Involvement of prelimbic cortex neurons and related circuits in the acquisition of cooperative learning by pairs of rats

Social behaviors such as cooperation are crucial for mammals. A deeper knowledge of the neuronal mechanisms underlying cooperation can be beneficial for people suffering from pathologies with impaired social behavior. Our aim was to study the brain activity when two animals synchronize their behavior to obtain a mutual reinforcement. In a previous work, we showed that the activity of the prelimbic cortex (PrL) was enhanced during cooperation in rats, especially in the ones leading most cooperative trials (leader rats). In this study, we investigated the specific cell type/s in the PrL contributing to cooperative behaviors. To this end, we collected rats' brains at key moments of the learning process to analyze the levels of c-FOS expression in the main cellular groups of the PrL (glutamatergic cells containing D1 and D2 receptors and interneurons). Leader rats showed increased c-FOS activity in cells expressing D1 receptors during cooperation. In addition, we analyzed the levels of anxiety, dominance, and locomotor behavior, finding that leader rats are in general less anxious and less dominant than followers. We also recorded local field potentials (LFPs) from the PrL, the nucleus accumbens septi (NAc), and the basolateral amygdala (BLA). Spectral analysis showed that delta activity in PrL and NAc increased when rats cooperated, while BLA activity in delta and theta bands decreased considerably during cooperation. The PrL and NAc also increased their connectivity in the high theta band during cooperation. Thus, the present work identifies the specific PrL cell types engaged in this behavior, as well as its connectivity with subcortical brain regions (BLA, NAc) during cooperation.

Atypical antipsychotic Lumateperone Beyond Schizophrenia: Seeking clarity in a time of Uncertainty

Lumateperone (ITI-007) is a serotonin 5HT2A tosylate salt with high affinity for dopamine D2 and D1 receptors and the serotonin transporter. It is unusual in that it controls serotonin, dopamine, and glutamate neurotransmission concurrently, all of which have been implicated in severe mental illness. Consider it a multi-targeted ligand and multifunctional modulator of the serotoninergic system with possible precognitive, antipsychotic, antidepressant, and anxiolytic properties. While lumateperone has been explored as a new agent for schizophrenia therapy, it also provides a unique therapeutic option for a range of other psychiatric and neurological diseases, including behavioural signs of dementia or Alzheimer's disease, sleep problems, and bipolar depression. Additionally, it had a better safety profile than placebo, with no significant extrapyramidal side effects, hyperprolactinemia, or changes in cardiometabolic or endocrine characteristics. Additional study is needed to validate and analyse lumateperone's effectiveness, as well as to identify prospective therapeutic targets. This article gives a comprehensive overview of the most notable results and potential future applications of this chemical in personalised medicine, particularly for neurodegenerative diseases.

Effects of methamphetamine-induced neurotoxicity on striatal long-term potentiation

Rationale Methamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions. Objectives Therefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice. Methods Mice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology. Results Under these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices. Conclusions Together, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.

Quantifying the inverted U: A meta-analysis of prefrontal dopamine, D1-receptors, and working memory

Dopamine in the prefrontal cortex can be disrupted in human disorders that affect cognitive function such as Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), and schizophrenia. Dopamine has a powerful effect on prefrontal circuits via the D1-type dopamine receptor (D1DR). It has been proposed that prefrontal dopamine has "inverted U-shaped" dynamics, with optimal dopamine and D1DR signaling required for optimal cognitive function. However, the quantitative relationship between prefrontal dopamine and cognitive function is not clear. Here, we conducted a meta-analysis of published manipulations of prefrontal dopamine and the effects on working memory, a high-level executive function in humans, primates, and rodents that involves maintaining and manipulating information over seconds to minutes. We reviewed 646 papers and found that 75 studies met criteria for inclusion. Our quantification of effect sizes for dopamine, D1DRs, and behavior revealed a negative quadratic slope. This is consistent with the proposed inverted U-shape of prefrontal dopamine and D1DRs and working memory performance, explaining 10% of the variance. Of note, the inverted quadratic fit was much stronger for prefrontal D1DRs alone, explaining 26% of the variance, compared to prefrontal dopamine alone, explaining 10% of the variance. Taken together, these data, derived from a variety of manipulations and systems, demonstrate that optimal prefrontal dopamine signalling is linked with higher cognitive function. Our results provide insight into the fundamental dynamics of prefrontal dopamine, which could be useful for pharmacological interventions targeting prefrontal dopaminergic circuits, and into the pathophysiology of human brain disease.

