Dopamine Modulation Research Articles

A Biologically Inspired Behavior Control for the Unexpected Uncertainty With Motivated Developmental Network

During the movement of the mobile robot, except the common scenario, sometimes, the robot has to face the unexpected uncertainty in the environment. Traditional methods to address this problem generally use the task-specific method from the engineering perspective, lacking flexibility in the changing environment and being difficult to respond to the environmental challenges. Because of the function of the brain’s neuromodulatory system, human beings have ability to respond to the ever-changing environment quickly. To simulate the working mechanism of the human brain in responding to the unexpected uncertainty in the environment, this article presents a motivated developmental network (MDN) to offer a control configuration for an artificial agent to face the unexpected uncertainty in the environment, through introducing the acetylcholine/norepinephrine (ACh/NE) systems to the MDN. Taking the regulation role of ACh/NE in serotonin and dopamine (DA) into account, a novel learning rate for the hidden layer neurons of the MDN is proposed. Moreover, a novel composite mechanism is presented to decide the moving direction of the agent. Under the modulation of DA, serotonin, ACh, and NE, the agent can perform specific functions effectively, e.g., chase a target and elude the obstacle, especially the sudden obstacle. Goal-directed pursuing behavior in three simulation cases illustrates the effect of the presented neural modulatory systems, for instance, dealing with the unexpected uncertainty, realizing the attentional effort, reinforcement learning, etc. To the best of our knowledge, this article is the first endeavor to address the unexpected uncertainty with the MDN.

Efficacy of Asenapine in Schizophrenia Resistant to Clozapine Combined with Electroconvulsive Therapy: A Case Report.

Schizophrenic patients resistant to antipsychotics are diagnosed as having treatment-refractory schizophrenia, and they are treated with clozapine. However, clozapine is sometimes combined with electroconvulsive therapy (ECT) if clozapine monotherapy fails. In this report, a severe treatment-refractory schizophrenic patient who did not respond to clozapine even with ECT, but who recovered with asenapine monotherapy, is presented. Asenapine, considered a serotonin spectrum dopamine modulator, is a new atypical antipsychotic with unique pharmacological features that is used not only for schizophrenia, but also for bipolar disorder. The unique features of asenapine may be effective for some treatment-refractory schizophrenic patients.

The anterior caudate nucleus supports impulsive choices triggered by pramipexole.

Pramipexole is a dopamine agonist used as a treatment in PD and restless legs syndrome to reduce motor symptoms, but it often induces impulse control disorders. In particular, patients with impulse control disorders tend to make more impulsive choices in the delay discounting task, that is, they choose small immediate rewards over larger delayed ones more often than patients without impulse control disorders and healthy subjects do. Yet the site of action of pramipexole that produces these impulsive choices remains unknown. Based on the heterogeneity of corticostriatal projections and the massive dopamine innervation of the striatum, we hypothesized that impulsive choices triggered by dopamine treatments may be supported by a specific striatal territory. This study aims to determine by which anteriorstriatum territory the Pramipexole trigger impulsive choices; the caudate nucleus, the ventral striatum or the putamen. We compared pramipexole intramuscular injections to intracerebral microinjections within the three striatal territories in healthy monkeys trained to execute the delay discounting task, a behavioral paradigm typically used to evaluate impulsive choices. We found that pramipexole intramuscular injections induced impulsive choices in all monkeys. Local microinjections were performed inside the anterior caudate nucleus, ventral striatum, and anterior putamen and reproduced those impulsive choices when pramipexole was directly injected into the caudate nucleus, whereas injections into the ventral striatum or putamen had no effect on monkeys' choices. These results, consistent with clinical studies, suggest that impulsive choices triggered by pramipexole are supported by the caudate nucleus, allowing us to emphasize the importance of dopamine modulation inside this striatal territory in decision processes underlying impulsive behaviors. © 2019 International Parkinson and Movement Disorder Society.

