Phasic Dopamine Signaling Research Articles

Individual differences in modulation of dopamine release in a rodent model of substance abuse vulnerability

Despite significant advances in understanding the neurobiology underlying substance use disorders (SUDs), about 20.3 million Americans still suffered from SUD in 2018. This is due, in part, to limited effectiveness of current treatment strategies. Development of more effective treatments may be advanced by the ability to identify markers of increased risk of developing SUD following initial drug use and to target treatments to this vulnerable subpopulation. This need to better understand individual differences in SUD vulnerability is demonstrated in that only 10–20% of individuals that experiment with drugs of abuse ultimately develop SUD. Some behavioral traits such as sensation seeking are predictive of increased vulnerability, but the neurobiology underlying these individual differences remains unclear. To investigate this neurobiology, sensation seeking can be modeled in rodents by examining locomotor response to a novel environment. Rodents that demonstrate higher locomotor response to an inescapable novel environment (high responders; HR) acquire self‐administration (SA) of drugs more rapidly and stably compared to low responders (LR). Phasic firing of mesolimbic dopamine (DA) neurons plays an integral role in encoding reward‐associations and occurs in response to unexpected rewards and reward‐predictive stimuli. HR rats show increased phasic DA signaling to reward‐predictive cues compared to LR rats. Nicotinic acetylcholine receptors (nAChRs) on DA terminals in the nucleus accumbens (NAc) modulate DA release in an action potential‐independent manner through acetylcholine signaling. Our lab has previously shown that locomotor response to a novel environment can predict nAChR modulation of phasic DA signals in the NAc. Specifically, desensitization or blockade of α6β2‐containing nAChRs within the NAc was found to augment phasic DA signal in brain slices of HR but not LR animals. In the present study, we used ex vivo fast‐scan cyclic voltammetry (FSCV) to further investigate the role of NAc nAChRs in modulating DA release in HRs versus LRs. We find that modulation of DA release by α7 nAChRs can be predicted by locomotor response to novelty at phasic‐like stimulations. Given the role that nAChRs play in Ca2+ entry into the cell, we additionally tested the possibility that differential Ca2+ utilization is one mechanism underlying differential DA modulation by nAChRs and utilized pharmacological manipulations to test possible voltage‐gated Ca2+ channel (VGCC) subtype‐specific effects. Here, we demonstrate that lowered Ca2+ concentration unmasks a diverging DA release profile between HRs and LRs at stimulation frequencies modeling phasic firing and find that P/Q‐type VGCCs appear to drive these individual differences in Ca2+ utilization. In sum, these data help form a more coherent understanding of the mechanisms underlying individual differences in vulnerability. Investigating these mechanisms allows us to better identify behavioral and neurochemical markers of substance abuse risk in humans and to ultimately stimulate development of more individualized and effective treatments.Support or Funding InformationK99/R00 DA 311791, P50 DA006634, P50 AA026117, T32 DA041349‐03, Peter F. McManus Charitable Trust

Time‐of‐Day Variation in Learning, Reward‐Associated Behaviors, and in Rapid Dopamine Signaling

