Pharmacological manipulations of the dorsomedial and dorsolateral striatum during fear extinction reveal opposing roles in fear renewal.

Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.

Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons.

Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2 receptors (D2Rs). In this study, we found that amphetamine-driven dopamine release unbalanced D1-SPN and D2-SPN Ca2+ activity in mice, but that antipsychotic efficacy was associated with the reversal of abnormal D1-SPN, rather than D2-SPN, dynamics, even for drugs that are D2R selective or lacking any dopamine receptor affinity. By contrast, a clinically ineffective drug normalized D2-SPN dynamics but exacerbated D1-SPN dynamics under hyperdopaminergic conditions. Consistent with antipsychotic effect, selective D1-SPN inhibition attenuated amphetamine-driven changes in locomotion, sensorimotor gating and hallucination-like perception. Notably, antipsychotic efficacy correlated with the selective inhibition of D1-SPNs only under hyperdopaminergic conditions-a dopamine-state-dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. Our findings provide new insights into antipsychotic drug mechanism and reveal an important role for D1-SPN modulation.

A Dopamine D1 Agonist Versus Methylphenidate in Modulating Prefrontal Cortical Working Memory.

Methylphenidate is used widely to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants has significant side effects. This study used a rodent model (spontaneously hypertensive rat) of spatial working memory (sWM) to compare the effects of methylphenidate with the novel dopamine D1-like receptor agonist 2-methyldihydrexidine. Acute oral administration of methylphenidate (1.5 mg/kg) caused sWM improvement in half of the tested rats, but impairment in the others. Both improvement or impairment were eliminated by administration of the D1 antagonist SCH39266 directly into the prefrontal cortex (PFC). Conversely, 2-methyldihydrexidine showed greater sWM improvement compared with methylphenidate without significant impairment in any subject. Its effects correlated negatively with vehicle-treated baseline performance (i.e., rats with lower baseline performance improved more than rats with higher baseline performance). These behavioral effects were associated with neural activities in the PFC. Single neuron firing rate was changed, leading to the alteration in neuronal preference to correct or error behavioral responses. Overall, 2-methyldihydrexidine was superior to methylphenidate in decreasing the neuronal preference, prospectively, in the animals whose behavior was improved. In contrast, methylphenidate, but not 2-methyldihydrexidine, significantly decreased neuronal preference, retrospectively, in those animals who had impaired performance. These results suggest that a D1 agonist may be more effective than methylphenidate in regulating sWM-related behavior through neural modulation of the PFC, and thus may be superior to methylphenidate or other stimulants as ADHD pharmacotherapy. SIGNIFICANCE STATEMENT: Methylphenidate is effective in ADHD by its indirect agonist stimulation of dopamine and/or adrenergic receptors, but the precise effects on specific targets are unclear. This study compared methylphenidate to a dopamine D1 receptor-selective agonist by investigating effects on working memory occurring via neural modulation in the prefrontal cortex. The data suggest that pharmacological treatment selectively targeting the dopamine D1 may offer a superior approach to ADHD pharmacotherapy.

Systemic D1-R and D2-R antagonists in non-human primates differentially impact learning and memory while impairing motivation and motor performance.

Dopamine (DA) modulates cognition in part via differential activation of D1 and D2 receptors within the striatum and prefrontal cortex, yet evidence for cognitive impairments stemming from DA blockade or deficiency is inconsistent. Given the predominance of D1 over D2 receptors (R) in the prefrontal cortex of primates, D1-R blockade should more strongly influence frontal executive function (including working memory), while D2-R blockade should impair processes more strongly associated with the dorsal striatum (including cognitive flexibility, and learning). To test how systemic DA blockade disrupts cognition, we administered D1-R and D2-R like antagonists to healthy monkeys while they performed a series of cognitive tasks. Two selective DA receptor antagonist drugs (SCH-23390 hydrochloride: D1/D5-R antagonist; or Eticlopride hydrochloride: D2/D3-R antagonist) or placebo (0.9% saline) were systemically administered. Four tasks were used: (1) 'visually guided reaching', to test response time and accuracy, (2) 'reversal learning', to test association learning and attention, (3) 'self-ordered sequential search' to test spatial working memory, and (4) 'delayed match to sample' to test object working memory. Increased reach response times and decreased motivation to work for liquid reward was observed with both the D1/D5-R and D2/D3-R antagonists at the maximum dosages that still enabled task performance. The D2/D3-R antagonist impaired performance in the reversal learning task, while object and spatial working memory performance was not consistently affected in the tested tasks for either drug. These results are consistent with the theory that systemic D2/D3-R antagonists preferentially influence striatum processes (cognitive flexibility) while systemic D1/D5-R administration is less detrimental to frontal executive function.

