbnonVTA neurons). CalbVTA neurons were abundant in males, but were scarce or absent in females. There was no difference in the number of CalbnonVTA neurons between sexes. Additionally, we found that emergence of CalbVTA neurons requires two testicular androgen actions that occur first in the postnatal period and second in the peripubertal period. Chemogenetic analyses of CalbVTA neurons indicated a role in modulating sexual motivation in males. Knockdown of Calb1 in the MPOA reduced the intromission required for males to complete copulation. These findings provide strong evidence that a male-specific neural pathway from the MPOA to the VTA is organized by the two-step actions of testicular androgens for the modulation of sexually motivated behavior.SIGNIFICANCE STATEMENT The MPOA is a sexually dimorphic region of the brain that regulates social behaviors, although its sexual dimorphism is not fully understood. Here, we describe a population of MPOA neurons that contribute to the sexual dimorphism. These neurons only exist in masculinized brains, and they project their axons to the ventral tegmental area, where they link to the dopamine system. Emergence of such neurons requires two testicular androgen actions that occur first in the postnatal period and second in the peripubertal period. These MPOA neurons endow masculinized brains with a neural pathway from the MPOA to the ventral tegmental area and modulate sexually motivated behavior in males.

Whole-Body Vibration Prevents Neuronal, Neurochemical, and Behavioral Effects of Morphine Withdrawal in a Rat Model.

Peripheral mechanoreceptor-based treatments such as acupuncture and chiropractic manipulation have shown success in modulating the mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) of the midbrain and projecting to the nucleus accumbens (NAc) of the striatum. We have previously shown that mechanoreceptor activation via whole-body vibration (WBV) ameliorates neuronal and behavioral effects of chronic ethanol exposure. In this study, we employ a similar paradigm to assess the efficacy of WBV as a preventative measure of neuronal and behavioral effects of morphine withdrawal in a Wistar rat model. We demonstrate that concurrent administration of WBV at 80 Hz with morphine over a 5-day period significantly reduced adaptations in VTA GABA neuronal activity and NAc DA release and modulated expression of δ-opioid receptors (DORs) on NAc cholinergic interneurons (CINs) during withdrawal. We also observed a reduction in behavior typically associated with opioid withdrawal. WBV represents a promising adjunct to current intervention for opioid use disorder (OUD) and should be examined translationally in humans.

2-Ethylhexyl Diphenyl Phosphate Causes Obesity in Zebrafish by Stimulating Overeating via Inhibition of Dopamine Receptor D2.

Obesity is a popular public health problem worldwide and is mainly caused by overeating, but little is known about the impacts of synthetic chemicals on obesity. Herein, we evaluated the obesogenic effect caused by 2-ethylhexyl diphenyl phosphate (EHDPHP) on zebrafish. Adult zebrafish were exposed to 5, 35, and 245 μg/L of EHDPHP for 21 days. Results showed that EHDPHP exposure significantly promoted the feeding behavior of zebrafish, as evidenced by shorter reaction time, increased average food intake, feeding rate, and intake frequency (p < 0.05). Transcriptomic, real-time quantitative PCR, and neurotransmitter analyses revealed that the dopamine (DA) receptor D2 (DRD2) was inhibited, which interfered with the DA neural reward regulation system, thus stimulating food addiction to zebrafish. This was further verified by the restored DRD2 after 7 days of Halo (a DRD2 agonist) treatment. A strong interaction between EHDPHP and DRD2 was identified via molecular docking. As a consequence of the abnormal feeding behavior, the exposed fish exhibited significant obesity evidenced by increased body weight, body mass index, plasma total cholesterol, triglyceride, and body fat content. Additionally, the pathways linked to Parkinson's disease, alcoholism, and cocaine addiction were also disrupted, implying that EHDPHP might cause other neurological disorders via the disrupted DA system.