Deletion of Glycogen Synthase Kinase-3β in D2 Receptor–Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor–Dependent Synaptic Plasticity

BackgroundCortical dopaminergic systems are critically involved in prefrontal cortex (PFC) functions, especially in working memory and neurodevelopmental disorders such as schizophrenia. GSK-3β (glycogen synthase kinase-3β) is highly associated with cAMP (cyclic adenosine monophosphate)–independent dopamine D2 receptor (D2R)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via D2Rs remains unclear. MethodsThis study explored how conditional cell-type–specific ablation of GSK-3β in D2R+ neurons (D2R-GSK-3β−/−) in the brain affects synaptic function in the medial PFC (mPFC). Both male and female (postnatal days 60–90) mice, including 140 D2R, 24 D1R, and 38 DISC1 mice, were used. ResultsThis study found that NMDA receptor (NMDAR) function was significantly increased in layer V pyramidal neurons in mPFC of D2R-GSK-3β−/− mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of D2R-GSK-3β−/− mice. This change was accompanied by a significant increase in enrichment of activator histone mark H3K27ac at the promoters of both Grin2a and Grin2b genes. In addition, altered short- and long-term synaptic plasticity, along with an increased spine density in layer V pyramidal neurons, were detected in D2R-GSK-3β−/− mice. Indeed, D2R-GSK-3β−/− mice also exhibited a resistance of working memory impairment induced by injection of NMDAR antagonist MK-801. Notably, either inhibiting GSK-3β or disrupting the D2R-DISC1 complex was able to reverse the mutant DISC1-induced decrease of NMDAR-mediated currents in the mPFC. ConclusionsThis study demonstrates that GSK-3β modulates cognition via D2R-DISC1 interaction and epigenetic regulation of NMDAR expression and function.

Dimensions of control for subthreshold oscillations and spontaneous firing in dopamine neurons

Dopaminergic neurons (DAs) of the rodent substantia nigra pars compacta (SNc) display varied electrophysiological properties in vitro. Despite this, projection patterns and functional inputs from DAs to other structures are conserved, so in vivo delivery of consistent, well-timed dopamine modulation to downstream circuits must be coordinated. Here we show robust coordination by linear parameter controllers, discovered through powerful mathematical analyses of data and models, and from which consistent control of DA subthreshold oscillations (STOs) and spontaneous firing emerges. These units of control represent coordinated intracellular variables, sufficient to regulate complex cellular properties with radical simplicity. Using an evolutionary algorithm and dimensionality reduction, we discovered metaparameters, which when regressed against STO features, revealed a 2-dimensional control plane for the neuron’s 22-dimensional parameter space that fully maps the natural range of DA subthreshold electrophysiology. This plane provided a basis for spiking currents to reproduce a large range of the naturally occurring spontaneous firing characteristics of SNc DAs. From it we easily produced a unique population of models, derived using unbiased parameter search, that show good generalization to channel blockade and compensatory intracellular mechanisms. From this population of models, we then discovered low-dimensional controllers for regulating spontaneous firing properties, and gain insight into how currents active in different voltage regimes interact to produce the emergent activity of SNc DAs. Our methods therefore reveal simple regulators of neuronal function lurking in the complexity of combined ion channel dynamics.

Modulation of brain serotonin by benzyl butyl phthalate in Fundulus heteroclitus (mummichog).

Endocrine-disrupting chemicals have been known to alter important animal behaviors by modulating serotonin (5-hydroxytryptamine, 5-HT) and dopamine. F. heteroclitus (mummichog) brain serotonin and dopamine levels were quantified by enzyme-linked immunosorbent assay (ELISA) following a 28-day exposure regimen involving daily doses of either 0.1 mg l-1 benzyl butyl phthalate (BBP) dissolved in acetone or acetone alone (0.1 mg l-1). No differences in mean brain mass or total protein homogenate were induced by exposure to the acetone vehicle or BBP in acetone. The acetone vehicle had no effect on dopamine, serotonin, or tyrosine hydroxylase levels, but acetone did decrease tryptophan hydroxylase levels (p = 0.011). Exposure to BBP in acetone decreased dopamine (p = 0.024), increased serotonin (p < 0.001), reduced tryptophan hydroxylase as compared to the acetone vehicle alone (p < 0.001), and had no significant effect on tyrosine hydroxylase levels. This study is the first to report modulation of F. heteroclitus brain serotonin and its enzyme tryptophan hydroxylase following sub-lethal exposure to BBP in an acetone vehicle. In addition, modulation of brain dopamine in F. heteroclitus, sans simultaneous modulation of tyrosine hydroxylase, was also observed. These findings support the use of F. heteroclitus for assessing sub-lethal BBP exposure.

