Distinct effects of (R)‐modafinil and its (R)‐ and (S)‐fluoro‐analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats

Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure–activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy. Here, we have tested the effects of the clinically available (R)‐enantiomer of MOD on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured in vivo by fast‐scan cyclic voltammetry and by microdialysis in Sprague‐Dawley rats. We have compared these results with those obtained under identical experimental conditions with two novel and enantiopure bis(F) analogs of MOD, JBG1‐048 and JBG1‐049. The results show that (R)‐modafinil (R‐MOD), JBG1‐048, and JBG1‐049, when administered intravenously with cumulative drug‐doses, will block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight the mechanistic underpinnings of R‐MOD and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders.     

A novel biosensor with high signal‐to‐noise ratio for real‐time measurement of dopamine levels in vivo

Fast‐scan cyclic voltammetry (FSCV) is an established method for measuring dopamine (DA) levels in the brain in real time. However, it is difficult to discriminate DA from other monoamines such as serotonin (5‐hydroxytryptamine, 5‐HT) and norepinephrine (NE). We report a novel DA‐specific biosensor consisting of a carbon‐fiber electrode coated with an ion‐exchange membrane, a layer containing monoamine oxidase B, and a cellulose membrane. We performed FSCV using the probe to monitor the amount of DA in vitro and in vivo. First, we measured currents in vitro in phosphate‐buffered saline as we added one micromole each of DA, 5‐HT, and NE. The results confirmed that the biosensor selectively detected DA. Next, we implanted the probe in the striatum of male rats to investigate whether it could selectively detect changes in the DA content in vivo. The probe detected both the tonic change induced by methamphetamine administration and the phasic change induced by electrical stimulation of the medial forebrain bundle. In contrast, the electrode in the 6‐hydroxydopamine–lesioned striatum did not respond to systemic selective serotonin or serotonin/norepinephrine reuptake inhibitors, confirming its selectivity. Furthermore, the probe in the striatum could still detect changes in the DA level 1 week after electrode implantation. The results suggest that the novel biosensor can measure real‐time changes in DA levels in vivo with a relatively high signal‐to‐noise ratio.     

Cocaine self‐administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine

Dopaminergic projections from the ventral midbrain to the nucleus accumbens (NAc) have long been implicated in encoding associations between reward availability and environmental stimuli. As such, this circuit is instrumental in guiding behaviors towards obtaining maximal rewards based on previous experience. Cocaine acts on the dopamine system to exert its reinforcing effects and it is thought that cocaine‐induced dysregulation of dopamine neurotransmission contributes to the difficulty that cocaine addicts exhibit in selecting environmentally appropriate behaviors. Here we used cocaine self‐administration combined with in vivo fast scan cyclic voltammetry in anesthetised rats to examine the function of the ventral tegmental area to NAc projection neurons. Over 5 days of cocaine self‐administration (fixed‐ratio 1; 1.5 mg/kg/injection; 40 injections/day), animals increased their rate of intake. Following cocaine self‐administration, there was a marked reduction in ventral tegmental area‐stimulated NAc dopamine release. Additionally, there was a decreased augmentation of stimulated dopamine overflow in response to a cocaine challenge. These findings demonstrate that cocaine induces a hypodopaminergic state, which may contribute to the inflexible drug‐taking and drug‐seeking behaviors observed in cocaine abusers. Additionally, tolerance to the ability of cocaine to elevate dopamine may lead to increased cocaine intake in order to overcome decreased effects, another hallmark of cocaine abuse.     