Prenatal opioid exposure inhibits microglial sculpting of the dopamine system during adolescence

The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. However, little is know about the mechanisms by which prenatal opioid exposure leads to long term changes in reward circuit function and behavior. Microglia, the resident immune cells of the brain, are known to respond to perinatal opioid exposure and to sculpt neural circuits during development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors in the nucleus accumbens (NAc) is required for the natural development decline in NAc-D1R that occurs between adolescence and adulthood. Morever, this microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. Here, we show that maternal oxycodone self-administration during pregnancy leads to higher D1R density within the NAc in adult male, but not female, offspring in rats. Furthermore, adolescent microglial phagocytosis of D1R is reduced following prenatal oxycodone exposure. Ths work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to long-term changes in neural systems.

VTA-IC dopaminergic inputs enhances the salience to consolidate aversive but not appetitive taste recognition memory via D1 receptors

Taste memory involves storing information through plasticity changes in the neural network of taste, including the insular cortex (IC) and ventral tegmental area (VTA), a critical provider of dopamine. Although a VTA-IC dopaminergic pathway has been demonstrated, its role to consolidate taste recognition memory remains poorly understood. We found that photostimulation of dopaminergic neurons in the VTA or VTA-IC dopaminergic terminals of TH-Cre mice increases the salience to facilitate consolidation of a novel taste stimulus regardless of its hedonic value, without altering their taste palatability. Importantly, the inhibition of the D1-like receptor into the IC impairs the salience to facilitate consolidation of an aversive taste recognition memory. Finally, our results showed that VTA photostimulation improves the salience to facilitate consolidation of a conditioned taste aversion memory through the D1-like receptor into the IC. It is concluded that the dopamine activity from the VTA into IC is required to increase the salience to facilitate consolidation of a taste recognition memory. Notably, the D1-like receptor activity into the IC is required to consolidate both innate and learned aversive taste memories but not appetitive taste memory.

Behavioural and Neurochemical Effects of Acute (±) 3,4 methylenedioxymethamphetamine (MDMA) in the Dopamine D1 Receptor Mutant Rat

<p>Rationale: (±) 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is a recreationally abused psychostimulant that leads to detrimental effects on memory performance. MDMA’s acute effects on memory are 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 impair memory performance through an MDMA-induced increase in dopamine (DA) release, leading to overstimulation of DA D1 receptors. The overstimulation of D1 receptors during acute MDMA exposure is thought to indirectly impair memory by increasing a subject’s susceptibility to proactive interference, leading to a perseverative pattern of responding during memory tasks. Objective: This project investigates the hypothesis that acute MDMA impairs memory performance via overstimulation of D1 receptors. The acute actions of MDMA will be assessed using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional DA D1 receptors. On the basis that acute MDMA impairs memory function via overstimulation of D1 receptors it is predicted that, compared to control rats, DAD1-/- rats will be protected from the acute memory deficits caused by MDMA. Due to the novelty of the DAD1-/- rat model, prior to the assessment of the acute effects of MDMA on memory performance in these rats, behavioural and neurochemical characterisations will be conducted. Methods: Firstly, a behavioural characterisation was conducted to explore the tendencies of DAD1-/- rats, compared to controls, in a drug free state. Behaviours relevant for motivation and reward, movement, and memory were the focus of the behavioural investigation due to evidence suggesting a role for D1-like receptors in these functions. Secondly, a neurochemical assessment of DAD1-/- and controls rats in response to MDMA (3 mg/kg) was assayed using c-fos expression, a marker for neuronal activity, in several brain regions with known DA innervation. Thirdly, to assess the acute effects of MDMA on memory performance, DAD1-/- and control rats were trained on a spatial working memory T-maze task, delayed non-matching to position (DNMTP), over 25 sessions. Once trained, rats were administered either 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 three time each. In addition, to further investigate the hypothesis that overstimulation of D1 receptors impairs memory performance, the effects of a D1 receptor agonist, SKF 81297 (0.5, 1, 1.5, 3, 4.5 mg/kg) on DNMTP performance were also assessed. Results: The behavioural characterisation revealed that DAD1-/- rats are capable of performing many behaviours relevant for reward processing, movement and memory function. However, DAD1-/- rats were impaired with regard to some reward-related behaviours, such as the acquitision of lever pressing for sugar pellets. The assessment of c-fos expression demonstrated that DAD1-/- rats express less c-fos in the medial prefrontal cortex, striatum and nucleus accumbens compared to control rats following MDMA administration. Lastly, the effects of acute MDMA administration on memory performance were tested. During the third block of MDMA administration, control rats demonstrated decreased accuracy on the DMNTP task at both the 2.25 and 3 mg/kg doses. The decrease in accuracy during MDMA exposure in control rats was driven by an increase in perseverative errors. On the contrary, DAD1-/- rats were not impaired on the DNMTP task following acute MDMA at any of the doses tested. Administration of SKF 81297 did not lead to any systematic changes in performance, but at the 3 mg/kg dose DAD1-/- rats displayed increased accuracy compared to control rats. Conclusions: DAD1-/- rats were protected from an MDMA-induced decrease in accuracy on the DNMTP task compared to control rats. This finding challenges the assumption that MDMA’s acute effects on memory performance are wholly due to serononergic mechanisms. Specifically, the current study provides evidence for the hypothesis that acute MDMA exposure impairs memory performance in rats.</p>