Approximately one in five adults in the United States suffers from at least one psychiatric disorder. Research has shown that biological rhythms in physiology and behavior play a role in a number of psychiatric disorders, like depression and substance use disorder (SUD). For example, time‐of‐day variation has been observed in craving for nicotine, heroin, and cocaine in abstinent individuals. However, we have yet to fully delineate how these rhythms mediate variations in motivated behavior, learning, and reward seeking. This is critical as aberrant motivation and learning are hallmarks in these disorders. The mesolimbic dopamine (DA) system is implicated in the neurobiology of motivation and learning, and research has shown time‐of‐day variations in DA tone. Less work has focused on rapid DA signals that are critical for motivation and learning. Thus, the purpose of this study was to examine time‐of‐day variations in incentive motivational properties of reward‐associated cues and learning and the degree to which the magnitude of mesolimbic DA release in the nucleus accumbens (NAc) corresponded to dynamic shifts in motivation and learning across time‐of‐day. Our central hypothesis is that there are critical times within the day that confer increased sensitivity to reward‐associated cues, which are mediated by time‐of‐day variations in the magnitude of phasic DA signaling. To test this hypothesis, we examined the magnitude of NAc DA signaling to stimulations that mimic both tonic and phasic firing of mesolimbic DA neurons in rats. We used ex vivo fast scan cyclic voltammetry (FSCV) at four different time points across the 12:12 light/dark cycle. Our data demonstrate robust time‐of‐day differences in DA release magnitude following stimulations that model both phasic (≥20 Hz) and tonic (5 Hz) firing. Given that the phasic/tonic ratio of DA release magnitude was greatest midway through the dark cycle and lowest midway through the light cycle, we examined whether behavioral paradigms sensitive to DA release magnitude would fluctuate consistently with these DA oscillations. We therefore utilized Pavlovian paradigms in rodents to measure incentive motivational aspects and conditioned approach towards a reward‐associated cue, during midway through the light cycle and midway through the dark cycle. Furthermore, since DA release and motivated behavior is modulated by striatal cholinergic interneuron (CIN) activity via nicotinic receptors (nAChRs) located on DA axons, we examined whether both DA release and incentive motivation was altered following nicotine exposure. Lastly, we utilized optogenetics to unmask the circuitry underlying these diurnal variations. Our current data suggest that rats midway through their dark cycle exhibit increased sensitivity to reward‐associated cues, which may be mediated by rapid DA release that is modulated by oscillations in CIN activity. These novel data support that there are be times within the day in which an individual may be more vulnerable to reward‐associated cues, which may correspond to variations in rapid DA signaling mediated by CIN oscillations throughout the day.Support or Funding InformationK99/R00 DA031791P50 DA006634P50 AA026117Peter F. McManus Charitable Trust

Abundance Compensates Kinetics: Similar Effect of Dopamine Signals on D1 and D2 Receptor Populations.

The neuromodulator dopamine plays a key role in motivation, reward-related learning, and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signaling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, because of slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signaling.SIGNIFICANCE STATEMENT Current models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.

Phasic dopamine responses to a food-predictive cue are suppressed by the glucagon-like peptide-1 receptor agonist Exendin-4

Phasic dopamine activity is evoked by reliable predictors of food reward and plays a role in cue-triggered, goal-directed behavior. While this important signal is modulated by physiological state (e.g. hunger, satiety), the mechanisms by which physiological state is integrated by dopamine neurons is only beginning to be elucidated. Activation of central receptors for glucagon-like peptide-1 (GLP-1R) via long-acting agonists (e.g., Exendin-4) suppresses food intake and food-directed motivated behavior, in part, through action in regions with dopamine cell bodies, terminals, and/or neural populations that directly target the mesolimbic dopamine system. However, the effects of GLP-1R activation on cue-evoked, phasic dopamine signaling remain unknown. Here, in vivo fiber photometry was used to capture real-time signaling dynamics selectively from dopamine neurons in the ventral tegmental area of male and female transgenic (tyrosine hydroxylase-Cre; TH:Cre+) rats trained to associate an audio cue with the brief availability of a sucrose solution. Cue presentation evoked a brief spike in dopamine activity. Administration of Exendin-4 (Ex4; 0, 0.05, 0.1 μg) to the lateral ventricle both dose-dependently suppressed sucrose-directed behaviors and the magnitude of cue-evoked dopamine activity. Moreover, the amplitude of cue evoked dopamine activity was significantly correlated with subsequent sucrose-directed behaviors. While female rats exhibited overall reduced dopamine responses to the sucrose-paired cue relative to males, there was no significant interaction with Ex4. Together, these findings support a role for central GLP-1Rs in modulating a form of dopamine signaling that influences approach behavior and provide a potential mechanism whereby GLP-1 suppresses food-directed behaviors.

