Dual roles of dopaminergic pathways in olfactory learning and memory in the oriental fruit fly, Bactrocera dorsalis.

Dopamine (DA) is a key regulator of associative learning and memory in both vertebrates and invertebrates, and it is widely believed that DA plays a key role in aversive conditioning in invertebrates. However, the idea that DA is involved only in aversive conditioning has been challenged in recent studies on the fruit fly (Drosophila melanogaster), ants and crabs, suggesting diverse functions of DA modulation on associative plasticity. Here, we present the results of DA modulation in aversive olfactory conditioning with DEET punishment and appetitive olfactory conditioning with sucrose reward in the oriental fruit fly, Bactrocera dorsalis. Injection of DA receptor antagonist fluphenazine or chlorpromazine into these flies led to impaired aversive learning, but had no effect on the appetitive learning. DA receptor antagonists impaired both aversive and appetitive long-term memory retention. Interestingly, the impairment on appetitive memory was rescued not only by DA but also by octopamine (OA). Blocking the OA receptors also impaired the appetitive memory retention, but this impairment could only be rescued by OA, not by DA. Thus, we conclude that in B. dorsalis, OA and DA pathways mediate independently the appetitive and aversive learning, respectively. These two pathways, however, are organized in series in mediating appetitive memory retrieval with DA pathway being at upstream. Thus, OA and DA play dual roles in associative learning and memory retrieval, but their pathways are organized differently in these two cognitive processes - parallel organization for learning acquisition and serial organization for memory retrieval.

Sex similarities and dopaminergic differences in interval timing.

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

No major effect of dopamine receptor 1/5 antagonist SCH-23390 on epileptic activity in the Tg2576 mouse model of amyloidosis.

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease.

Brain connectivity changes to fast versus slow dopamine increases.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Dopamine transmission in the tail striatum: Regional variation and contribution of dopamine clearance mechanisms.

The striatum can be divided into four anatomically and functionally distinct domains: the dorsolateral, dorsomedial, ventral and the more recently identified caudolateral (tail) striatum. Dopamine transmission in these striatal domains underlies many important behaviours, yet little is known about this phenomenon in the tail striatum. Furthermore, the tail is divided anatomically into four divisions (dorsal, medial, intermediate and lateral) based on the profile of D1 and D2 dopamine receptor-expressing medium spiny neurons, something that is not seen elsewhere in the striatum. Considering this organisation, how dopamine transmission occurs in the tail striatum is of great interest. We recorded evoked dopamine release in the four tail divisions, with comparison to the dorsolateral striatum, using fast-scan cyclic voltammetry in rat brain slices. Contributions of clearance mechanisms were investigated using dopamine transporter knockout (DAT-KO) rats, pharmacological transporter inhibitors and dextran. Evoked dopamine release in all tail divisions was smaller in amplitude than in the dorsolateral striatum and, importantly, regional variation was observed: dorsolateral ≈ lateral > medial > dorsal ≈ intermediate. Release amplitudes in the lateral division were 300% of that in the intermediate division, which also exhibited uniquely slow peak dopamine clearance velocity. Dopamine clearance in the intermediate division was most dependent on DAT, and no alternative dopamine transporters investigated (organic cation transporter-3, norepinephrine transporter and serotonin transporter) contributed significantly to dopamine clearance in any tail division. Our findings confirm that the tail striatum is not only a distinct dopamine domain but also that each tail division has unique dopamine transmission characteristics. This supports that the divisions are not only anatomically but also functionally distinct. How this segregation relates to the overall function of the tail striatum, particularly the processing of multisensory information, is yet to be determined.

Nucleus accumbens core dopamine D2 receptors are required for performance of the odor span task in male rats.