Frequency-dependency of the involvement of dopamine D1/D5 and beta-adrenergic receptors in hippocampal LTD triggered by locus coeruleus stimulation.

Patterned stimulation of the locus coeruleus (LC, 100 Hz), in conjunction with test-pulse stimulation of hippocampal afferents, results in input-specific long-term depression (LTD) of synaptic plasticity in the hippocampus. Effects are long-lasting and have been described in Schaffer-collateral-CA1 and perforant path-dentate gyrus synapses in behaving rats. To what extent LC-mediated hippocampal LTD (LC-LTD) is frequency-dependent is unclear. Here, we report that LC-LTD can be triggered by LC stimulation with 2 and 5 Hz akin to tonic activity, 10 Hz equivalent to phasic activity, and 100 Hz akin to high-phasic activity in the dentate gyrus (DG) of freely behaving rats. LC-LTD at both 2 and 100 Hz can be significantly prevented by an NMDA receptor antagonist. The LC releases both noradrenaline (NA) and dopamine (DA) from its hippocampal terminals and may also trigger hippocampal DA release by activating the ventral tegmental area (VTA). Unclear is whether both neurotransmitters contribute equally to hippocampal LTD triggered by LC stimulation (LC-LTD). Both DA D1/D5 receptors (D1/D5R) and beta-adrenergic receptors (ß-AR) are critically required for hippocampal LTD that is induced by patterned stimulation of hippocampal afferents, or is facilitated by spatial learning. We, therefore, explored to what extent these receptor subtypes mediate frequency-dependent hippocampal LC-LTD. LC-LTD elicited by 2, 5, and 10 Hz stimulation was unaffected by antagonism of ß-AR with propranolol, whereas LC-LTD induced by these frequencies was prevented by D1/D5R-antagonism using SCH23390. By contrast, LC-LTD evoked at 100 Hz was prevented by ß-AR-antagonism and only mildly affected by D1/D5R-antagonism. Taken together, these findings support that LC-LTD can be triggered by LC activity at a wide range of frequencies. Furthermore, the contribution of D1/D5R and ß-AR to hippocampal LTD that is triggered by LC activity is frequency-dependent and suggests that D1/D5R may be involved in LC-mediated hippocampal tonus.

Dopamine D1 and D4 receptors contribute to light adaptation in ON-sustained retinal ganglion cells.

The adaptation of ganglion cells to increasing light levels is a crucial property of the retina. The retina must respond to light intensities that vary by 10-12 orders of magnitude, but the dynamic range of ganglion cell responses covers only ∼3 orders of magnitude. Dopamine is a crucial neuromodulator for light adaptation and activates receptors in the D1 and D2 families. Dopamine type D1 receptors (D1Rs) are expressed on horizontal cells and some bipolar, amacrine, and ganglion cells. In the D2 family, D2Rs are expressed on dopaminergic amacrine cells and D4Rs are primarily expressed on photoreceptors. However, the roles of activating these receptors to modulate the synaptic properties of the inputs to ganglion cells are not yet clear. Here, we used single-cell retinal patch-clamp recordings from the mouse retina to determine how activating D1Rs and D4Rs changed the light-evoked and spontaneous excitatory inputs to ON-sustained (ON-s) ganglion cells. We found that both D1R and D4R activation decrease the light-evoked excitatory inputs to ON-s ganglion cells, but that only the sum of the peak response decrease due to activating the two receptors was similar to the effect of light adaptation to a rod-saturating background. The largest effects on spontaneous excitatory activity of both D1R and D4R agonists was on the frequency of events, suggesting that both D1Rs and D4Rs are acting upstream of the ganglion cells.NEW & NOTEWORTHY Dopamine by bright light conditions allows retinal neurons to reduce sensitivity to adapt to bright light conditions. It is not clear how and why dopamine receptors modulate retinal ganglion cell signaling. We found that both D1 and D4 dopamine receptors in photoreceptors and inner retinal neurons contribute significantly to the reduction in sensitivity of ganglion cells with light adaptation. However, light adaptation also requires dopamine-independent mechanisms that could reflect inherent sensitivity changes in photoreceptors.