Enduring increases in anxiety‐like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats

Social isolation (SI) rearing, a model of early life stress, results in profound behavioral alterations, including increased anxiety‐like behavior, impaired sensorimotor gating and increased self‐administration of addictive substances. These changes are accompanied by alterations in mesolimbic dopamine function, such as increased dopamine and metabolite tissue content, increased dopamine responses to cues and psychostimulants, and increased dopamine neuron burst firing. Using voltammetric techniques, we examined the effects of SI rearing on dopamine transporter activity, vesicular release and dopamine D2‐type autoreceptor activity in the nucleus accumbens core. Long–Evans rats were housed in group (GH; 4/cage) or SI (1/cage) conditions from weaning into early adulthood [postnatal day (PD) 28–77]. After this initial housing period, rats were assessed on the elevated plus‐maze for an anxiety‐like phenotype, and then slice voltammetry experiments were performed. To study the enduring effects of SI rearing on anxiety‐like behavior and dopamine terminal function, another cohort of similarly reared rats was isolated for an additional 4 months (until PD 174) and then tested. Our findings demonstrate that SI rearing results in lasting increases in anxiety‐like behavior, dopamine release and dopamine transporter activity, but not D2 activity. Interestingly, GH‐reared rats that were isolated as adults did not develop the anxiety‐like behavior or dopamine changes seen in SI‐reared rats. Together, our data suggest that early life stress results in an anxiety‐like phenotype, with lasting increases in dopamine terminal function.     

Effect of moderate ethanol dose on dopamine uptake in rat nucleus accumbens in vivo

The present study was designed to evaluate the effects of a moderate dose of ethanol (1 g/kg) on dopamine (DA) dynamics in rat nucleus accumbens (NAc) using fast-scan cyclic voltammetry. Voltammetric recordings were made every 100 ms at a carbon fiber microelectrode, positioned in the NAc core. Acute ethanol did not significantly alter DA uptake parameters (K(m) and V(max)), but amplitudes of the DA signals were decreased after the drug in both freely moving and anesthetized rats. Therefore, the present in vivo voltammetry results suggest that DA uptake changes are not involved in ethanol-induced increases in extracellular DA concentrations.     

Terminal effects of ethanol on dopamine dynamics in rat nucleus accumbens: an in vitro voltammetric study

To assess the direct effects of acute ethanol on dopamine (DA) terminals, evoked DA release and uptake were measured in rat nucleus accumbens slices using fast-scan cyclic voltammetry. Low and moderate concentrations of ethanol (20, 45 and 100 mM) did not alter evoked DA release, while high concentrations (150 and 200 mM) significantly decreased DA release (18 and 36%, respectively) in a calcium-dependent manner. No significant difference was found between the rate of DA disappearance measured before and after the drug. These data indicate that uptake of DA through the dopamine transporter is unaffected by ethanol, even at high concentrations. Therefore, low to moderate concentrations of ethanol have no effect on DA dynamics at the level of the nerve terminal in the nucleus accumbens. This is consistent with the hypothesis that cell body regions of DA neurons are the primary target for the stimulating and reinforcing effects of ethanol. High concentrations of ethanol can locally depress DA release, and this may correlate with the sedative actions of the drug.     

Modulation of striatal dopamine dynamics by cocaine self‐administration and amphetamine treatment in female rats

Despite decades of research into the neurobiological basis of cocaine abuse, pharmacotherapeutic treatments for cocaine addiction have been largely ineffective. Converging evidence from preclinical research and from outpatient clinical trials suggest that treatment with amphetamine is efficacious in reducing cocaine intake. Although it has been suggested that amphetamine treatment reduces cocaine intake as an agonist replacement therapy, we have shown recently that multiple aspects of dopamine signaling are altered by cocaine self‐administration and returned to pre‐cocaine function by amphetamine treatment in the nucleus accumbens of male rats. Here, we sought to determine if these effects were also evident in female subjects, and across regions of the striatum. Female rats performed 5 days of cocaine self‐administration (1.5 mg kg^?1 inj^?1, 40 inj/day) and were treated with a single amphetamine (0.56 mg/kg) or saline infusion 1 hr prior to killing. We then used ex vivo fast‐scan cyclic voltammetry in the nucleus accumbens core or dorsolateral caudate‐putamen to examine dopamine signaling and cocaine potency. We found that in the nucleus accumbens core, cocaine self‐administration decreased dopamine uptake rate and cocaine potency, and both alterations were restored by amphetamine treatment. In the dorsolateral caudate‐putamen, neither cocaine self‐administration nor amphetamine treatment altered dopamine uptake; however, cocaine potency was decreased by self‐administration and returned to control levels by amphetamine. Together, these findings support a role for amphetamine treatment for cocaine addiction outside of agonist replacement therapy, and suggest that the development of cocaine tolerance is similar across sexes.     