Aripiprazole “Induced” and Aripiprazole “Worsened” Parkinsonism

Abstract Aripiprazole, a novel neuroleptic and dopamine system stabilizer, is hailed as 3rd generation neuroleptic by some and claimed to have partial agonistic activity at D2 receptors (D2R), distinguishing it from other antipsychotics-D2 dopamine receptor antagonists. Many studies have extensively described extrapyramidal syndrome (EPS) profiles of earlier atypical neuroleptics including clozapine, quetiapine, olanzapine, ziprasidone, and risperidone. Despite the claimed D2R agonistic mechanism, EPS due to aripiprazole is sporadically reported – here below we report two such cases across two different baselines. One in a patient with no baseline Parkinsonism, another in a patient with well controlled Parkinson’s disease.

Win-Paired Cues Modulate the Effect of Dopamine Neuron Sensitization on Decision Making and Cocaine Self-administration: Divergent Effects Across Sex

BackgroundBoth psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. MethodsTo probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings. ResultsIn the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. ConclusionsWhile these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities.

Secondary metal doped cuprous-cyanoimidazole frameworks for triple-mode detection of dopamine

BackgroundsMetal-organic framework-based nanozymes enable several opportunities for designing novel analysis methods for the detection of pesticides, heavy metal ions, and biomolecules; however, practical applications are still limited by a complicated synthesis route, lower catalytic activity, and single detection mode. Dopamine (DA) is a crucial catecholamine substance in the human body that acts as a neurotransmitter regulating a variety of physiological functions of the central nervous system. Therefore, it is highly significant to explore simple nanozymes synthesis methods for constructing a multiple analysis system to detection DA. ResultsHerein, we elaborately selected cobalt ions as the secondary metal doping in cuprous-cyanoimidazole frameworks (CuCo-CIFs) with a mass-production strategy. CuCo-CIFs possess intrinsic peroxidase-like activity that can convert hydrogen peroxide into various reactive oxygen species (i.e., 1O2, OH·, O2·-) and thereby oxidize colorless 3,3′,5,5′-tetramethylbenzidine (TMB) and DA to blue oxTMB and orange polydopamine (PDA), respectively. The absorption of the detection system increases at 460 nm while decreases at 652 nm as the concentration of DA increases under near-neutral pH (6.1), resulting in a color transition from blue to orange. Consequently, an unprecedented triple-mode analysis system of DA monitored by naked eyes, ratiometric-absorption, and scanometric was constructed. The limit of detection for the ratiometric-absorption and scanometric mode can reach 20 nM and 28 nM, respectively. CuCo-CIFs were successfully used for the rapid and accurate detection of DA in practical samples. SignificanceAs a simple, low-cost, multi-mode colorimetric platform, this kind of nanozyme detection with peroxidase-like activity exhibits significant potential for the detection of DA. Our work not only expands the applications of MOFs in analytical fields but also addresses the general challenges faced by nanozyme-based colorimetric detection systems of DA. This work provides valuable insights for the rational application of nanozyme and the design of new analysis systems.

Chronic Deep Brain Stimulation of the Human Nucleus Accumbens Region Disrupts the Stability of Intertemporal Preferences.