(Invited) Integration of In Vivo Electroanalytical and Genetic Techniques to Decode Local Catecholamine Circuits in the Brain

Electroanalytical methods, especially, fast-scan cyclic voltammetry (FSCV) coupled with carbon-fiber microelectrodes, have been widely used to study rapid changes in neurochemical concentrations and provide a local view of neurotransmission in real time. However, electroanalytical methods alone are limited to understand the distinct roles of local neural circuits in different brain areas or even subregions of the same brain area. In recent years, the development of novel genetic approaches such as optogenetics and chemogenetics have made it possible to selectively target and control (excite or inhibit) specific neural circuits in a neurochemically heterogeneous brain without affecting surrounding cells or fibers of passage. In this study, we demonstrate that a novel combination of in vivo FSCV coupled with chemogenetics permits us to determine local catecholamine transmission by individually manipulating dopamine (DA) or norepinephrine (NE) neurons and how chemogenetic modulation of DA or NE transmission is correlated with behavioral changes. These findings will be the fundamental framework to understand how individual local catecholamine circuits are distinctly linked to essential brain functions as well as common psychiatric and neurodegenerative diseases.

Cellular and Synaptic Dysfunctions in Parkinson's Disease: Stepping out of the Striatum.

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson’s disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed.

Multidisciplinary and Comparative Investigations of Potential Psychobiotic Effects of Lactobacillus Strains Isolated From Newborns and Their Impact on Gut Microbiota and Ileal Transcriptome in a Healthy Murine Model.

Psychobiotics are probiotic microorganisms that may exert positive influence on the psychological status of the host. Studies have revealed immunological and microbiological correlations of gut microbiota and the gut-brain axis, and have investigated psychobiotics based on the findings of the gut-brain axis. Considering their mode of actions, the present study sets anti-inflammatory effect, neurotransmitter modulation, and gut microbiota modulation as three essential criteria to evaluate Lactobacillus casei ATG-F1 (F1), L. reuteri ATG-F3 (F3), and L. reuteri ATG-F4 (F4) isolated from newborns as psychobiotics candidates in a healthy mouse model and compares the results with a non-treated control group and an ampicillin-induced gut dysbiosis (Amp) group as a negative control. The F3 and F4 strains showed anti-inflammatory effects in vitro in RAW264.7 murine macrophages, and the level of anti-inflammatory cytokine interleukin (IL)-10 increased in ileums of mice orally administered with the F4 strain. Serum dopamine level significantly increased only in the F4-treated group as compared with the control group. Serum serotonin level was unaffected in Lactobacillus-treated groups, while a significant decrease in serum serotonin level was observed in the Amp group. Bacteroidetes population increased in fecal samples of the F4-treated group as compared with the control, and Bacteroidales S24-7 and Prevotellaceae population significantly increased at family level in fecal samples from the F4-treated group as compared with the control. In contrast, the Amp group showed an increase in the level of Proteobacteria and a decrease in the level of Bacteroidetes as compared with the control group. Transcriptome analysis revealed a distinctive clustering in ileums from the F4-treated group as compared to other experimental groups. In addition, the circadian rhythm pathway showed maximum enrichment in ileums of Lactobacillus-treated mice, and the F4-treated group showed the highest fold changes in circadian rhythm-related genes (Dbp, Per1, Per2, and Per3). Conclusively, L. reuteri ATG-F4 is suggested as a potential psychobiotics through demonstrations of anti-inflammatory effects, serum dopamine modulation, and gut microbiota modulation in a healthy murine model in the present study. Moreover, we carefully suggest gut circadian rhythm modulation as another important criterion of psychobiotics, which may have an important role in the gut-brain axis.

Dysfunctional striatal dopamine signaling in Huntington's disease.

Dopamine signaling in the striatum is critical for a variety of behaviors including movement, behavioral flexibility, response to reward and many forms of learning. Alterations to dopamine transmission contribute to pathological features of many neurological diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disorder caused by a CAG repeat expansion in the Huntingtin gene. The striatum is preferentially degenerated in HD, and this region receives dopaminergic input from the substantia nigra. Studies of HD patients and genetic rodent models have shown changes to levels of dopamine and its receptors in the striatum, and alterations in dopamine receptor signaling and modulation of other neurotransmitters, notably glutamate. Throughout his career, Dr. Michael Levine's research has furthered our understanding of dopamine signaling in the striatum of healthy rodents and HD mouse models. This review will focus on the work of his group and others in elucidating alterations to striatal dopamine signaling that contribute to pathophysiology in HD mouse models, and how these findings relate to human HD studies. We will also discuss current and potential therapeutic interventions for HD that target the dopamine system, and future research directions for this field.