RATIONALE: The nucleus accumbens (NAc) core gates motivationally relevant behavioral action sequences through afferents from cortical and subcortical brain regions. While the role of the NAc core in reward and effort-based decision making is well established, its role in working memory (WM) processes is incompletely understood. The odor span task (OST) has been proposed as a measure of non-spatial working memory capacity (WMC) as it requires rodents to select a novel odor from an increasing number of familiar odors to obtain a food reward. OBJECTIVE: To assess the role of the NAc core in the OST using (1) reversible chemical inactivation and (2) selective blockade of dopamine D1 and D2 receptors in the area. METHODS: Well-trained male rats were tested on the OST following intra-NAc core infusions of muscimol/baclofen, the D1 receptor antagonist SCH-23390 (1 µg/hemisphere) and the D2 receptor antagonist eticlopride (1 µg/hemisphere). Behavioral measurements included the average odor span, maximum odor span, choice latency, searching vigor, and patterns of responding during foraging that may relate to impulsivity. RESULTS: Chemical inactivation of the NAc core significantly decreased odor span relative to sham and vehicle conditions. Selective antagonism of D2, but not D1, receptors in the NAc core also produced deficits in odor span. We found that secondary behavioral measures of choice latency, searching vigor, and responding to the first odor stimulus encountered were largely unaffected by treatment. CONCLUSIONS: These findings suggest that D2 receptors in the NAc core are required for OST performance.

Divergent Acute and Enduring Changes in 50-kHz Ultrasonic Vocalizations in Rats Repeatedly Treated With Amphetamine and Dopaminergic Antagonists: New Insights on the Role of Dopamine in Calling Behavior.

BACKGROUND: Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to nonpharmacological and pharmacological stimuli, with addictive psychostimulants being the most effective drugs that elicit calling behavior in rats. Earlier investigations found that dopamine D1-like and D2-like receptors modulate the emission of 50-kHz USVs stimulated in rats by the acute administration of addictive psychostimulants. Conversely, information is lacking on how dopamine D1-like and D2-like receptors modulate calling behavior in rats that are repeatedly treated with addictive psychostimulants. METHODS: We evaluated the emission of 50-kHz USVs in rats repeatedly treated (×5 on alternate days) with amphetamine (1 mg/kg, i.p.) either alone or together with (1) SCH 23390 (0.1-1 mg/kg, s.c.), a dopamine D1 receptor antagonist; (2) raclopride (0.3-1 mg/kg, s.c.), a selective dopamine D2 receptor antagonist; or (3) a combination of SCH 23390 and raclopride (0.1 + 0.3 mg/kg, s.c.). Calling behavior of rats was recorded following pharmacological treatment, as well as in response to the presentation of amphetamine-paired cues and to amphetamine challenge (both performed 7 days after treatment discontinuation). RESULTS: Amphetamine-treated rats displayed a sensitized 50-kHz USV emission during repeated treatment, as well as marked calling behavior in response to amphetamine-paired cues and to amphetamine challenge. Antagonism of D1 or D2 receptors either significantly suppressed or attenuated the emission of 50-kHz USVs in amphetamine-treated rats, with a maximal effect after synergistic antagonism of both receptors. CONCLUSIONS: These results shed further light on how dopamine transmission modulates the emission of 50-kHz USVs in rats treated with psychoactive drugs.

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions.

BACKGROUND: Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. METHODS: GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. RESULTS: Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. CONCLUSIONS: DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Fluorescent Tools for the Imaging of Dopamine D2 -Like Receptors.

The family of dopamine D2 -like receptors represents an interesting target for a variety of neurological diseases, e. g. Parkinson's disease (PD), addiction, or schizophrenia. In this study we describe the synthesis of a new set of fluorescent ligands as tools for visualization of dopamine D2 -like receptors. Pharmacological characterization in radioligand binding studies identified UR-MN212 (20) as a high-affinity ligand for D2 -like receptors (pKi (D2long R)=8.24, pKi (D3 R)=8.58, pKi (D4 R)=7.78) with decent selectivity towards D1 -like receptors. Compound 20 is a neutral antagonist in a Go1 activation assay at the D2long R, D3 R, and D4 R, which is an important feature for studies using whole cells. The neutral antagonist 20, equipped with a 5-TAMRA dye, displayed rapid association to the D2long R in binding studies using confocal microscopy demonstrating its suitability for fluorescence microscopy. Furthermore, in molecular brightness studies, the ligand's binding affinity could be determined in a single-digit nanomolar range that was in good agreement with radioligand binding data. Therefore, the fluorescent compound can be used for quantitative characterization of native D2 -like receptors in a broad variety of experimental setups.

Refining the study of decision-making in animals: differential effects of d-amphetamine and haloperidol in a novel touchscreen-automated Rearing-Effort Discounting (RED) task and the Fixed-Ratio Effort Discounting (FRED) task.

