Differential Roles of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, and Prefrontal Cortex in Regulating Response to Methylphenidate: Insights from Neuronal and Behavioral Studies in Freely Behaving Rats.

A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose-response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals' behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further increases in firing rate as compared to the initial MPD responses. The majority of neurons recorded from animals expressing behavioral tolerance responded to chronic MPD with decreases in their firing rate as compared to the initial MPD exposures. Each of the six brain areas studied-the ventral tegmental area, locus coeruleus, dorsal raphe, nucleus accumbens, prefrontal cortex, and caudate nucleus (VTA, LC, DR, NAc, PFC, and CN)-responds significantly (p < 0.001) differently to MPD, suggesting that each one of the above brain areas exhibits different roles in the response to MPD. Moreover, this study demonstrates that it is essential to evaluate neuronal activity responses to psychostimulants based on the animals' behavioral responses to acute and chronic effects of the drug from several brain areas simultaneously to obtain accurate information on each area's role in response to the drug.

Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial.

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values ≥ 4.21, p-values ≤ 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.

Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations.

The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. In rodents, MCH acts on MCHR1, a G protein-coupled receptor, which is widely expressed in the brain and abundantly localized to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different experimental models and methodologies, including organotypic brain slice cultures from rat prefrontal cortex (PFC) and caudate-putamen (CPu), in vivo pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (designer receptors exclusively activated by designer drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation or indirectly through optogenetic and chemogenetic-mediated excitation of MCH-neuron, caused cilia shortening, detected by the quantification of the presence of ADCY3 protein, a known primary cilia marker. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induced cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions and implicate MCHR1 present at primary cilia as a potential therapeutic target for the treatment of pathological conditions characterized by impaired primary cilia function associated with the modification of its length.

Inactivation of posterior but not anterior dorsomedial caudate-putamen impedes learning with self-administered nicotine stimulus in male rats.

The rodent caudate-putamen is a large heterogeneous neural structure with distinct anatomical connections that differ in their control of learning processes. Previous research suggests that the anterior and posterior dorsomedial caudate-putamen (a- and p-dmCPu) differentially regulate associative learning with a non-contingent nicotine stimulus. The current study used bilateral NMDA-induced excitotoxic lesions to the a-dmCPu and p-dmCPu to determine the functional involvement of a-dmCPu and p-dmCPu in appetitive learning with contingent nicotine stimulus. Rats with a-dmCPu, p-dmCPu, or sham lesions were trained to lever-press for intravenous nicotine (0.03 mg/kg/inf) followed by access to sucrose 30 s later. After 1, 3, 9, and 20 nicotine-sucrose training sessions, appetitive learning in the form of a goal-tracking response was assessed using a non-contingent nicotine-alone test. All rats acquired nicotine self-administration and learned to retrieve sucrose from a receptacle at equal rates. However, rats with lesions to p-dmCPu demonstrated blunted learning of the nicotine-sucrose association. Our primary findings show that rats with lesions to p-dmCPu had a blunted goal-tracking response to a non-contingent nicotine administration after 20 consecutive days of nicotine-sucrose pairing. Our findings extend previous reports to a contingent model of nicotine self-administration and show that p-dmCPu is involved in associative learning with nicotine stimulus using a paradigm where rats voluntarily self-administer nicotine infusions that are paired with access to sucrose-a paradigm that closely resembles learning processes observed in humans.

Neuroinflammation and L-dopa-induced abnormal involuntary movements in 6-hydroxydopamine-lesioned rat model of Parkinson's disease are counteracted by combined administration of a 5-HT1A/1B receptor agonist and A2A receptor antagonist.