Altering Opioid Neuromodulation in the Songbird Basal Ganglia Modulates Vocalizations.

Although the interplay between endogenous opioids and dopamine (DA) in the basal ganglia (BG) is known to underlie diverse motor functions, few studies exist on their role in modulating speech and vocalization. Vocal impairment is a common symptom of Parkinson’s disease (PD), wherein DA depletion affects striosomes rich in μ-opioid receptors (μ-ORs). Symptoms of opioid addiction also include deficiencies in verbal functions and speech. To understand the interplay between the opioid system and BG in vocalization, we used adult male songbirds wherein high levels of μ-ORs are expressed in Area X, a BG region which is part of a circuit similar to the mammalian thalamocortical-basal ganglia loop. Changes in DA, glutamate and GABA levels were analyzed during the infusion of different doses of the μ-OR antagonist naloxone (50 and 100 ng/ml) specifically in Area X. Blocking μ-ORs in Area X with 100 ng/ml naloxone led to increased levels of DA in this region without altering the number of songs directed toward females (FD). Interestingly, this manipulation also led to changes in the spectro-temporal properties of FD songs, suggesting that altered opioid modulation in the thalamocortical-basal ganglia circuit can affect vocalization. Our study suggests that songbirds are excellent model systems to explore how the interplay between μ-ORs and DA modulation in the BG affects speech/vocalization.

Physiological aging at striatal synapses.

Mike Levine's body of work guides thinking on how the basal ganglia process information to create coordinated movements and skill learning throughout the life span and in disease. This special issue is a nod to Mike's career and a well-deserved gesture by the neuroscience community thanking him for the impact he has made on many people's careers and the field of basal ganglia physiology. This paper reviews how aging impacts basal ganglia processing with a focus on single cell and synaptic physiology. This review begins with the work Mike did with his collaborators Nat Buchwald, Chester Hull and Jay Schneider. These early studies paved the way for subsequent studies on changes in synaptic processing that occur with aging in the basal ganglia. The primary focus of this review is aging at corticostriatal synapses. Corticostriatal synapses show reduced expression of both short-term and long-term synaptic potentiation. The roles of age-related changes in calcium homeostasis, vesicle cycling, dopamine modulation, and NMDA receptor function in aging's effect on synaptic plasticity are discussed. The article ends with a review of mitochondrial aging theory as it applies to age-induced changes in corticostriatal synaptic function.

Multiple tracking and machine learning reveal dopamine modulation for area-restricted foraging behaviors via velocity change in Caenorhabditis elegans

Food exploration is an essential survival behavior in organisms. To find food efficiently, many organisms use a foraging strategy called area-restricted search (ARS) wherein individuals first turn more frequently, restricting their search to one area, then turn less frequently, moving along a straight path to widen the search area. Previous research suggests that the nematode Caenorhabditis elegans shows ARS behavior by changing turn frequency, and that dopamine is a crucial determinant. However, the effects of dopamine on multiple behavioral parameters have remained unknown. Here, we evaluated turn (pirouette) frequency, moving velocity, and specific area occupancy (cell occupancy) over time by using a multiple-worms tracking system. In the control (mock) experiments, all parameters changed over time, but no changes were observed in experiments with dopamine pre-exposed and dopamine-deficient animals. In inverse reinforcement learning analysis, the value function for specific velocity was found to modulate over time in mock animals only. These results demonstrate that dopamine regulates ARS via changes not only to pirouette frequency change but also to velocity.

Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

Aging and dopamine modulation have both been independently shown to influence the functional connectivity of brain networks during rest. Dopamine modulation is known to decline during the course of aging. Previous evidence also shows that the dopamine transporter gene (DAT1) influences the re-uptake of dopamine and the anyA9 genotype of this gene is associated with higher striatal dopamine signaling. Expanding these two lines of prior research, we investigated potential interactive effects between aging and individual variations in the DAT1 gene on the modular organization of brain acvitiy during rest. The graph-theoretic metrics of modularity, betweenness centrality and participation coefficient were assessed in 41 younger (age 20–30 years) and 37 older (age 60–75 years) adults. Age differences were only observed in the participation coefficient in carriers of the anyA9 genotype of the DAT1 gene and this effect was most prominently observed in the default mode network. Furthermore, we found that individual differences in the values of the participation coefficient correlated with individual differences in fluid intelligence and a measure of executive control in the anyA9 carriers. The correlation between participation coefficient and fluid intelligence was mainly shared with age-related differences, whereas the correlation with executive control was independent of age. These findings suggest that DAT1 genotype moderates age differences in the functional integration of brain networks as well as the relation between network characteristics and cognitive abilities.

F174. Testosterone Modulation of Sex Steroid and Dopamine–Related mRNAs During Adolescence in the Mesolimbic Pathway

F174. Testosterone Modulation of Sex Steroid and Dopamine–Related mRNAs During Adolescence in the Mesolimbic Pathway

Reward Prediction Error Modulates Saccade Vigor.

Movement vigor, defined as the reciprocal of the latency from availability of reward to its acquisition, changes with reward magnitude: movements exhibit shorter reaction time and increased velocity when they are directed toward more rewarding stimuli. This invigoration may be due to release of dopamine before movement onset, which has been shown to be modulated by events that signal reward prediction error (RPE). Here, we generated an RPE event in the milliseconds before movement onset and tested whether there was a relationship between RPE and vigor. Human subjects (both sexes) made saccades toward an image. During execution of the primary saccade, we probabilistically changed the position and content of that image, encouraging a secondary saccade. On some trials, the content of the secondary image was more valuable than the first image, resulting in a positive RPE (+RPE) event that preceded the secondary saccade. On other trials, this content was less valuable (-RPE event). We found that reaction time of the secondary saccade was affected in an orderly fashion by the magnitude and direction of the preceding RPE event: the most vigorous saccades followed the largest +RPE, whereas the least vigorous saccades followed the largest -RPE. Presence of the secondary saccade indicated that the primary saccade had experienced a movement error, inducing trial-to-trial adaptation. However, this learning from movement error was not modulated by the RPE event. The data suggest that RPE events, which are thought to transiently alter the release of dopamine, modulate the vigor of the ensuing movement.SIGNIFICANCE STATEMENT Does dopamine release in response to a stimulus serve to invigorate the ensuing movement? To test this hypothesis, we relied on the fact that reward prediction error (RPE) is a strong modulator of dopamine. Our innovation was a task in which an RPE event occurred precisely before onset of a stimulus-driven movement. We probabilistically produced a combination of large or small, negative or positive RPE events and observed that saccade vigor carried a robust signature of the preceding RPE event: high vigor saccades followed +RPE events, whereas low vigor saccades followed -RPE events. This suggests that in humans, vigor is partly controlled through release of dopamine in the moments before onset of a movement.

Dopamine Modulation of Prefrontal Cortex Activity Is Manifold and Operates at Multiple Temporal and Spatial Scales

Although the function of dopamine in subcortical structures is largely limited to reward and movement, dopamine neurotransmission in the prefrontal cortex (PFC) is critical to a multitude of temporally and functionally diverse processes, such as attention, working memory, behavioral flexibility, action planning, and sustained motivational and affective states. How does dopamine influence computation of these temporally complex functions? We find causative links between sustained and burst patterns of phasic dopamine neuron activation and modulation of medial PFC neuronal activity at multiple spatiotemporal scales. These include a multidirectional and weak impact on individual neuron rateactivity but a robust influence on coordinated ensemble activity, gamma oscillations, and gamma-theta coupling that persisted for minutes. In addition, PFC network responses to burst pattern of dopamine firing wereselectively strengthened in behaviorally active states. This multiplex mode of modulation by dopamine input may enable PFC to compute and generate spatiotemporally diverse and specialized outputs.