Risky decision-making predicts dopamine release dynamics in nucleus accumbens shell.

The risky decision-making task (RDT) measures risk-taking in a rat model by assessing preference between a small, safe reward and a large reward with increasing risk of punishment (mild foot shock). It is well-established that dopaminergic drugs modulate risk-taking; however, little is known about how differences in baseline phasic dopamine signaling drive individual differences in risk preference. Here, we used in vivo fixed potential amperometry in male Long-Evans rats to test if phasic nucleus accumbens shell (NACs) dopamine dynamics are associated with risk-taking. We observed a positive correlation between medial forebrain bundle-evoked dopamine release in the NACs and risky decision-making, suggesting that risk-taking is associated with elevated dopamine sensitivity. Moreover, "risk-taking" subjects were found to demonstrate greater phasic dopamine release than "risk-averse" subjects. Risky decision-making also predicted enhanced sensitivity to the dopamine reuptake inhibitor nomifensine, and elevated autoreceptor function. Importantly, this hyperdopaminergic phenotype was selective for risky decision-making, as delay discounting performance was not predictive of phasic dopamine release or dopamine supply. These data identify phasic NACs dopamine release as a possible therapeutic target for alleviating the excessive risk-taking observed across multiple forms of psychopathology.

Accelerated development of cocaine-associated dopamine transients and cocaine use vulnerability following traumatic stress.

Post-traumatic stress disorder and cocaine use disorder are highly co-morbid psychiatric conditions. The onset of post-traumatic stress disorder generally occurs prior to the development of cocaine use disorder, and thus it appears that the development of post-traumatic stress disorder drives cocaine use vulnerability. We recently characterized a rat model of post-traumatic stress disorder with segregation of rats as susceptible and resilient based on anxiety-like behavior in the elevated plus maze and context avoidance. We paired this model with in vivo fast scan cyclic voltammetry in freely moving rats to test for differences in dopamine signaling in the nucleus accumbens core at baseline, in response to a single dose of cocaine, and in response to cocaine-paired cues. Further, we examined differences in the acquisition of cocaine self-administration across groups. Results indicate that susceptibility to traumatic stress is associated with alterations in phasic dopamine signaling architecture that increase the rate at which dopamine signals entrain to cocaine-associated cues and increasethe magnitude of persistent cue-evoked dopamine signals following training. These changes in phasic dopamine signaling correspond with increases in the rate at which susceptible rats develop excessive cocaine-taking behavior. Together, our studies demonstrate that susceptibility to traumatic stress is associated with a cocaine use-vulnerable phenotype and suggests that differences in phasic dopamine signaling architecture may contribute to the process by which this vulnerability occurs.

Role of homeostatic feedback mechanisms in modulating methylphenidate actions on phasic dopamine signaling in the striatum of awake behaving rats

Methylphenidate is an established treatment for attention-deficit hyperactivity disorder that also has abuse potential. Both properties may relate to blocking dopamine and norepinephrine reuptake. We measured the effects of methylphenidate on dopamine dynamics in freely moving rats. Methylphenidate alone had no effect on the amplitude of phasic responses to cues or reward. However, when administered with the D2 receptor antagonist raclopride, methylphenidate increased dopamine responses, while raclopride alone had no effect. Using brain slices of substantia nigra or striatum, we confirmed that methylphenidate effects on firing rate of nigral dopamine neurons and dopamine release from terminals are constrained by negative feedback. A computational model using physiologically relevant parameters revealed that actions of methylphenidate on norepinephrine and dopamine transporters, and the effects of changes in tonic dopamine levels on D2 receptors, are necessary and sufficient to account for the experimental findings. In addition, non-linear fitting of the model to the data from freely moving animals revealed that methylphenidate significantly slowed the initial cue response dynamics. These results show that homeostatic regulation of dopamine release in the face of changing tonic levels of extracellular dopamine should be taken into account to understand the therapeutic benefits and abuse potential of methylphenidate.