Regional specificity in the real‐time development of phasic dopamine transmission patterns during acquisition of a cue–cocaine association in rats

Drug seeking is significantly regulated by drug‐associated cues and associative learning between environmental cues and cocaine reward is mediated by dopamine transmission within the nucleus accumbens (NAc). However, dopamine transmission during early acquisition of a cue–cocaine association has never been assessed because of the technical difficulties associated with resolving cue‐evoked and cocaine‐evoked dopamine release within the same conditioning trial. Here, we used fast‐scan cyclic voltammetry to measure sub‐second fluctuations in dopamine concentration within the NAc core and shell during the initial acquisition of a cue–cocaine Pavlovian association. Within the NAc core, cue‐evoked dopamine release developed during conditioning. However, within the NAc shell, the predictive cue appeared to cause an unconditioned decrease in dopamine concentration. The pharmacological effects of cocaine also differed between sub‐regions, as cocaine increased phasic dopamine release events within the NAc shell but not the core. Thus, real‐time measurements not only revealed the initial development of a conditioned neurochemical response but also demonstrated differential phasic dopamine transmission patterns across NAc sub‐regions during the acquisition of a cue–cocaine association.     

Insulin in the ventral tegmental area reduces cocaine‐evoked dopamine in the nucleus accumbens in vivo

Mesolimbic dopamine circuits, implicated in incentive motivation, are sensitive to changes in metabolic state such as weight loss and diet‐induced obesity. These neurons are important targets for metabolic hormones such as leptin, glucagon‐like peptide‐1, ghrelin and insulin. Insulin receptors are located on dopamine neurons in the ventral tegmental area (VTA) and we have previously demonstrated that insulin induces long‐term depression of excitatory synapses onto VTA dopamine neurons. While insulin can decrease dopamine concentration in somatodendritic regions, it can increase dopamine in striatal slices. Whether insulin directly targets the VTA to alter dopamine release in projection areas, such as the nucleus accumbens (NAc), remains unknown. The main goal of the present experiments was to examine NAc dopamine concentration following VTA administration of insulin. Using in vivo FSCV to detect rapid fluctuations in dopamine concentration, we showed that intra‐VTA insulin via action at insulin receptors reduced pedunculopontine nucleus‐evoked dopamine release in the NAc. Furthermore, intra‐VTA insulin reduced cocaine‐potentiated NAc dopamine. Finally, intra‐VTA or intranasal insulin decreased locomotor responses to cocaine, an effect blocked by an intra‐VTA administered insulin receptor antagonist. Together, these data demonstrate that mesolimbic dopaminergic projections are important targets of the metabolic hormone, insulin.     

Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self‐administration

Competitive dopamine receptor antagonists increase the rate of cocaine self‐administration. As the rate of self‐administration at a particular unit dose is determined by the satiety threshold and the elimination half‐life (t_1/2) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters in rats. The plasma cocaine concentration at the time of each self‐administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self‐administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self‐administer cocaine, SCH23390 had no effect on the plasma steady‐state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t_1/2 at a dose that accelerated cocaine self‐administration. A constant cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self‐administration. SCH23390, or the D₂ dopamine receptor antagonist (?)eticlopride, reinstated self‐administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist‐induced acceleration of cocaine self‐administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first‐order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased interinjection intervals. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Withdrawal from extended‐access cocaine self‐administration results in dysregulated functional activity and altered locomotor activity in rats