The emerging role of heterodimerisation and interacting proteins in ghrelin receptor function.

Ghrelin is a peptide hormone secreted primarily by the stomach that acts upon the growth hormone secretagogue receptor (GHSR1), a G protein-coupled receptor whose functions include growth hormone secretion, appetite regulation, energy expenditure, regulation of adiposity, and insulin release. Following the discovery that GHSR1a stimulates food intake, receptor antagonists were developed as potential therapies to regulate appetite. However, despite reductions in signalling, the desired effects on appetite were absent. Studies in the past 15 years have demonstrated GHSR1a can interact with other transmembrane proteins, either by direct binding (i.e. heteromerisation) or via signalling cross-talk. These interactions have various effects on GHSR1a signalling including preferential coupling to one pathway (i.e. biased signalling), coupling to a unique G protein (G protein switching), suppression of GHSR1a signalling, and enhancement of signalling by both receptors. While many of these interactions have been shown in cells overexpressing the proteins of interest and remain to be verified in tissues, substantial evidence exists showing that GHSR1a and the dopamine receptor D1 (DRD1) form heteromers, which promote synaptic plasticity and formation of hippocampal memory. Additionally, a reduction in GHSR1a-DRD1 complexes in favour of establishment of GHSR1a-Aß complexes correlates with Alzheimer's disease, indicating that GHSR1a heteromers may have pathological functions. Herein, we summarise the evidence published to date describing interactions between GHSR1a and transmembrane proteins, discuss the experimental strengths and limitations of these studies, describe the physiological evidence for each interaction, and address their potential as novel drug targets for appetite regulation, Alzheimer's disease, insulin secretion, and inflammation.

Involvement of Midbrain Dopamine Neuron Activity in Negative Reinforcement Learning in Mice.

The activity of the midbrain dopamine system reflects the valence of environmental events and modulates various brain structures to modify an organism's behavior. A series of recent studies reported that the direct and indirect pathways in the striatum are critical for instrumental learning, but the dynamic changes in dopamine neuron activity that occur during negative reinforcement learning are still largely unclear. In the present study, by using a negative reinforcement learning paradigm employing foot shocks as aversive stimuli, bidirectional changes in substantia nigra pars compacta (SNc) dopamine neuron activity in the learning and habituation phases were observed. The results showed that in the learning phase, before mice had mastered the skill of escaping foot shocks, the presence of foot shocks induced a transient reduction in the activity of SNc dopamine neurons; however, in the habituation phase, in which the learned skill was automated, it induced a transient increase. Microinjection of a dopamine D1 receptor (D1R) or D2 receptor (D2R) antagonist into the dorsomedial striatum (DMS) significantly impaired learning behavior, suggesting that the modulatory effects of dopamine on both the direct and indirect pathways are required. Moreover, during the learning phase, excitatory synaptic transmission to DMS D2R-expressing medium spiny neurons (D2-MSNs) was potentiated. However, upon completion of the learning and habituation phases, the synapses onto D1R-expressing medium spiny neurons (D1-MSNs) were potentiated, and those onto D2-MSNs were restored to normal levels. The bidirectional changes in both SNc dopamine neuron activity and DMS synaptic plasticity might be the critical neural correlates for negative reinforcement learning.

Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis.

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward.

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).

D1- and D2-like receptors differentially mediate the effects of dopaminergic transmission on cost-benefit evaluation and motivation in monkeys.

It has been widely accepted that dopamine (DA) plays a major role in motivation, yet the specific contribution of DA signaling at D1-like receptor (D1R) and D2-like receptor (D2R) to cost-benefit trade-off remains unclear. Here, by combining pharmacological manipulation of DA receptors (DARs) and positron emission tomography (PET) imaging, we assessed the relationship between the degree of D1R/D2R blockade and changes in benefit- and cost-based motivation for goal-directed behavior of macaque monkeys. We found that the degree of blockade of either D1R or D2R was associated with a reduction of the positive impact of reward amount and increasing delay discounting. Workload discounting was selectively increased by D2R antagonism. In addition, blocking both D1R and D2R had a synergistic effect on delay discounting but an antagonist effect on workload discounting. These results provide fundamental insight into the distinct mechanisms of DA action in the regulation of the benefit- and cost-based motivation, which have important implications for motivational alterations in both neurological and psychiatric disorders.

Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists.

The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.

The role of dopamine D1 receptors in MDMA-induced memory impairments.

(±) 3,4-Methylenedioxymethamphetamine (MDMA) is a recreationally abused psychostimulant that impairs memory performance. This effect is often attributed to a working memory impairment resulting from compromised serotonin systems. However, recent evidence from non-human animal experimental studies suggests that acute MDMA may indirectly impair memory performance through overstimulation of dopamine (DA) D1 receptors, which increases perseverative responding during memory tasks. This hypothesis was explored using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional D1 receptors. Adult male Wistar DAD1-/- rats and wild type controls were trained over 25 sessions on a spatial working memory T-maze delayed non-matching to position (DNMTP) task. Once trained, the rats were administered MDMA (1.5, 2.25 and 3 mg/kg) or saline fifteen minutes prior to testing on DNMTP with all subjects experiencing all drug doses and saline three times. We predicted that controls would demonstrate decreased task accuracy following MDMA, driven by an increase in perseverative errors. In contrast, we predicted that DAD1-/- rats would be protected from MDMA-induced perseverative errors due to their reduced D1 receptor function. As predicted, during the third block of MDMA administration, control rats demonstrated decreased task accuracy following 2.25 and 3 mg/kg doses, driven by an increase in perseverative errors. In addition, DAD1-/- rats were protected from MDMA-induced task deficits. These findings challenge the assumption that MDMA's acute effects on memory performance are predominantly due to serotonergic mechanisms and provide support for the hypothesis that acute MDMA impairs memory performance in rats via overstimulation of D1 receptors by increasing perseverative behaviour.

Accumbens and amygdala in taste recognition memory: The role of d1 dopamine receptors.

The attenuation of taste neophobia (AN) is a good model for studying the structural and neurochemical mechanisms of the emotional component of memory because taste recognition memory exhibits the unique feature of being necessarily linked to hedonic properties. Whilst novel tastes elicit cautious neophobic responses, taste exposures which are not followed by aversive consequences attenuate neophobia as the taste becomes safe and palatable. Given the involvement of the nucleus accumbens in reward and of the amygdala in emotional memories, we applied c-Fos immunohistochemistry as an index of neural activity in Wistar rats that were exposed to a vinegar solution for one, two or six days. An inverse pattern of accumbens nucleus vs amygdala activity was found on the second exposure day on which AN occurred. The number of c-Fos positive cells in the nucleus accumbens shell increased whilst the number of c-Fos positive cells in the basolateral amygdala decreased. Further analyses revealed a positive correlation between AN and the number of c-Fos positive cells in the accumbens shell but a negative correlation in the basolateral amygdala. Furthermore the accumbens-amygdala interplay relevant for AN seems to be mediated by dopamine D1 receptors (D1DR). The injection of SCH23390 (D1DR antagonist) in both the accumbens shell and the basolateral amygdala on the second taste exposure resulted in selectively impaired AN but had opposite long term effects. This finding supports the relevance of a dopaminergic network mediated by D1DRs in the nucleus accumbens shell and basolateral amygdala which is critical for adding the emotional component during the formation of taste memory.

Nonlinear Effects of Dopamine D1 Receptor Activation on Visuomotor Coordination Task Performance.

Dopamine plays an important role in the modulation of neuroplasticity, which serves as the physiological basis of cognition. The physiological effects of dopamine depend on receptor subtypes, and the D1 receptor is critically involved in learning and memory formation. Evidence from both animal and human studies shows a dose-dependent impact of D1 activity on performance. However, the direct association between physiology and behavior in humans remains unclear. In this study, four groups of healthy participants were recruited, and each group received placebo or medication inducing a low, medium, or high amount of D1 activation via the combination of levodopa and a D2 antagonist. After medication, fMRI was conducted during a visuomotor learning task. The behavioral results revealed an inverted U-shaped effect of D1 activation on task performance, where medium-dose D1 activation led to superior learning effects, as compared to placebo as well as low- and high-dose groups. A respective dose-dependent D1 modulation was also observed for cortical activity revealed by fMRI. Further analysis demonstrated a positive correlation between task performance and cortical activation at the left primary motor cortex. Our results indicate a nonlinear curve of D1 modulation on motor learning in humans and the respective physiological correlates in corresponding brain areas.