When choosing between rewards that differ in temporal proximity (intertemporal choice), human preferences are typically stable, constituting a clinically relevant transdiagnostic trait. Here we show, in female and male human patients undergoing deep brain stimulation (DBS) of the anterior limb of the internal capsule/NAcc region for treatment-resistant obsessive-compulsive disorder, that long-term chronic (but not phasic) DBS disrupts intertemporal preferences. Hierarchical Bayesian modeling accounting for temporal discounting behavior across multiple time points allowed us to assess both short-term and long-term reliability of intertemporal choice. In controls, temporal discounting was highly reliable, both long-term (6 months) and short-term (1 week). In contrast, in patients undergoing DBS, short-term reliability was high, but long-term reliability (6 months) was severely disrupted. Control analyses confirmed that this effect was not because of range restriction, the presence of obsessive-compulsive disorder symptoms or group differences in choice stochasticity. Model-agnostic between- and within-subject analyses confirmed this effect. These findings provide initial evidence for long-term modulation of cognitive function via DBS and highlight a potential contribution of the human NAcc region to intertemporal preference stability over time.SIGNIFICANCE STATEMENT Choosing between rewards that differ in temporal proximity is in part a stable trait with relevance for many mental disorders, and depends on prefrontal regions and regions of the dopamine system. Here we show that chronic deep brain stimulation of the human anterior limb of the internal capsule/NAcc region for treatment-resistant obsessive-compulsive disorder disrupts the stability of intertemporal preferences. These findings show that chronic stimulation of one of the brain's central motivational hubs can disrupt preferences thought to depend on this circuit.

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis.

The concurrent use of several medications is a common practice in the treatment of complex psychiatric conditions. One such commonly used combination is aripiprazole (ARI), an antipsychotic, and trazodone (TRZ), an antidepressant. In addition to their effects on dopamine and serotonin systems, both of these compounds are inhibitors of the 7-dehydrocholesterol reductase (DHCR7) enzyme. To evaluate the systemic and nervous system distribution of ARI and TRZ and their effects on cholesterol biosynthesis, adult mice were treated with both ARI and TRZ for 21 days. The parent drugs, their metabolites, and sterols were analyzed in the brain and various organs of mice using LC-MS/MS. The analyses revealed that ARI, TRZ, and their metabolites were readily detectable in the brain and organs, leading to changes in the sterol profile. The levels of medications, their metabolites, and sterols differed across tissues with notable sex differences. Female mice showed higher turnover of ARI and more cholesterol clearance in the brain, with several post-lanosterol intermediates significantly altered. In addition to interfering with sterol biosynthesis, ARI and TRZ exposure led to decreased ionized calcium-binding adaptor molecule 1 (IBA1) and increased DHCR7 protein expression in the cortex. Changes in sterol profile have been also identified in the spleen, liver, and serum, underscoring the systemic effect of ARI and TRZ on sterol biosynthesis. Long-term use of concurrent ARI and TRZ warrants further studies to fully evaluate the lasting consequences of altered sterol biosynthesis on the whole body.

Repeated Cocaine Intake Differentially Impacts Striatal D2/3 Receptor Availability, Psychostimulant-Induced Dopamine Release, and Trait Behavioral Markers of Drug Abuse.

Current research indicates that altered dopamine (DA) transmission in the striatum contributes to impulsivity and novelty-seeking, and it may mediate a link concerning a higher susceptibility to drug abuse. Whether increased susceptibility to drug abuse results from a hyperdopaminergic or hypodopaminergic state is still debated. Here, we simultaneously tracked changes in DA D2/3 receptor (D2/3R) availability and amphetamine-(AMPH)-induced DA release in relation to impulsivity and novelty-seeking prior to, and following, cocaine self-administration (SA) in Roman high- (RHA) and low- (RLA) avoidance rats. We found that high-impulsive/high novelty-seeking RHA rats exhibited lower D2/3R availabilities and higher AMPH-induced DA release in the striatum that predicted higher levels of cocaine intake compared with RLAs. Cocaine SA did not alter striatal D2/3R availability or impulsivity in RHA or RLA rats. Critically, cocaine exposure led to a baseline-dependent blunting of stimulated DA release in high-impulsive/high novelty-seeking RHA rats only, and to a baseline-dependent increase in novelty-seeking in low-impulsive/low novelty-seeking RLA rats only. Altogether, we propose that susceptibility to drug abuse results from an innate hyper-responsive DA system, promoting impulsive action and novelty-seeking, and producing stronger initial drug-reinforcing effects that contribute to the initiation and perpetuation of drug use. However, with repeated cocaine use, a tolerance to drug-induced striatal DA elevations develops, leading to a compensatory increase in drug consumption to overcome the reduced reward effects.