Alpha1-adrenergic receptor blockade in the ventral tegmental area modulates conditional stimulus-induced cocaine seeking

Exposure to drug-associated cues evokes drug-craving and upregulates noradrenaline (NA) and dopamine (DA) system activity. Importantly, conditional stimulus-induced drug-seeking behavior depends particularly on phasic DA signaling downstream from the ventral tegmental area (VTA), a midbrain structure key for the regulation of cocaine seeking. In particular, the activity of the alpha1-adrenergic receptor (α1-AR), which has recently been hypothesized to modulate salience encoding, is capable of bidirectional regulation of VTA dopaminergic activity. Thus, the impact of the conditional stimuli (CSs) on drug-seeking behavior might involve α1-AR signaling in the VTA. To date, the role of VTA α1-ARs in regulating CS-induced cocaine seeking has not been studied. In male Sprague–Dawley rats, we found that intra-VTA terazosin, a selective α1-AR antagonist, attenuated CS-induced cocaine seeking in a novel context and under extinction conditions, as well as CS-induced reinstatement of cocaine seeking. In contrast, terazosin microinfusion in a dose that attenuated CS-induced cocaine seeking had no effects on CS-induced food seeking or stress (2 mg/kg yohimbine)-evoked reinstatement of cocaine seeking. The potential nonspecific effects (sedative, anxiogenic) of α1-AR blockade of the VTA were also measured in the open-field test. Finally, using immunostaining, we demonstrated dopamine β-hydroxylase (DBH)-positive afferents in the VTA of cocaine-abstinent rats, providing a neuroanatomical substrate for the α1-AR mechanism. These results demonstrated for the first time that NAergic signaling via VTA α1-ARs potently and selectively regulates CS-induced cocaine seeking. Our findings provide new neuronal mechanisms that regulate cocaine craving.

Local GABAA Receptor-Mediated Suppression of Dopamine Release within the Nucleus Accumbens.

Benzodiazepines make up a class of psychoactive drugs that act as allosteric co-activators of the inhibitory GABAA receptor. These drugs are useful for the treatment of several psychiatric disorders but also hold considerable abuse liability. Despite the common use and misuse of benzodiazepines, the mechanisms through which these drugs exert their reinforcing effects remain incompletely understood. Transient phasic increases in dopamine levels are believed to play an important role in defining the reinforcing properties of drugs of abuse, and we recently demonstrated that systemic administration of benzodiazepines increased the frequency of these events but concomitantly reduced their amplitude. This observation provides insight into the pharmacological effects of benzodiazepines on dopamine signaling, but the processes through which benzodiazepines drive changes in phasic dopamine signals remain unclear. In these studies, we investigated the mechanisms through which benzodiazepines may reduce the phasic dopamine transient amplitude. We tested the effect of the benzodiazepine diazepam and the GABAA agonist muscimol on evoked dopamine release from nucleus accumbens brain slices using fast scan cyclic voltammetry. We found that both diazepam and muscimol reduce dopamine release and that reductions in dopamine release following GABAA receptor activation can be blocked by co-application of a GABAB receptor antagonist. These results suggest that activation of GABAA receptors in the nucleus accumbens decreases dopamine release by disinhibition of local GABA signaling and subsequent activation of GABAB receptors. Overall, this work provides a putative mechanism through which benzodiazepines reduce the amplitude of phasic dopamine release in vivo.

Mode of Sucrose Delivery Alters Reward-Related Phasic Dopamine Signals in Nucleus Accumbens.