Effort-based decision-making is impaired in multiple psychopathologies leading to significant impacts on the daily life of patients. Preclinical studies of this important transdiagnostic symptom in rodents are hampered, however, by limitations present in currently available decision-making tests, including the presence of delayed reinforcement and off-target cognitive demands. Such possible confounding factors can complicate the interpretation of results in terms of decision-making per se. In this study we addressed this problem using a novel touchscreen Rearing-Effort Discounting (RED) task in which mice choose between two single-touch responses: rearing up to touch an increasingly higher positioned stimulus to obtain a High Reward (HR) or touching a lower stimulus to obtain a Low Reward (LR). To explore the putative advantages of this new approach, RED was compared with a touchscreen version of the well-studied Fixed Ratio-based Effort Discounting (FRED) task, in which multiple touches are required to obtain an HR, and a single response is required to obtain an LR. Results from dopaminergic (haloperidol and d-amphetamine), behavioral (changes in the order of effort demand; fixed-ratio schedule in FRED or response height in RED), and dietary manipulations (reward devaluation by pre-feeding) were consistent with the presence of variables that may complicate interpretation of conventional decision-making tasks, and demonstrate how RED appears to minimize such variables.

Differential Roles of the D1- and D2-Like Dopamine Receptors Within the Ventral Tegmental Area in Modulating the Antinociception Induced by Forced Swim Stress in the Rat.

Several preclinical and clinical studies indicate that exposure to acute stress may decrease pain perception and increases pain tolerance. This phenomenon is called stress-induced analgesia (SIA). A variety of neurotransmitters, including dopamine, is involved in the SIA. Dopaminergic neurons in the mesolimbic circuits, originating from the ventral tegmental area (VTA), play a crucial role in various motivational, rewarding, and pain events. The present study aimed to investigate the modulatory role of VTA dopaminergic receptors in the antinociceptive responses evoked by forced swim stress (FSS) in a model of acute pain. One hundred-five adult male albino Wistar rats were subjected to stereotaxic surgery for implanting a unilateral cannula into the VTA. After one week of recovery, separate groups of animals were given different doses of SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.3 µl) as D1- and D2-like receptor antagonists into the VTA, respectively. Then, the animals were exposed to FSS for a 6-min period, and the pain threshold was measured using the tail-flick test over a 60-min time set intervals. Results indicated that exposure to FSS produces a prominent antinociceptive response, diminishing by blocking both dopamine receptors in the VTA. Nonetheless, the effect of a D1-like dopamine receptor antagonist on FSS-induced analgesia was more prominent than that of a D2-like dopamine receptor antagonist. The results demonstrated that VTA dopaminergic receptors contribute to the pain process in stressful situations, and it might be provided a practical approach to designing new therapeutic agents for pain management.

Acute and chronic glutamate NMDA antagonist treatment attenuates dopamine D1 antagonist-induced reduction of nicotine self-administration in female rats.

Multiple interacting neural systems are involved in sustaining nicotine reinforcement. We and others have shown that dopamine D1 receptors and glutamate NMDA receptors both play important roles in nicotine reinforcement. Blockade of D1 receptors with the antagonist SCH-23390 (0.02 mg/kg) both acutely and chronically significantly decreased nicotine self-administration in rats. Blockade of NMDA receptors (10 mg/kg) acutely with memantine significantly increased nicotine self-administration, but chronic blockade of NMDA receptors with memantine significantly decreased nicotine self-administration. The current study examined the interactions of acute and chronic administration of SCH-23390 and memantine on nicotine self-administration in female rats. Replicating earlier studies, acute and chronic SCH-23390 significantly decreased nicotine self-administration and memantine had a biphasic effect with acute administration increasing nicotine self-administration and chronic memantine showed a non-significant trend toward decreasing it. However, chronic interaction study showed that memantine significantly attenuated the decrease in nicotine self-administration caused by chronic SCH-23390. These studies provide important information that memantine attenuates the efficacy of D1 antagonist SCH 23390 in reducing nicotine-self-administration. These two drugs do not appear to have mutually potentiating effects to aid tobacco cessation.

Nucleus accumbens and dorsal medial striatal dopamine and neural activity are essential for action sequence performance.