Much work has focused on determining the consequences of cocaine self‐administration on specific neurotransmitter systems, thus neglecting the global changes that occur. Previous imaging studies have focused on the effects of cocaine self‐administration in the presence of high blood levels of cocaine, but have not determined the functional effects of cocaine self‐administration after cocaine has cleared. Extended‐access cocaine self‐administration, where animals administer cocaine for 6 h each day, results in escalation in the rate of cocaine intake and is believed to model the transition from recreational use to addiction in humans. We aimed to determine the functional changes following acute (48 h) withdrawal from an extended‐access, defined‐intake self‐administration paradigm (5 days, 40 injections/day, 6 h/day), a time point when behavioral changes are present. Using the 2‐[¹⁴C]deoxyglucose method to measure rates of local cerebral glucose metabolism, an indicator of functional activity, we found reductions in circuits related to learning and memory, attention, sleep, and reward processing, which have important clinical implications for cocaine addiction. Additionally, lower levels of functional activity were found in the dorsal raphe and locus coeruleus, suggesting that cocaine self‐administration may have broader effects on brain function than previously noted. These widespread neurochemical reductions were concomitant with substantial behavioral differences in these animals, highlighted by increased vertical activity and decreased stereotypy. These data demonstrate that behavioral and neurochemical impairments following cocaine self‐administration are present in the absence of drug and persist after cocaine has been cleared.     

Acute and long‐term response of dopamine nigrostriatal synapses to a single,low‐dose episode of 3‐nitropropionic acid‐mediated chemical hypoxia

The goal of the present investigation was to determine the persistence of striatal (DA) dopaminergic dysfunction after a mild chemically induced hypoxic event in Fisher 344 rats. To this end, we gave a single injection of the mitochondrial complex II inhibitor 3‐nitropropionic acid (3‐NP; 16.5 mg/kg, i.p.) to 2‐month old male F344 rats and measured various indices of striatal DA functioning and lipid peroxidation over a 3‐month span. Separate groups of rats were used to measure rod walking, evoked DA release, DA content, malondialdehyde (MDA) accumulation, DA receptor binding, and tyrosine hydroxylase (TH) activity. The results showed that 3‐NP exposure reduced most measures of DA functioning including motoric ability, DA release, and D₂ receptor densities for 1 to 3 months postdrug administration. Interestingly, DA content was reduced 1 week after 3‐NP exposure, but rose to 147% of control values 1 month after 3‐NP treatment. MDA accumulation, a measure of lipid peroxidation activity, was increased 24 h and 1 month after 3‐NP treatment. 3‐NP did not affect TH activity, suggesting that alterations in DA functioning were not the result of nigrostriatal terminal loss. These data demonstrate that a brief mild hypoxic episode caused by 3‐NP exposure has long‐term detrimental effects on the functioning of the nigrostriatal DA system. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Striatal dopamine transmission is reduced after chronic nicotine with a decrease in α6‐nicotinic receptor control in nucleus accumbens

Nicotine directly regulates striatal dopamine (DA) neurotransmission via presynaptic nicotinic acetylcholine receptors (nAChRs) that are α6β2 and/or α4β2 subunit‐containing, depending on region. Chronic nicotine exposure in smokers upregulates striatal nAChR density, with some reports suggesting differential impact on α6‐ or α4‐containing nAChRs. Here, we explored whether chronic nicotine exposure modifies striatal DA transmission, whether the effects of acute nicotine on DA release probability persist and whether there are modifications to the regulation of DA release by α6‐subunit‐containing (*) relative to non‐α6* nAChRs in nucleus accumbens (NAc) and in caudate‐putamen (CPu). We detected electrically evoked DA release at carbon‐fiber microelectrodes in striatal slices from mice exposed for 4–8 weeks to nicotine (200 μg/mL in saccharin‐sweetened drinking water) or a control saccharin solution. Chronic nicotine exposure subtly reduced striatal DA release evoked by single electrical pulses, and in NAc enhanced the range of DA release evoked by different frequencies. Effects of acute nicotine (500 nm ) on DA release probability and its sensitivity to activity were apparent. However, in NAc there was downregulation of the functional dominance of α6‐nAChRs (α6α4β2β3), and an emergence in function of non‐α6* nAChRs. In CPu, there was no change in the control of DA release by its α6 nAChRs (α6β2β3) relative to non‐α6. These data suggest that chronic nicotine subtly modifies the regulation of DA transmission, which, in NAc, is through downregulation of function of a susceptible population of α6α4β2β3 nAChRs. This imbalance in function of α6:non‐α6 nAChRs might contribute to DA dysregulation in nicotine addiction.     