Several lines of evidence have strongly implicated neuroinflammation in Parkinson's disease (PD) progression and l-dopa-induced dyskinesia. The present study investigated whether early subchronic pretreatment with the serotonin 5-HT1A/1B receptor agonist eltoprazine plus the adenosine A2A receptor antagonist preladenant counteracted l-dopa-induced abnormal involuntary movements (AIMs, index of dyskinesia), and neuroinflammation, in unilateral 6-hydroxydopamine(6-OHDA)-lesioned rat model of PD. The immunoreactivity of glial fibrillary acidic protein (GFAP), and the colocalization of ionized calcium binding adaptor molecule-1 (IBA-1), with interleukin (IL)-1ß, tumor-necrosis-factor-α (TNF-α) and IL-10 were evaluated in the denervated caudate-putamen (CPu) and substantia nigra pars-compacta (SNc). The combined subchronic pretreatment with l-dopa plus eltoprazine and preladenant reduced AIMs induced by acute l-dopa challenge in these rats and decreased GFAP and IBA-1 immunoreactivity induced by the drug in both CPu and SNc, with reduction in IL-1ß in IBA-1-positive cells in both CPu and SNc, and in TNF-α in IBA-1-positive cells in SNc. Moreover, a significant increase in IL-10 in IBA-1-positive cells was observed in SNc. Evaluation of immediate early-gene zif-268 (index of neuronal activation) after l-dopa challenge, showed an increase in its expression in denervated CPu of rats pretreated with l-dopa or l-dopa plus preladenant compared with vehicle, whereas rats pretreated with eltoprazine, with or without preladenant, had lower zif-268 expression. Finally, tyrosine hydroxylase and dopamine transporter examined to evaluate neurodegeneration, showed a significant equal decrease in all experimental groups. The present findings suggest that combination of l-dopa with eltoprazine and preladenant may be promising therapeutic strategy for delaying the onset of dyskinesia, preserving l-dopa efficacy and reducing neuroinflammation markers in nigrostriatal system of 6-OHDA-lesioned rats.

LB100 attenuates methamphetamine-induced behavioral sensitization by inhibiting the Raf1-ERK 1/2 cascade in the caudate putamen.

Methamphetamine (METH) abuse has become a serious social problem. Behavioral sensitization is a common behavioral paradigm used to study the neurobiological mechanism that underlies drug addiction. Our previous study demonstrated that the activity of protein phosphatase 2A (PP2A) and the level of phosphorylated extracellular signal-related kinase 1/2 (p-ERK 1/2) are increased in the caudate putamen (CPu) of METH-sensitive mice. However, the relationship between PP2A and ERK 1/2 in METH-induced behavioral sensitization remains unknown. Some studies have indicated that Raf1 may be involved in this process. In this study, LB100, a PP2A inhibitor for treating solid tumors, was first used to clarify the relationship between PP2A and ERK 1/2. In addition, Western blot was used to examine the levels of p-Raf1 (Ser 259) and p-ERK 1/2 (Thr 202/Tyr 204) in the CPu, hippocampus (Hip) and nucleus accumbens (NAc). Our results showed that 2 mg/kg LB100 significantly attenuated METH-induced behavioral sensitization. Furthermore, Western blot analysis revealed that pretreatment with 2 mg/kg LB100 remarkably reversed METH-induced reduction of p-Raf1, as well as upregulation of p-ERK 1/2 in the CPu. Taken together, these results indicate that PP2A plays an important role in METH-induced behavioral sensitization and phosphorylates ERK 1/2 by dephosphorylating p-Raf1 in the CPu to further regulate METH-induced behavioral sensitization.

Levo-tetrahydropalmatine attenuates the acquisition of fentanyl-induced conditioned place preference and the changes in ERK and CREB phosphorylation expression in mice.