In studies of appetitive Pavlovian conditioning, rewards are often delivered to subjects in a manner that confounds several processes. For example, delivery of a sugar pellet to a rodent requires movement to collect the pellet and is associated with sensory stimuli such as the sight and sound of the pellet arrival. Thus, any neurochemical events occurring in proximity to the reward may be related to multiple coincident phenomena. We used fast-scan cyclic voltammetry in rats to compare nucleus accumbens dopamine responses to two different modes of delivery: sucrose pellets, which require goal-directed action for their collection and are associated with sensory stimuli, and intraoral infusions of sucrose, which are passively received and not associated with external stimuli. We found that when rewards were unpredicted, both pellets and infusions evoked similar dopamine release. However, when rewards were predicted by distinct cues, greater dopamine release was evoked by pellet cues than infusion cues. Thus, dopamine responses to pellets, infusions as well as predictive cues suggest a nuanced role for dopamine in both reward seeking and reward evaluation.

Challenges to Body Fluid Homeostasis Differentially Recruit Phasic Dopamine Signaling in a Taste-Selective Manner.

The internal environment of an organism must remain stable to ensure optimal performance and ultimately survival. The generation of motivated behaviors is an adaptive mechanism for defending homeostasis. Although physiological state modulates motivated behaviors, the influence of physiological state on phasic dopamine signaling, an underlying neurobiological substrate of reward-driven behavior, is underexplored. Here, we use sodium depletion and water restriction, manipulations of body fluid homeostasis, to determine the flexibility and specificity of dopamine responses. Changes in dopamine concentration were measured using fast-scan cyclic voltammetry in the nucleus accumbens shell of male rats in response to intraoral infusions of fluids that either satisfied or did not satisfy homeostatic need. Increases in dopamine concentration during intraoral infusions were observed only under conditions of physiological deficit. Furthermore, dopamine increases were selective and limited to those that satisfied the need state of the animal. Thus, dopamine neurons track fluid balance and respond to salt and water stimuli in a state- and taste-dependent manner. Using Fluoro-Gold tracing and immunohistochemistry for c-Fos and Foxp2, a marker of sodium-deprivation responsive neurons, we revealed brainstem populations of neurons that are activated by sodium depletion and project directly to the ventral tegmental area. The identified projections may modulate dopamine neuron excitability and consequently the state-specific dopamine release observed in our experiments. This work illustrates the impact of physiological state on mesolimbic dopamine signaling and a potential circuit by which homeostatic disruptions are communicated to mesolimbic circuitry to drive the selective reinforcement of biologically-required stimuli under conditions of physiological need.SIGNIFICANCE STATEMENT Motivated behaviors arise during physiological need and are highly selective for homeostasis-restoring stimuli. Although phasic dopamine signaling has been shown to contribute to the generation of motivated behaviors, the state and stimulus specificity of phasic dopamine signaling is less clear. These studies use thirst and sodium appetite to show that dopamine neurons dynamically track body fluid homeostasis and respond to water and salt stimuli in a state- and taste-dependent manner. We also identify hindbrain sodium deprivation-responsive neurons that project directly to the ventral tegmental area, where dopamine neuron cell bodies reside. This work demonstrates command of homeostasis over dopamine signaling and proposes a circuit by which physiological need drives motivated behavior by state- and taste-selective recruitment of phasic dopamine signaling.

Journal Digest

Journal Digest

Effects of feedback delay on learning from positive and negative feedback in patients with Parkinson's disease off medication

Phasic dopamine (DA) signals conveyed from the substantia nigra to the striatum and the prefrontal cortex crucially affect learning from feedback, with DA bursts facilitating learning from positive feedback and DA dips facilitating learning from negative feedback. Consequently, diminished nigro-striatal dopamine levels as in unmedicated patients suffering from Parkinson's Disease (PD) have been shown to lead to a negative learning bias. Recent studies suggested a diminished striatal contribution to feedback processing when the outcome of an action is temporally delayed. This study investigated whether the bias towards negative feedback learning induced by a lack of DA in PD patients OFF medication is modulated by feedback delay. To this end, PD patients OFF medication and healthy controls completed a probabilistic selection task, in which feedback was given immediately (after 800 ms) or delayed (after 6800 ms). PD patients were impaired in immediate but not delayed feedback learning. However, differences in the preference for positive/negative learning between patients and controls were seen for both learning from immediate and delayed feedback, with evidence of stronger negative learning in patients than controls. A Bayesian analysis of the data supports the conclusion that feedback timing did not affect the learning bias in the patients. These results hint at reduced, but still relevant nigro-striatal contribution to feedback learning, when feedback is delayed.