Separable striatal circuits have unique functions in Pavlovian and instrumental behaviors but how these roles relate to performance of sequences of actions with and without associated cues are less clear. Here, we tested whether dopamine transmission and neural activity more generally in three striatal subdomains are necessary for performance of an action chain leading to reward delivery. Male and female Long-Evans rats were trained to press a series of three spatially distinct levers to receive reward. We assessed the contribution of neural activity or dopamine transmission within each striatal subdomain when progression through the action sequence was explicitly cued and in the absence of cues. Behavior in both task variations was substantially impacted following microinfusion of the dopamine antagonist, flupenthixol, into nucleus accumbens core (NAc) or dorsomedial striatum (DMS), with impairments in sequence timing and numbers of rewards earned after NAc flupenthixol. In contrast, after pharmacological inactivation to suppress overall activity, there was minimal impact on total rewards earned. Instead, inactivation of both NAc and DMS impaired sequence timing and led to sequence errors in the uncued, but not cued task. There was no impact of dopamine antagonism or reversible inactivation of dorsolateral striatum on either cued or uncued action sequence completion. These results highlight an essential contribution of NAc and DMS dopamine systems in motivational and performance aspects of chains of actions, whether cued or internally generated, as well as the impact of intact NAc and DMS function for correct sequence performance.

The dopamine D1 receptor antagonist SCH-23390 blocks the acquisition, but not expression of mitragynine-induced conditioned place preference in rats.

Mitragynine (MG) is the primary active constituent of Mitragyna speciosa Korth (kratom), a psychoactive Southeast Asian plant with potential therapeutic use. Numerous studies support roles of dopaminergic system in drug reward. However, the involvement of the dopaminergic system in mediating MG reward and drug-seeking is poorly understood. Using conditioned place preference (CPP) paradigm, the present study aims to evaluate the roles of the dopamine (DA) D1 receptor in the acquisition and expression of MG-induced CPP in rats. The effects of SCH-23390, a selective DA D1 receptor antagonist, on the acquisition of MG-induced CPP were first investigated. Rats were pre-treated systemically with SCH-23390 (0, 0.1 and 0.3 mg/kg, i.p.) prior to MG (10 mg/kg) conditioning sessions. Next, we tested the effects of the DA D1 receptor antagonist on the expression of MG-induced CPP. Furthermore, the effects of a MG-priming dose (5 mg/kg) on the reinstatement of extinguished CPP were tested. The results showed that SCH-23390 dose-dependently suppressed the acquisition of a MG-induced CPP. In contrast, SCH-23390 had no effect on the expression of a MG-induced CPP. The findings of this study suggested a crucial role of the DA D1 receptor in the acquisition, but not the expression of the rewarding effects of MG in a CPP test. Furthermore, blockade of the D1-like receptor during conditioning did not prevent MG priming effects on CPP reinstatement test, suggesting no role for the DA D1 receptor in reinstatement sensitivity.

The dopamine receptor antagonist haloperidol disrupts behavioral responses of sea urchins and sea stars.

Despite lacking a brain and having an apparent symmetrically pentaradial nervous system, echinoderms are capable of complex, coordinated directional behavioral responses to different sensory stimuli. However, very little is known about the molecular and cellular mechanisms underlying these behaviors. In many animals, dopaminergic systems play key roles in motivating and coordinating behavior, and although the dopamine receptor antagonist haloperidol has been shown to inhibit the righting response of the sea urchin Strongylocentrotus purpuratus, it is not known whether this is specific to this behavior, in this species, or whether dopaminergic systems are needed in general for echinoderm behaviors. We found that haloperidol inhibited multiple different behavioral responses in three different echinoderm species. Haloperidol inhibited the righting response of the sea urchin Lytechinus variegatus and of the sea star Luidia clathrata. It additionally inhibited the lantern reflex of S. purpuratus, the shell covering response of L. variegatus and the immersion response of L. variegatus, but not S. purpuratus or L. clathrata. Our results suggest that dopamine is needed for the neural processing and coordination of multiple different behavioral responses in a variety of different echinoderm species.

The dopaminergic D1 receptor modulates the hyperactivity of Bapa mutant mice.