Prostaglandin E receptor EP1 enhances GABA‐mediated inhibition of dopaminergic neurons in the substantia nigra pars compacta and regulates dopamine level in the dorsal striatum

Dopamine (DA) is a neuromodulator that is critical for sensory‐motor, cognitive and emotional functions. We previously found that mice lacking prostaglandin E receptor EP1 showed impulsive emotional behaviors accompanied by enhanced DA turnover in the frontal cortex and striatum. Given that these behavioral phenotypes were corrected by DA receptor antagonists, we hypothesized that EP1 deficiency causes a hyperdopaminergic state for its behavioral phenotype. Here we tested this hypothesis by examining the EP1 action in the nigrostriatal dopaminergic system. We first used microdialysis and found an elevated extracellular DA level in the dorsal striatum of EP1‐deficient mice compared with wild‐type mice. Despite the EP1 expression in the striatum, neither deficiency nor activation of EP1 altered the intrastriatal control for DA release, uptake or degradation. Immunohistochemistry revealed punctate EP1 signals apposed with dopaminergic neurons in the substantia nigra pars compacta (SNc). Many EP1 signals were colocalized with a marker for GABAergic synapses. Further, an EP1 agonist enhanced GABA_A‐mediated inhibitory inputs to SNc dopaminergic neurons in midbrain slices. Therefore, the prostaglandin E₂‐EP1 signaling directly enhances GABAergic inputs to SNc dopaminergic neurons. The lack of this EP1 action may lead to a hyperdopaminergic state of EP1‐deficient mice.     

Electrophysiological evidence of mediolateral functional dichotomy in the rat accumbens during cocaine self‐administration: tonic firing patterns

Given the increasing research emphasis on putative accumbal functional compartmentation, we sought to determine whether neurons that demonstrate changes in tonic firing rate during cocaine self‐administration are differentially distributed across subregions of the NAcc. Rats were implanted with jugular catheters and microwire arrays targeting NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell and rostral pole shell). Recordings were obtained after acquisition of stable cocaine self‐administration (0.77 mg/kg/0.2mL infusion; fixed‐ratio 1 schedule of reinforcement; 6‐h daily sessions). During the self‐administration phase of the experiment, neurons demonstrated either: (i) tonic suppression (or decrease); (ii) tonic activation (or increase); or (iii) no tonic change in firing rate with respect to rates of firing during pre‐ and post‐drug phases. Consistent with earlier observations, tonic decrease was the predominant firing pattern observed. Differences in the prevalence of tonic increase firing were observed between the core and the dorsal shell and dorsal shell–core border regions, with the latter two areas exhibiting a virtual absence of tonic increases. Tonic suppression was exhibited to a greater extent by the dorsal shell–core border region relative to the core. These differences could reflect distinct subregional afferent processing and/or differential sensitivity of subpopulations of NAcc neurons to cocaine. Ventrolateral shell firing topographies resembled those of core neurons. Taken together, these observations are consistent with an emerging body of literature that differentiates the accumbens mediolaterally and further advances the likelihood that distinct functions are subserved by NAcc subregions in appetitive processing.     