Sexual Dimorphism of Behavioral Response to Dopamine Modulation in Drosophila

IntroductionDespite considerable evidence that women are more vulnerable to addiction than men, biomedical research has been performed almost exclusively in males, and the results assumed to apply equally to men and women. Recent NIH policy regarding inclusion of sex as a biological variable is contributing to more proportional evaluation and greater translational value of future publications, but the current body of literature contains very little regarding sex differences in Drosophila melanogaster response to psychostimulants. While studying the contributions of the serotonergic system on psychostimulant response in Drosophila using DREADD technology and the Drosophila Activity Monitoring System (DAMS), we found sexually dimorphic behavioral responses to methamphetamine in numerous strains of Drosophila. Although tangential to our initial objective, we explored the influence of sex as a biological variable on locomotor response to dopaminergic modulation.ObjectiveTo describe sexually dimorphic behavioral responses to dopaminergic modulation in several strains of Drosophila.MethodsRecently eclosed, non‐entrained, male and female flies (n=16/group) were fed 5 mM methamphetamine in vehicle medium or vehicle medium (10% sucrose, 1% agarose gel) and monitored in the DAMS under constant light conditions for one week. Beam breaks recorded by the DAMS were summed into one‐hour bins and group means were calculated. Group means were then evaluated individually with repeat measures ANOVA, and included in a meta‐analysis using sex (male, female) as subgroups. A separate experiment used two wild‐type strains with established locomotor differences to evaluate the influence of sex and strain on locomotor response to 3 mM DL‐α‐Methyltyrosine (metyrosine), a tyrosine 3‐monooxygenase inhibitor. Metyrosine administration and DAMS monitoring was performed as described above, and group means were then evaluated using repeat measures ANOVA.ResultsMale and female flies displayed significantly increased locomotor activity than control flies when fed methamphetamine. Female flies of all strains displayed significantly higher baseline activity than male flies, but significantly less methamphetamine‐induced increases in locomotor activity than male flies. While male flies fed methamphetamine displayed persistent, steady increases in locomotor activity throughout the studies, female flies fed methamphetamine displayed progressively smaller locomotor differences Days 4–7, and no behavioral differences from control flies on Day 8.Male and female flies displayed significantly decreased decreased locomotor activity than control flies when fed metyrosine. Female flies of both strains displayed significantly higher baseline activity than male flies, but significantly more metyrosine‐induced decreases in locomotor activity than male flies. Metyrosine‐induced reductions in locomotor activity were persistent and steady for both male and female flies throughout the duration of the experiment.Support or Funding InformationThis work was supported in whole by the National Institute on Drug Abuse of the National Institutes of Health under award number R21DA039462. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain

A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.

(237) Periaqueductal Gray Dopaminergic Neurons Modulate Peripheral Inflammatory Hyperalgesia

Neural dopamine (DA) modulators such as ᴅ-amphetamine and methylphenidate provide a promising new approach to treating pain. Though the mechanism by which they produce analgesia is poorly understood, these psychostimulants are antinociceptive and counteract the opioid-induced side effects of respiratory depression and sedation. Despite their potential, DA-modulating drugs have never been adopted clinically for pain relief, possibly due to a lack of understanding their mechanism of action. Considering previous evidence of a role of DA neurons from the periaqueductal gray (PAG) in pain modulation, we hypothesized that PAG DA neurons are antinociceptive and contribute significantly to the analgesic effect of ᴅ-amphetamine via descending spinal cord inhibition at the rostral ventral medulla (RVM). Male C57BL/6 mice that had received carrageenan in the hind paw were treated intraperitoneally with ᴅ-amphetamine, and its analgesic effect was compared with the analgesia produced by morphine. Separate groups of mice were stereotaxically prepared with infusion cannula targeted to either the PAG or RVM. We observed that the inhibition of thermal hyperalgesia in the mouse model of carrageenan-induced inflammatory pain by systemic ᴅ-amphetamine (6mg/kg) was similar to that produced by morphine (3mg/kg), and that ᴅ-amphetamine increased cFOS expression in PAG DA neurons. Targeted microinfusion of ᴅ-amphetamine, L-DOPA, or a selective D2 receptor agonist, but not a D1 agonist, into the PAG also attenuated thermal hyperalgesia, suggesting a role for D2 receptors in PAG-mediated analgesia. Finally, systemic ᴅ-amphetamine-mediated analgesia was prevented when neural transmission through the RVM was inhibited by local pretreatment with the GABAA receptor agonist muscimol. These findings indicate a modulatory role of D2 receptors and descending inhibition through GABAergic receptors at the RVM in ᴅ-amphetamine-mediated analgesia. Importantly, they indicate that the use of stimulants could enhance pain control, potentially as an alternative to opioids, avoiding the deleterious side-effects responsible for the current opioid crisis.