The auditory context-dependent attenuation of taste neophobia depends on D1 dopamine receptor activity in mice.

Taste recognition memory in rodents is evident as taste neophobia disappears upon repeated taste exposures without aversive consequences, thus increasing the consumption of familiar edibles. The attenuation of taste neophobia (AN) induced by taste familiarity is auditory context-dependent in mice since neophobia to a familiar taste reappears with a novel auditory background. This effect depends on the integrity of the dorsal hippocampus but the potential role of dopamine has remained unexplored. In order to explore the involvement of dopamine through D1 dopamine receptors in AN, C57BL/6 mice were exposed to a 3% vinegar taste solution for 10 min throughout several consecutive days. An experimentally-controlled auditory background was used to define a context, which could either change or remain constant throughout all the drinking sessions. Systemic administration of the D1 dopamine receptor antagonist SCH-23390 induced a similar effect to that of an auditory context change while it was kept constant and systemic administration of SKF-81297 prevented the contextual modulation of AN when the auditory context changed. Additionally, SCH-23390 injection on the following day to the auditory context change further impaired AN, thus suggesting the relevance of dopamine in the consolidation of the context dependency of taste recognition memory. We conclude that the context dependency of the AN involves dopaminergic activity mediated by D1 receptors which might be responsible for proper acquisition of safe taste recognition memory.

Role of hippocampal dopamine receptors in the antinociceptive responses induced by chemical stimulation of the lateral hypothalamus in animal model of acute pain.

Dopamine is the predominant catecholamine neurotransmitter in the mammalian brain which has been shown to play a critical role in antinociceptive process. Previous studies have shown that the role of CA1 region of the hippocampus in antinociception induced by stimulation of the lateral hypothalamus (LH) through the dopaminergic system in tonic pain. In this study, we tried to assess the involvement of intra-hippocampal D1- and D2-like dopamine receptors in the LH stimulation-induced antinociception during the tail-flick test as an animal model of acute pain. Ninety-five male Wistar rats were unilaterally implanted with two separate cannulae into the LH and CA1. Animals received intra-CA1 infusion of SCH-23390 (0.25, 1 and 4 µg/rat), as a D1-like dopamine receptor antagonist and sulpiride (0.125, 0.25, 1 and 4 µg/rat), as a D2-like dopamine receptor antagonist, 2 min before intra-LH administration of carbachol (250 nM/rat). The antinociceptive effects of SCH-23390 and sulpiride were measured by using a tail-flick analgesiometer and represented as the maximal possible effect (%MPE). Also, the locomotion tracking apparatus was used to measure the locomotor activity of animals. Results showed that intra-CA1 administration of SCH-23390 or sulpiride could prevent the intra-LH carbachol-induced antinociception. This effect was a little more dominant after blocking the D2-like dopamine receptor in the CA1. These findings revealed that D1- and D2-like dopamine receptors within the CA1 play an important role in antinociceptive responses induced by chemical stimulation of the LH. It could be suggested that dopamine receptors in the CA1 were triggered by LH orexinergic projections.

Dopaminergic Transmission Rapidly and Persistently Enhances Excitability of D1 Receptor-Expressing Striatal Projection Neurons.

Substantia nigra dopamine neurons have been implicated in the initiation and invigoration of movement, presumably through their modulation of striatal projection neuron (SPN) activity. However, the impact of native dopaminergic transmission on SPN excitability has not been directly demonstrated. Using perforated patch-clamp recording, we found that optogenetic stimulation of nigrostriatal dopamine axons rapidly and persistently elevated the excitability of D1 receptor-expressing SPNs (D1-SPNs). The evoked firing of D1-SPNs increased within hundreds of milliseconds of stimulation and remained elevated for ≥ 10 min. Consistent with the negative modulation of depolarization- and Ca2+-activated K+ currents, dopaminergic transmission accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, and transiently diminished action potential afterhyperpolarization. Persistent modulation was protein kinase A dependent and associated with a reduction in action potential threshold. Together, these data demonstrate that dopaminergic transmission potently increases D1-SPN excitability with a time course that could support subsecond and sustained behavioral control.

Local D2- to D1-neuron transmodulation updates goal-directed learning in the striatum.

Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits that mediate goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of spiny projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN transmodulation across the striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.