Levo-tetrahydropalmatine (L-THP) is the main active ingredient of Corydalis and Stephania and is widely used for its sedative, analgesic, and neuroleptic effects. Though L-THP is an antagonist of dopamine receptors and has been proven to be effective in treating drug addiction, its effect on fentanyl-induced reward learning still remains unclear. This experiment was designed to investigate the effects of L-THP on fentanyl-induced rewarding behavior through conditioned place preference (CPP) in mice. Western blot assays were used to dissect the accompanying changes in the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in related brain regions, including the hippocampus (Hip), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc), which may mediate the effects of L-THP on fentanyl-induced CPP. The results revealed that fentanyl could induce CPP in mice at doses of 0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, and 0.2 mg/kg, and L-THP could attenuate the acquisition of fentany-induced CPP at a dose of 10.0 mg/kg. The levels of p-ERK and p-CREB of the saline+fentanyl group (0.05 mg/kg) increased significantly in the Hip, NAc, and PFC compared to the saline+saline group. Furthermore, L-THP (10.0 mg/kg) co-administered with fentanyl during conditioning prevented the enhanced phosphorylation of ERK and CREB in the Hip, NAc, and PFC. Our research revealed that L-THP could suppress the rewarding properties of fentanyl-induced CPP, the inhibitory effect may be related to the suppression of ERK and CREB phosphorylation in the Hip, NAc, and PFC of mice. Thus, L-THP may have therapeutic potential for fentanyl addiction.

Perinatal activation of ERα and ERß but not GPER-1 masculinizes female rat caudate-putamen medium spiny neuron electrophysiological properties.

Exposure to steroid sex hormones such as 17ß-estradiol (estradiol) during early life potentially permanently masculinize neuron electrophysiological phenotype. In rodents, one crucial component of this developmental process occurs in males, with estradiol aromatized in the brain from testes-sourced testosterone. However, it is unknown whether most neuron electrophysiological phenotypes are altered by this early masculinization process, including medium spiny neurons (MSNs) of the rat caudate-putamen. MSNs are the predominant and primary output neurons of the caudate-putamen and exhibit increased intrinsic excitability in females compared to males. Here, we hypothesize that since perinatal estradiol exposure occurs in males, then a comparable exposure in females to estradiol or its receptor agonists would be sufficient to induce masculinization. To test this hypothesis, we injected perinatal female rats with estradiol or its receptor agonists and then later assessed MSN electrophysiology. Female and male rats on postnatal day 0 and 1 were systemically injected with either vehicle, estradiol, the estrogen receptor (ER)α agonist PPT, the ERß agonist DPN, or the G-protein-coupled receptor 1 (GPER-1) agonist G1. On postnatal days 19 ± 2, MSN electrophysiological properties were assessed using whole cell patch clamp recordings. Estradiol exposure abolished increased intrinsic excitability in female compared to male MSNs. Exposure to either an ERα or ERß agonist masculinized female MSN evoked action potential firing rate properties, whereas exposure to an ERß agonist masculinized female MSN inward rectification properties. Exposure to ER agonists minimally impacted male MSN electrophysiological properties. These findings indicate that perinatal estradiol exposure masculinizes MSN electrophysiological phenotype via activation of ERα and ERß.NEW & NOTEWORTHY This study is the first to demonstrate that estradiol and estrogen receptor α and ß stimulation during early development sexually differentiates the electrophysiological properties of caudate-putamen medium spiny neurons, the primary output neuron of the striatal regions. Overall, this evidence provides new insight into the neuroendocrine mechanism by which caudate-putamen neuron electrophysiology is sexually differentiated and demonstrates the powerful action of early hormone exposure upon individual neuron electrophysiology.

A single dose of escitalopram blunts the neural response in the thalamus and caudate during monetary loss.

Background: Selective serotonin reuptake inhibitors (SSRIs) show acute effects on the neural processes associated with negative affective bias in healthy people and people with depression. However, whether and how SSRIs also affect reward and punishment processing on a similarly rapid time scale remains unclear. Methods: We investigated the effects of an acute and clinically relevant dose (20 mg) of the SSRI escitalopram on brain response during reward and punishment processing in 19 healthy participants. In a doubleblind, placebo-controlled study using functional MRI, participants performed a well-established monetary reward task at 3 time points: at baseline; after receiving placebo or escitalopram; and after receiving placebo or escitalopram following an 8-week washout period. Results: Acute escitalopram administration reduced blood-oxygen-level-dependent (BOLD) response during punishment feedback in the right thalamus (family-wise error corrected [FWE] p = 0.013 at peak level) and the right caudate head (pFWE = 0.011 at peak level) compared to placebo. We did not detect any significant BOLD changes during reward feedback. Limitations: We included only healthy participants, so interpretation of findings are limited to the healthy human brain and require future testing in patient populations. The paradigm we used was based on monetary stimuli, and results may not be generalizable to other forms of reward. Conclusion: Our findings extend theories of rapid SSRI action on the neural processing of rewarding and aversive stimuli and suggest a specific and acute effect of escitalopram in the punishment neurocircuitry.