The mutant bate-palmas ("claps"; symbol - bapa) mice induced by the mutagenic chemical ENU present motor incoordination and postural alterations. A previous study showed that bapa mice present increased motor/exploratory behaviors during the prepubertal period due to increased striatal tyrosine hydroxylase expression, suggesting striatal dopaminergic system hyperactivity. This study aimed to evaluate the involvement of striatal dopaminergic receptors in the hyperactivity of bapa mice. Male bapa mice and their wild strain (WT) were used. Spontaneous motor behavior was observed in the open-field test, and stereotypy was evaluated after apomorphine administration. The effects of DR1 and DR2 dopaminergic antagonists (SCH-23,390; sulpiride) and the striatal DR1 and D2 receptor gene expression were evaluated. Relative to WT, bapa mice showed: 1) increased general activity for four days; 2) increased rearing and sniffing behavior and decreased immobility after apomorphine; 3) blockage of rearing behavior after the DR2 antagonist but no effect after DR1 antagonist; 4) blockage of sniffing behavior after the DR1 antagonist in bapa and WT mice but no effect after the DR2 antagonist; 5) increased immobility after the DR1 antagonist but no effect after the DR2 antagonist; 6) increased expression of striatal DR1 receptor gene and reduced the DR2 expression gene after apomorphine administration. Bapa mice showed increased activity in open field behavior. The increased rearing behavior induced by apomorphine of bapa mice resulted from the increased gene expression of the DR1 receptor.

Assessing attention and impulsivity in the variable stimulus duration and variable intertrial interval rodent continuous performance test schedules using dopamine receptor antagonists in female C57BL/6JRj mice.

RATIONALE: Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in attention and impulsivity. OBJECTIVE: To examine the roles of dopamine receptors in attention and impulsivity behaviours measured in the rCPT variable stimulus duration (vSD) and the variable intertrial interval schedules (vITI) using DA receptor antagonists. METHODS: Two cohorts of 35 and 36 female C57BL/6JRj mice were examined separately in the rCPT, vSD, and vITI schedules, respectively. Both cohorts received antagonists of the following receptors: D1/5 (SCH23390, SCH: 0.01, 0.02, 0.04 mg/kg) and D2/3 (raclopride, RAC 0.03, 0.10, 0.30 mg/kg) in consecutive balanced Latin square designs with flanking reference measurements. The antagonists were subsequently examined for effects on locomotor activity. RESULTS: SCH showed similar effects in both schedules, and the effects were reference-dependent in the vITI schedule. SCH reduced responding, but improved response accuracy, impulsivity, discriminability, and locomotor activity. RAC showed mixed effects on responsivity, but improved accuracy and discriminability. The discriminability improvement was driven by an increase in hit rate in the vITI schedule and a reduction in false alarm rate in the vSD schedule. RAC also decreased locomotor activity. CONCLUSION: Both D1/5 and D2/3 receptor antagonism reduced responding, but the outcome on discriminability differed, stemming from individual effects on hit and false alarm rate, and the weight of omissions within the calculation. The effects of SCH and RAC suggest that endogenous DA increases responding and impulsivity, but reduces accuracy and shows mixed effects on discriminability.

Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D1 and D2 receptors.

Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D2 receptor (D2-R) vs. D1 receptor (D1-R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examined the ability of Lu AF35700 (preferential D1-R>D2-R antagonist), to reverse the alterations in thalamo-cortical activity induced by phencyclidine (PCP), used as a pharmacological model of schizophrenia. Lu AF35700 reversed the PCP-induced alteration of neuronal discharge and low frequency oscillation (LFO, 0.15-4 Hz) in thalamo-cortical networks. Likewise, Lu AF35700 prevented the increased c-fos mRNA expression induced by PCP in thalamo-cortical regions of awake rats. We next examined the contribution of D1-R and D2-R to the antipsychotic reversal of PCP effects. The D2-R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Remarkably, the combination of sub-effective doses of haloperidol and SCH-23390 (DA D1-R antagonist) fully reversed the PCP-induced fall in thalamo-cortical LFO. However, unlike with haloperidol, SCH-23390 elicited different degrees of potentiation of the effects of low clozapine and Lu AF35700 doses. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors.

Blockade of the Dopamine D3 Receptor Attenuates Opioids-Induced Addictive Behaviours Associated with Inhibiting the Mesolimbic Dopamine System.

Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.