Kappa opioid receptor agonist U50,488 inhibits dopamine more in caudal than rostral nucleus accumbens core.

The nucleus accumbens (NAc) core is involved in regulating stress and shaping reward seeking behaviours. Multiple neuromodulators, including dynorphin/kappa opioid receptor (KOR) and dopamine systems, converge in this area to influence behavioural outcomes. KOR activation acutely inhibits dopamine release and chronically depresses overall dopamine transmission. Recently, studies in the NAc shell have revealed that the impact of KOR activation on behaviour is regionally specific, and these rostro-caudal differences are likely driven by greater control of KORs over dopamine inhibition in the caudal compared with rostral subregion. Given the importance of NAc core, particularly the interaction between KORs and dopamine in regulating reward seeking behaviours, we examined the impact of KOR activation on dopamine release and uptake along the rostro-caudal axis in the NAc core of male and female mice. Using ex vivo fast scan cyclic voltammetry, we observed that KOR mediated inhibition of dopamine release was significantly greater in caudal compared with rostral NAc core with no significant sex differences observed. These data suggest that KORs regulate dopamine release differentially along the rostro-caudal axis, providing a new axis on which to examine the process by which the KOR/dopamine system controls reward encoding.

Sex and age differences in mice models of effort-based decision-making and anergia in depression: the role of dopamine, and cerebral-dopamine-neurotrophic-factor.

Mesolimbic dopamine (DA) regulates vigor in motivated behavior. While previous results have mainly been performed in male rodents, the present studies compared CD1 male and female mice in effort-based decision-making tests of motivation. These tests offered choices between several reinforcers that require different levels of effort (progressive ratio/choice task and 3-choice-T-maze task). Sweet reinforcers were used in both tasks. In the operant tasks, females worked harder as the task required more effort to access a 10% sucrose solution. Although males and females did not differ in preference for 10% vs 3% solutions under free concurrent presentation, females consumed more of the 10% solution when tested alone. The operant task requires a long period of training and changes in the DA system due to age can be mediating long-term changes in effort. Thus, age and sex factors were evaluated in the T-maze task, which requires only a short training period. Both sexes and ages were equally active when habituated to the running wheel (RW), but females consumed more sweet pellets than males, especially at an older age. Both sexes had a strong preference for the RW compared to more sedentary reinforcers in the 3-choice-T-maze test, but older animals spent less time running and ate more than the young ones. The DA-depleting agent tetrabenazine reduced time running in older mice but not in adolescents. Cerebral-dopamine-neurotrophic-factor was reduced in older mice of both sexes compared to adolescent mice. These results emphasize the importance of taking into account differences in sex and age when evaluating willingness to exert effort for specific reinforcers.

Attenuation of morphine conditioned place preference and reinstatement by vitamin D.

Opioid action in the brain involves the dopamine-reward system as well as non-dopamine pathways. Since vitamin D also modulates the brain's dopamine system, the question of this study was how vitamin D might affect the opioid influences on the reward system. Therefore, the objective of this study was to investigate the possible effect of vitamin D on the conditioned place preference (CPP) induced by morphine, as a valuable model of assessment of the reinforcing properties of opioids by associating the context to the rewarding properties of the addictive drugs. Male Wistar rats were randomly divided into two main groups that either received saline (morphine vehicle) or morphine (5 mg/kg, intraperitoneally) for CPP. Each of the main groups was divided into three vitamin D treatment subgroups: vitamin D vehicle and vitamin D (5 and 10 μg/kg, intraperitoneally). Vitamin D injections were started 1 week ahead of the experiment (two injections) or immediately after post-conditioning and in both cases, it was continued twice weekly throughout the CPP. Administration of vitamin D (10 μg/kg) before conditioning in CPP markedly attenuated morphine expression in the post-conditioning test. Receiving vitamin D (5 or 10 μg/kg) before or after conditioning significantly attenuated morphine reinstatement. Administration of vitamin D after opioid conditioning facilitated morphine memory extinction and attenuated morphine reinstatement. Vitamin D is probably a valuable addition to be considered as a part of the treatment for prevention or minimizing the dependency or relapse to opioids.