The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway.

Previous preclinical and clinical investigations have focused on the L-type calcium channel (LTCC) as a potential therapeutic target for substance abuse. While some clinical studies have examined the ability of LTCC blockers to alter cocaine's subjective effects, very few LTCC studies have examined cocaine relapse. Here, we examined whether ventral tegmental area (VTA)-specific or systemic administration of the LTCC inhibitor, isradipine, altered cocaine-seeking behavior in a rat model. Male Sprague-Dawley rats first received 10 days of cocaine self-administration training (2 h sessions), where active lever depression resulted in delivery of a ∼0.5 mg/kg cocaine infusion paired with a tone + light cue. Rats then underwent 10 days of forced abstinence, without access to cocaine or cocaine cues. Rats were then returned to the opertant chamber for the cue-induced cocaine-seeking test, where active lever depression in the original training context resulted in tone + light cue presentation. We found VTA specific or systemic isradipine administration robustly attenuated cocaine-seeking, without altering cocaine-taking nor natural reward seeking. Dopamine (DA) signaling in the nucleus accumbens (NAc) core is necessary and sufficient for cue-induced drug-seeking. Surprisingly in our study, isradipine enhanced tonic and phasic DA signaling in cocaine abstinent rats, with no change in sucrose abstinent nor naïve rats. Strikingly, isradipine's behavioral effects were dependent upon NAc core DA receptor activation. Together, our findings reveal a novel mechanism by which the FDA-approved drug, isradipine, could act to decrease cocaine relapse.

Phasic Dopamine Signals in the Nucleus Accumbens that Cause Active Avoidance Require Endocannabinoid Mobilization in the Midbrain

Phasic dopamine (DA) release accompanies approach toward appetitive cues. However, a role for DA in the active avoidance of negative events remains undetermined. Warning signals informing footshock avoidance are associated with accumbal DA release, whereas depression of DA is observed with unavoidable footshock. Here, we reveal a causal role of phasic DA in active avoidance learning; specifically, optogenetic activation of DA neurons facilitates avoidance, whereas optical inhibition of these cells attenuates it.Furthermore, stimulation of DA neurons during presentation of a fear-conditioned cue accelerates the extinction of a passive defensive behavior (i.e.,freezing). Dopaminergic control of avoidance requires endocannabinoids (eCBs), as perturbing eCB signaling in the midbrain disrupts avoidance, which is rescued by optical stimulation of DA neurons. Interestingly, once the avoidance task is learned, neither DA nor eCB manipulations affect performance, suggesting that once acquisition occurs, expression of this behavior is subserved by other anatomical frameworks. Our findings establish an instrumental role for DA release in learning active responses to aversive stimuli and its control by eCB signaling.

Evaluation of the hypothesis that phasic dopamine constitutes a cached-value signal.

The phasic dopamine error signal is currently argued to be synonymous with the prediction error in Sutton and Barto (1987, 1998) model-free reinforcement learning algorithm (Schultz et al., 1997). This theory argues that phasic dopamine reflects a cached-value signal that endows reward-predictive cues with the scalar value inherent in reward. Such an interpretation does not envision a role for dopamine in more complex cognitive representations between events which underlie many forms of associative learning, restricting the role dopamine can play in learning. The cached-value hypothesis of dopamine makes three concrete predictions about when a phasic dopamine response should be seen and what types of learning this signal should be able to promote. We discuss these predictions in light of recent evidence which we believe provide particularly strong tests of their validity. In doing so, we find that while the phasic dopamine signal conforms to a cached-value account in some circumstances, other evidence demonstrate that this signal is not restricted to a model-free cached-value reinforcement learning signal. In light of this evidence, we argue that the phasic dopamine signal functions more generally to signal violations of expectancies to drive real-world associations between events.