Altered mRNA Levels of Stress-Related Peptides in Mouse Hippocampus and Caudate-Putamen in Withdrawal after Long-Term Intermittent Exposure to Tobacco Smoke or Electronic Cigarette Vapour.

Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive-compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.

A link between synaptic plasticity and reorganization of brain activity in Parkinson's disease.

The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D2 receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D2 receptors (using 11C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D2 binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain.

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function.

Effects of gonadectomy and dihydrotestosterone on neuronal plasticity in motivation and reward related brain regions in the male rat.

Gonadal hormones affect neuronal morphology to ultimately regulate behaviour. In female rats, oestradiol mediates spine plasticity in hypothalamic and limbic brain structures, contributing to long-lasting effects on motivated behaviour. Parallel effects of androgens in male rats have not been extensively studied. Here, we investigated the effect of both castration and androgen replacement on spine plasticity in the nucleus accumbens shell and core (NAcSh and NAcC), caudate putamen (CPu), medial amygdala (MeA) and medial preoptic nucleus (MPN). Intact and castrated (gonadectomy [GDX]) male rats were treated with dihydrotestosterone (DHT, 1.5 mg) or vehicle (oil) in three experimental groups: intact-oil, GDX-oil and GDX-DHT. Spine density and morphology, measured 24 hours after injection, were determined through three-dimensional reconstruction of confocal z-stacks of DiI-labelled dendritic segments. We found that GDX decreased spine density in the MPN, which was rescued by DHT treatment. DHT also increased spine density in the MeA in GDX animals compared to intact oil-treated animals. By contrast, DHT decreased spine density in the NAcSh compared to GDX males. No effect on spine density was observed in the NAcC or CPu. Spine length and spine head diameter were unaffected by GDX and DHT in the investigated brain regions. In addition, immunohistochemistry revealed that DHT treatment of GDX animals rapidly increased the number of cell bodies in the NAcSh positive for phosphorylated cAMP response-element binding protein, a downstream messenger of the androgen receptor. These findings indicate that androgen signalling plays a role in the regulation of spine plasticity within neurocircuits involved in motivated behaviours.

Differential functional dysconnectivity of caudate nucleus subdivisions in Parkinson's disease.

Caudate dopaminergic dysfunction is implied in the pathophysiology of patients with Parkinson's disease (PD). Still, connectivity specificities of the caudate nucleus (CN) subdivisions and the effect of dopamine are poorly understood. We collected MRI and neuropsychological data from 34 PD patients and 26 age- and sex-matched healthy elderly individuals (HEs) in this study. Resting-state functional connectivity analysis revealed that compared to the other CN subdivisions, the CN head was more strongly connected to the default mode network (DMN), the CN body to the frontoparietal network (FPN), and the CN tail to the visual network in HEs. PD patients off medication showed reduced connectivity within all these subdivision networks. In PD patients on medication, functional connectivity in the CN head network was significantly improved in the medial prefrontal cortex and in the body network it was improved in the dorsolateral prefrontal cortex. These improvements contributed to ameliorated motivation and cognitive function in PD patients. Our results highlighted the specific alterations and dopamine modulation in these CN subdivision networks in PD, which may provide insight into the pathophysiology and therapeutics of this disease.

Pain-modulating effects of oxytocin in patients with chronic low back pain.