Electrophysiological evidence of mediolateral functional dichotomy in the rat nucleus accumbens during cocaine self‐administration II: phasic firing patterns

In the cocaine self‐administering rat, individual nucleus accumbens (NAcc) neurons exhibit phasic changes in firing rate within minutes and/or seconds of lever presses (i.e. slow phasic and rapid phasic changes, respectively). To determine whether neurons that demonstrate these changes during self‐administration sessions are differentially distributed in the NAcc, rats were implanted with jugular catheters and microwire arrays in different NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell, or rostral pole). Neural recording sessions were typically conducted on days 13–17 of cocaine self‐administration (0.77 mg/kg per 0.2‐mL infusion; fixed‐ratio 1 schedule of reinforcement; 6‐h daily sessions). Pre‐press rapid phasic firing rate changes were greater in lateral accumbal (core and ventrolateral shell) than in medial accumbal (dorsal shell and rostral pole shell) subregions. Slow phasic pattern analysis revealed that reversal latencies of neurons that exhibited change + reversal patterns differed mediolaterally: medial NAcc neurons exhibited more early reversals and fewer progressive/late reversals than lateral NAcc neurons. Comparisons of firing patterns within individual neurons across time bases indicated that lateral NAcc pre‐press rapid phasic increases were correlated with tonic increases. Tonic decreases were correlated with slow phasic patterns in individual medial NAcc neurons, indicative of greater pharmacological sensitivity of neurons in this region. On the other hand, the bias of the lateral NAcc towards increased pre‐press rapid phasic activity, coupled with a greater prevalence of tonic increase firing, may reflect particular sensitivity of these neurons to excitatory afferent signaling and perhaps differential pharmacological influences on firing rates between regions.     

The selective dopamine D3 receptor antagonist SB‐277011A attenuates drug‐ or food‐deprivation reactivation of expression of conditioned place preference for cocaine in male sprague‐dawley rats

We determined the effect of the selective dopamine D₃ receptor antagonist SB‐277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague–Dawley rats. Animals paired with the cocaine‐associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine‐paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty‐four hours later, the administration of 5 mg kg^?1 i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine‐induced CPP. In contrast, administration of 1 ml kg^?1 i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D₃ receptor antagonist SB‐277011A (3–24 mg kg^?1 i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB‐277011A (6 or 12 mg kg^?1 i.p.) given 30 min before the test session. SB‐277011A (12 or 24 mg kg^?1 i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug‐associated cues by cocaine or food deprivation is attenuated by selective antagonism of D₃ receptors. Synapse 69:336–344, 2015. © 2015 Wiley Periodicals, Inc.     

Sustained N‐methyl‐d‐aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling

Chronic N‐methyl‐d ‐aspartate receptor (NMDAR) hypofunction has been proposed as a contributing factor to symptoms of schizophrenia. However, it is unclear how sustained NMDAR hypofunction throughout development affects other neurotransmitter systems that have been implicated in the disease. Dopamine neuron biochemistry and activity were examined to determine whether sustained NMDAR hypofunction causes a state of hyperdopaminergia. We report that a global, genetic reduction in NMDARs led to a remodeling of dopamine neurons, substantially affecting two key regulators of dopamine homeostasis, i.e. tyrosine hydroxylase and the dopamine transporter. In NR1 knockdown mice, dopamine synthesis and release were attenuated, and dopamine clearance was increased. Although these changes would have the effect of reducing dopamine transmission, we demonstrated that a state of hyperdopaminergia existed in these mice because dopamine D₂ autoreceptors were desensitized. In support of this conclusion, NR1 knockdown dopamine neurons have higher tonic firing rates. Although the tonic firing rates are higher, phasic signaling is impaired, and dopamine overflow cannot be achieved with exogenous high‐frequency stimulation that models phasic firing. Through the examination of several parameters of dopamine neurotransmission, we provide evidence that chronic NMDAR hypofunction leads to a state of elevated synaptic dopamine. Compensatory mechanisms to attenuate hyperdopaminergia also impact the ability to generate dopamine surges through phasic firing.