Use of fast-scan cyclic voltammetry to assess phasic dopamine release in rat models of early postpartum maternal behavior and neglect.

Maternal behavior (MB) is a complex response to infant cues, orchestrated by postpartum neurophysiology. Although mesolimbic dopamine contributes toward MB, little is known about real-time dopamine fluctuations during the postpartum period. Thus, we used fast-scan cyclic voltammetry to measure individual dopamine transients in the nucleus accumbens of early postpartum rats and compared them with dopamine transients in virgins and in postpartum females exposed to cocaine during pregnancy, which is known to disrupt MB. We hypothesized that dopamine transients are normally enhanced postpartum and support MB. In anesthetized rats, electrically evoked dopamine release was larger and clearance was faster in postpartum females than in virgins and gestational cocaine exposure blocked the change in clearance. In awake rats, control mothers showed more dopamine transients than cocaine-exposed mothers during MB. Salient pup-produced stimuli may contribute toward differences in maternal phasic dopamine by evoking dopamine transients; supporting the feasibility of this hypothesis, urine composition (glucose, ketones, and leukocytes) differed between unexposed and cocaine-exposed infants. These data, resulting from the novel application of fast-scan cyclic voltammetry to models of MB, support the hypothesis that phasic dopamine signaling is enhanced postpartum. Future studies with additional controls can delineate which aspects of gestational cocaine reduce dopamine clearance and transient frequency.

Evaluating oral flavorant effects on nicotine self-administration behavior and phasic dopamine signaling

Understanding how tobacco product flavor additives, such as flavorants in electronic cigarettes, influence smoking behavior and addiction is critical for informing public health policy decisions regarding tobacco product regulation. Here, we developed a combined intraoral (i.o.) and intravenous (i.v.) self-administration paradigm in rats to determine how flavorants influence self-administration behavior. By combining i.o. flavorant delivery with fast scan cyclic voltammetry (FSCV) or i.v. nicotine self-administration in adult, male rats, we examined whether flavors alter phasic dopamine (DA) signaling and nicotine self-administration. Oral administration of 10% sucrose or 0.32% saccharin, but not 0.005% menthol, increased phasic DA release in the nucleus accumbens (NAc). Oral sucrose or saccharin, when combined with i.v. nicotine delivery, also led to increased self-administration behavior. Specifically, combined i.o. sucrose and i.v. nicotine decreased responding compared to sucrose alone, and increased responding compared to nicotine alone. In contrast, i.o. flavorants did not alter motivational breakpoint in a progressive ratio task. Oral menthol, which did not alter i.v. nicotine administration, reversed oral nicotine aversion (50 and 100 mg/L) in a two-bottle choice test. Here, we demonstrate that i.o. appetitive flavorants that increase phasic DA signaling also increase self-administration behavior when combined with i.v. nicotine delivery. Additionally, oral menthol effects were specific to oral nicotine, and were not observed with i.v. nicotine-mediated reinforcement. Together, these preclinical findings have important implications regarding menthol and sweet flavorant additive effects on tobacco product use and can be used to inform policy decisions on tobacco product flavorant regulation.

The effect of single-dose methylphenidate on the rate of error-driven learning in healthy males: a randomized controlled trial.