The neuropeptide oxytocin (OT) has been shown to play a modulatory role in nociception. However, analgesic effects of OT in chronic pain conditions remain elusive and the neural underpinnings have not yet been investigated in humans. Here, we conducted an exploratory, randomized, placebo-controlled, cross-over study to examine effects of intranasal OT in male patients suffering from chronic low back pain (CBP) versus healthy controls (HC). N = 22 participants with CBP and 22 HCs were scanned using functional magnetic resonance imaging (fMRI) while they continuously rated either spontaneously occurring back pain or acute thermal pain stimuli applied to the lower back. During heat pain processing we found that OT versus PL attenuated pain intensity ratings and increased BOLD responses in the caudate nucleus of the striatum in CBP versus HCs. Spontaneously experienced pain in contrast to heat pain was associated with activation changes in the medial frontal cortex (MFC) and the anterior cingulate cortex (ACC) as reported in previous studies. However, we did not observe OT effects on spontaneously experienced pain in CBP patients. Overall, our preliminary data may suggest that the striatum is a key structure underlying the pain-modulating effects of OT in patients with chronic pain and adds to the growing evidence linking the neuropeptide to pain modulation in humans. Further studies on neuronal OT effects in larger samples of chronic back pain patients are needed to understand probable mechanisms of OT effects in chronic pain. This article is part of the special issue on Neuropeptides.

Sex difference in dopamine D1-D2 receptor complex expression and signaling affects depression- and anxiety-like behaviors.

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.

The prefrontal cortex and the caudate nucleus respond conjointly to methylphenidate (Ritalin). Concomitant behavioral and neuronal recording study.

Methylphenidate (MPD) is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Recently, it is being abused for cognitive enhancement and recreation leading to concerns regarding its addictive potential. The prefrontal cortex (PFC) and caudate nucleus (CN) are two of the brain structures involved in the motive/reward circuit most affected by MPD and are also thought to be responsible for ADHD phenomena. This study is unique in that it investigated acute and chronic, dose-response MPD exposure on animals' behavior activity concomitantly with PFC and CN neuronal circuitry in freely behaving adult animals without the interference of anesthesia. Further, it compared acute and chronic MPD action on over 1,000 subcortical and cortical neurons simultaneously, allowing for a more accurate interpretation of drug action on corticostriatal neuronal circuitry. For this experiment, four groups of animals were used: saline (control), 0.6, 2.5, and 10.0 mg/kg MPD following acute and repetitive exposure. The data shows that the same MPD dose elicits behavioral sensitization in some animals and tolerance in others and that the PFC and CN neuronal activity correlates with the animals' behavioral responses to MPD. The expression of sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. In general, a greater percentage of CN units responded to both acute and chronic MPD exposure as compared to PFC units. Dose response differences between the PFC and the CN units were observed. The dichotomy that some PFC and CN units responded to the same MPD dose by excitation and other units by attenuation in neuronal firing rate is discussed. In conclusion, to understand the mechanism of action of the drug, it is essential to study, simultaneously, on more than one brain site, the electrophysiological and behavioral effects of acute and chronic drug exposure, as sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. The behavioral and neuronal data obtained from this study indicates that chronic MPD exposure results in behavioral and biochemical changes consistent with a substance abuse disorder.

Methamphetamine acutely alters frontostriatal resting state functional connectivity in healthy young adults.

Chronic use of methamphetamine impairs frontostriatal structure and function, which may result in increased incentive-motivational responses to drug cues and decreased regulation of drug-seeking behavior. However, less is known regarding how the drug affects these circuits after acute administration. The current study examined the effects of a single dose of methamphetamine on resting state frontostriatal functional connectivity in healthy volunteers. Participants (n = 22, 12 female) completed two sessions in which they received methamphetamine (20 mg) and placebo before a resting state scan during functional magnetic resonance imaging. Participants also provided self-report measures of euphoria and stimulation at regular intervals. We conducted seed-based voxelwise functional connectivity analyses using three bilateral striatal seed regions: nucleus accumbens (NAcc), caudate, and putamen and compared connectivity following methamphetamine versus placebo administration. Additionally, we conducted correlational analyses to assess if drug-induced changes in functional connectivity were related to changes in subjective response. Methamphetamine increased NAcc functional connectivity with medial frontal regions (ie, orbitofrontal cortex, medial frontal gyrus, and superior frontal gyrus) and decreased NAcc functional connectivity with subgenual anterior cingulate cortex (ACC). Methamphetamine also increased functional connectivity between putamen and left inferior frontal gyrus (IFG), and individuals who displayed greater drug-induced increase in connectivity reported less euphoria and stimulation. These findings provide important information regarding the effects of methamphetamine on brain function in nonaddicted individuals. Further studies will reveal whether such effects contribute to the abuse potential of the drug and whether they are related to the frontostriatal impairments observed after chronic methamphetamine use.