Dopamine release in the nucleus accumbens promotes REM sleep and cataplexy

Patients with the sleep disorder narcolepsy suffer from excessive daytime sleepiness, disrupted nighttime sleep, and cataplexy-the abrupt loss of postural muscle tone during wakefulness, often triggered by strong emotion. The dopamine (DA) system is implicated in both sleep-wake states and cataplexy, but little is known about the function of DA release in the striatum and sleep disorders. Recording DA release in the ventral striatum revealed orexin-independent changes across sleep-wake states as well as striking increases in DA release in the ventral, but not dorsal, striatum prior to cataplexy onset. Tonic low-frequency stimulation of ventral tegmental efferents in the ventral striatum suppressed both cataplexy and rapid eye movement (REM) sleep, while phasic high-frequency stimulation increased cataplexy propensity and decreased the latency to REM sleep. Together, our findings demonstrate a functional role of DA release in the striatum in regulating cataplexy and REM sleep.

Non-covalent interactions in biocompatible platforms for drug delivery: Mg2(olsalazine) Metal-Organic Framework with phenylethylamine, dopamine and sertraline

Drug delivery systems can improve the efficacy of therapeutic substances. In this investigation, the biocompatible Mg2(olsalazine) [Mg2(olz)] framework is investigated as a delivery system of phenylethylamine, dopamine and sertraline, substances related to the functioning of the Central Nervous System. Experiments previously reported show that Mg2(olz) encapsulates phenylethylamine and, under physiological conditions, releases the molecules. The hypothesis of this work is that this is possible due to the presence of non-covalent interactions. The non-covalent interactions between Mg2(olz) and phenylethylamine, dopamine and sertraline are analyzed using Quantum Theory of Atoms in Molecules and Non-covalent Interaction Index. It was found that the coordinatively unsaturated metal site of Mg2(olz) is important for the formation of non-covalent interactions. Due to similarity of systems of dopamine and sertraline with that of phenylethylamine, we conclude that Mg2(olz) is also capable to encapsulate and release these two drugs, being a good proposal as a drug delivery system.

Deficiency of Cullin 3, a Protein Encoded by a Schizophrenia and Autism Risk Gene, Impairs Behaviors by Enhancing the Excitability of Ventral Tegmental Area (VTA) DA Neurons.

The dopaminergic neuromodulator system is fundamental to brain functions. Abnormal dopamine (DA) pathway is implicated in psychiatric disorders, including schizophrenia (SZ) and autism spectrum disorder (ASD). Mutations in Cullin 3 (CUL3), a core component of the Cullin-RING ubiquitin E3 ligase complex, have been associated with SZ and ASD. However, little is known about the function and mechanism of CUL3 in the DA system. Here, we show that CUL3 is critical for the function of DA neurons and DA-relevant behaviors in male mice. CUL3-deficient mice exhibited hyperactive locomotion, deficits in working memory and sensorimotor gating, and increased sensitivity to psychostimulants. In addition, enhanced DA signaling and elevated excitability of the VTA DA neurons were observed in CUL3-deficient animals. Behavioral impairments were attenuated by dopamine D2 receptor antagonist haloperidol and chemogenetic inhibition of DA neurons. Furthermore, we identified HCN2, a hyperpolarization-activated and cyclic nucleotide-gated channel, as a potential target of CUL3 in DA neurons. Our study indicates that CUL3 controls DA neuronal activity by maintaining ion channel homeostasis and provides insight into the role of CUL3 in the pathogenesis of psychiatric disorders.SIGNIFICANCE STATEMENT This study provides evidence that Cullin 3 (CUL3), a core component of the Cullin-RING ubiquitin E3 ligase complex that has been associated with autism spectrum disorder and schizophrenia, controls the excitability of dopamine (DA) neurons in mice. Its DA-specific heterozygous deficiency increased spontaneous locomotion, impaired working memory and sensorimotor gating, and elevated response to psychostimulants. We showed that CUL3 deficiency increased the excitability of VTA DA neurons, and inhibiting D2 receptor or DA neuronal activity attenuated behavioral deficits of CUL3-deficient mice. We found HCN2, a hyperpolarization-activated channel, as a target of CUL3 in DA neurons. Our findings reveal CUL3's role in DA neurons and offer insights into the pathogenic mechanisms of autism spectrum disorder and schizophrenia.

Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.

Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets.

Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated.

Dopamine transporter blockade during adolescence increases adult dopamine function, impulsivity, and aggression

Sensitive developmental periods shape neural circuits and enable adaptation. However, they also engender vulnerability to factors that can perturb developmental trajectories. An understanding of sensitive period phenomena and mechanisms separate from sensory system development is still lacking, yet critical to understanding disease etiology and risk. The dopamine system is pivotal in controlling and shaping adolescent behaviors, and it undergoes heightened plasticity during that time, such that interference with dopamine signaling can have long-lasting behavioral consequences. Here we sought to gain mechanistic insight into this dopamine-sensitive period and its impact on behavior. In mice, dopamine transporter (DAT) blockade from postnatal (P) day 22 to 41 increases aggression and sensitivity to amphetamine (AMPH) behavioral stimulation in adulthood. Here, we refined this sensitive window to P32-41 and identified increased firing of dopaminergic neurons in vitro and in vivo as a neural correlate to altered adult behavior. Aggression can result from enhanced impulsivity and cognitive dysfunction, and dopamine regulates working memory and motivated behavior. Hence, we assessed these behavioral domains and found that P32-41 DAT blockade increases impulsivity but has no effect on cognition, working memory, or motivation in adulthood. Lastly, using optogenetics to drive dopamine neurons, we find that increased VTA but not SNc dopaminergic activity mimics the increase in impulsive behavior in the Go/NoGo task observed after adolescent DAT blockade. Together our data provide insight into the developmental origins of aggression and impulsivity that may ultimately improve diagnosis, prevention, and treatment strategies for related neuropsychiatric disorders.

Partner-seeking and limbic dopamine system are enhanced following social loss in male prairie voles (Microtus ochrogaster).

Death of a loved one is recognized as one of life's greatest stresses, and 10%-20% of bereaved individuals will experience a complicated or prolonged grieving period that is characterized by intense yearning for the deceased. The monogamous prairie vole (Microtus ochrogaster) is a rodent species that forms pair bonds between breeding partners and has been used to study the neurobiology of social behaviors and isolation. Male prairie voles do not display distress after isolation from a familiar, same-sex conspecific; however, separation from a bonded female partner increases emotional, stress-related, and proximity-seeking behaviors. Here, we tested the investigatory response of male voles to partner odor during a period of social loss. We found that males who lost their partner spent significantly more time investigating partner odor but not non-partner social odor or food odor. Bachelor males and males in intact pairings did not respond uniquely to any odor. Furthermore, we examined dopamine (DA) receptor mRNA expression in the anterior insula cortex (aIC), nucleus accumbens (NAc), and anterior cingulate (ACC), regions with higher activation in grieving humans. While we found some effects of relationship type on DRD1 and DRD2 expression in some of these regions, loss of a high-quality opposite-sex relationship had a significant effect on DA receptor expression, with pair-bonded/loss males having higher expression in the aIC and ACC compared with pair-bonded/intact and nonbonded/loss males. Together, these data suggest that both relationship type and relationship quality affect reunion-seeking behavior and motivational neurocircuits following social loss of a bonded partner.