Norepinephrine mediates the adjustment of error-driven learning to match the rate of change of the environment, while phasic dopamine signals prediction errors. We tested the hypothesis that pharmacologic manipulation may modulate this process. We administered a single dose of methylphenidate, a norepinephrine/dopamine reuptake inhibitor, or placebo in double-blind randomized fashion to 20 healthy human males, who then performed a probabilistic learning task. Each subject was tested in two sessions, receiving methylphenidate in one session and placebo in the other, in randomized order. Task performance was quantified by the percentage of trials on which subjects chose the most likely option, while learning rate was measured using a computational model-based parameter as well as with a behavioral analogue of this parameter. There was a substance-by-session interaction effect on behavioral learning rate and model-based learning rate, such that subjects receiving methylphenidate exhibited higher learning rates than those receiving placebo in session 1, with no difference observed in session 2, suggesting that subjects retained the increased learning rate across sessions. Higher behavioral learning rate was associated with both higher task performance and with the model-based learning rate. Higher learning rates were advantageous given the high rate of change on the task. Subjects receiving methylphenidate and placebo began the task in session 1 with a similar behavioral learning rate, but those receiving methylphenidate rapidly increased learning rate toward the optimal value, suggesting that methylphenidate accelerated the adaptation of learning rate based on the environment. The results suggest that methylphenidate may improve disrupted probabilistic learning in disorders involving noradrenergic or dopaminergic dysfunction.

(Invited) A Hybrid CMOS-Graphene Integrated Sensing Platform for Subsecond Dopamine Detection

Understanding dopamine signaling in the brain has important scientific and clinical implications. However, a standard tool that is capable of measuring dopamine with high spatiotemporal resolution is currently unavailable. Here, we present a new integrated sensing platform for subsecond detection of dopamine by combining advanced silicon CMOS and graphene nanotechnology. We demonstrate the functionality of our heterogeneous integrated sensors through in vitro measurements. This integrated sensing technology makes the foundation for realizing neural probes that are capable of measuring dopamine concurrently in multiple locations in the brain with high temporal resolution. Fast-scan cyclic voltammetry (FSCV) using carbon fiber electrodes has proven to be a reliable method for in vivo detection of phasic dopamine signal. The FSCV measurement produces two overlapping current signals: (i) a large non-informative background current due to the charge and the discharge of the double layer capacitance, and (ii) a small faradaic signal due to the redox reactions of dopamine molecules. In FSCV, applying a fast voltage ramp increases the sensitivity and the temporal resolution. However, the non-informative background current also becomes larger at faster ramp rates, thereby making the detection of the small faradaic signal more difficult. Furthermore, the environmental noise is a limiting factor for the detection of dopamine at the physiological levels of interest, particularly in animals with large brains. Finally, the large cylindrical shape of carbon fiber electrodes complicates the development of multielectrode arrays, necessary for large-scale measurements of dopamine concentration. To address these technical challenges, we combine advances in nanofabrication with silicon chip manufacturing and create a heterogeneous integrated CMOS-graphene sensing platform that would enable accurate measurements of dopamine with high spatiotemporal resolution. To accurately measure the small faradaic current, we developed an integrated readout circuit using a standard 65nm process. Leveraging the high specificity of FSCV, the readout chip is configured to capture the signal of interest at about the redox potentials. Also, a fixed low-noise current continuously subtracts a large portion of the non-informative background current near the redox potentials, while maintaining the overall shape of the signal. Our readout approach, therefore, makes the CMOS chip compact and power-efficient. We replaced carbon fiber with a few-layer graphene film because the thin planar structure of graphene facilitates the fabrication of a multielectrode array. Furthermore, significant advances in large-area synthesis of graphene using chemical vapor deposition offer a manufacturable solution for large-scale deployment of this integrated sensing technology. These features enabled the direct integration of graphene sensor arrays on top of the CMOS readout chip. We validated the performance of our integrated sensing platform through in vitro measurements. In conclusion, we introduced and implemented a heterogeneous integrated CMOS-graphene sensor for measuring dopamine concentration using fast-scan cyclic voltammetry. Our core sensing technology offers a new pathway for developing the next generation of neural probes that can accurately monitor dopamine signaling with high spatiotemporal resolution in the brain.