Anticipation of monetary reward in amygdala, insula, caudate are predictors of pleasure sensitivity to d-Amphetamine administration.

BACKGROUND: Drug addiction and dependence continue as an unresolved source of morbidity and mortality. Two approaches to identifying risk for abuse and addiction are psychopharmacological challenge studies and neuroimaging experiments. The present study combined these two approaches by examining associations between self-reported euphoria or liking after a dose of d-amphetamine and neural-based responses to anticipation of a monetary reward. METHODS: Healthy young adults (N = 73) aged 19 and 26, without any history of alcohol/substance dependence completed four laboratory sessions in which they received oral d-amphetamine (20 mg) or placebo, and completed drug effect questionnaires. On a separate session they underwent a functional magnetic resonance imaging scan while they completed a monetary incentive delay task. During the task, we recorded neural signal related to anticipation of winning $5 or $1.50 compared to winning no money (WinMoney-WinZero), in reward related regions. RESULTS: Liking of amphetamine during the drug sessions was related to differences in activation during the WinMoney-WinZero conditions - in the amygdala (positive), insula (negative) and caudate (negative). In posthoc analyses, liking of amphetamine was also positively correlated with activation of the amygdala during anticipation of large rewards and negatively related to activation of the left insula to both small and large anticipated rewards. CONCLUSIONS: These findings suggest that individual differences in key regions of the reward network are related to rewarding subjective effects of a stimulant drug. To further clarify these relationships, future pharmacofMRI studies could probe the influence of amphetamine at the neural level during reward anticipation.

Resolvin D1 suppresses inflammation-induced hyperexcitability of nociceptive trigeminal neurons associated with mechanical hyperalgesia.

7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (resolvin D1 [RvD1]) is biosynthesized from docosahexaenoic acid (DHA), and belongs to a novel family of lipid mediators showing remarkable anti-inflammatory effects; however, the effect of RvD1 on inflammation-induced hyperexcitability of nociceptive neurons under in vivo conditions remains to be determined. The present study, therefore, investigated whether under in vivo conditions, systemic administration of RvD1 could attenuate the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis (SpVc) wide-dynamic range (WDR) neurons associated with hyperalgesia in rats. The threshold of escape from mechanical stimulation applied to the orofacial area in rats with complete Freund's adjuvant-induced inflammation was significantly lower than in naïve rats. The lowered mechanical threshold in rats with inflammation was returned to control levels following administration of RvD1 (3 ng/kg, i.p.) for 3 days. The mean discharge frequency of SpVc WDR neurons in rats with inflammation was significantly decreased after RvD1 administration for both non-noxious and noxious mechanical stimuli. Increased spontaneous discharge of SpVc WDR neurons in rats with inflammation was also significantly decreased after RvD1 administration. Noxious pinch-evoked afterdischarge frequency and occurrence in rats with inflammation was significantly diminished after RvD1 administration. Expansion of the receptive field in rats with inflammation also returned to control levels after RvD1 administration. These results suggest that administration of RvD1 attenuates inflammation-induced hyperexcitability of SpVc WDR neurons associated with inflammatory hyperalgesia. These findings support the idea that RvD1, derived from DHA, as well as DHA itself, are potential complementary or alternative therapeutic agents for the alleviation of inflammatory hyperalgesia.