Behavioural and Neurochemical Effects of Acute (±) 3,4 methylenedioxymethamphetamine (MDMA) in the Dopamine D1 Receptor Mutant Rat

<p>Rationale: (±) 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is a recreationally abused psychostimulant that leads to detrimental effects on memory performance. MDMA’s acute effects on memory are 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 impair memory performance through an MDMA-induced increase in dopamine (DA) release, leading to overstimulation of DA D1 receptors. The overstimulation of D1 receptors during acute MDMA exposure is thought to indirectly impair memory by increasing a subject’s susceptibility to proactive interference, leading to a perseverative pattern of responding during memory tasks. Objective: This project investigates the hypothesis that acute MDMA impairs memory performance via overstimulation of D1 receptors. The acute actions of MDMA will be assessed using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional DA D1 receptors. On the basis that acute MDMA impairs memory function via overstimulation of D1 receptors it is predicted that, compared to control rats, DAD1-/- rats will be protected from the acute memory deficits caused by MDMA. Due to the novelty of the DAD1-/- rat model, prior to the assessment of the acute effects of MDMA on memory performance in these rats, behavioural and neurochemical characterisations will be conducted. Methods: Firstly, a behavioural characterisation was conducted to explore the tendencies of DAD1-/- rats, compared to controls, in a drug free state. Behaviours relevant for motivation and reward, movement, and memory were the focus of the behavioural investigation due to evidence suggesting a role for D1-like receptors in these functions. Secondly, a neurochemical assessment of DAD1-/- and controls rats in response to MDMA (3 mg/kg) was assayed using c-fos expression, a marker for neuronal activity, in several brain regions with known DA innervation. Thirdly, to assess the acute effects of MDMA on memory performance, DAD1-/- and control rats were trained on a spatial working memory T-maze task, delayed non-matching to position (DNMTP), over 25 sessions. Once trained, rats were administered either 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 three time each. In addition, to further investigate the hypothesis that overstimulation of D1 receptors impairs memory performance, the effects of a D1 receptor agonist, SKF 81297 (0.5, 1, 1.5, 3, 4.5 mg/kg) on DNMTP performance were also assessed. Results: The behavioural characterisation revealed that DAD1-/- rats are capable of performing many behaviours relevant for reward processing, movement and memory function. However, DAD1-/- rats were impaired with regard to some reward-related behaviours, such as the acquitision of lever pressing for sugar pellets. The assessment of c-fos expression demonstrated that DAD1-/- rats express less c-fos in the medial prefrontal cortex, striatum and nucleus accumbens compared to control rats following MDMA administration. Lastly, the effects of acute MDMA administration on memory performance were tested. During the third block of MDMA administration, control rats demonstrated decreased accuracy on the DMNTP task at both the 2.25 and 3 mg/kg doses. The decrease in accuracy during MDMA exposure in control rats was driven by an increase in perseverative errors. On the contrary, DAD1-/- rats were not impaired on the DNMTP task following acute MDMA at any of the doses tested. Administration of SKF 81297 did not lead to any systematic changes in performance, but at the 3 mg/kg dose DAD1-/- rats displayed increased accuracy compared to control rats. Conclusions: DAD1-/- rats were protected from an MDMA-induced decrease in accuracy on the DNMTP task compared to control rats. This finding challenges the assumption that MDMA’s acute effects on memory performance are wholly due to serononergic mechanisms. Specifically, the current study provides evidence for the hypothesis that acute MDMA exposure impairs memory performance in rats.</p>

Functional Selectivity of Dopamine D1 Receptor Signaling: Retrospect and Prospect

Research progress on dopamine D1 receptors indicates that signaling no longer is limited to G protein-dependent cyclic adenosine monophosphate phosphorylation but also includes G protein-independent β-arrestin-related mitogen-activated protein kinase activation, regulation of ion channels, phospholipase C activation, and possibly more. This review summarizes recent studies revealing the complexity of D1 signaling and its clinical implications, and suggests functional selectivity as a promising strategy for drug discovery to magnify the merit of D1 signaling. Functional selectivity/biased receptor signaling has become a major research front because of its potential to improve therapeutics through precise targeting. Retrospective pharmacological review indicated that many D1 ligands have some degree of mild functional selectivity, and novel compounds with extreme bias at D1 signaling were reported recently. Behavioral and neurophysiological studies inspired new methods to investigate functional selectivity and gave insight into the biased signaling of several drugs. Results from recent clinical trials also supported D1 functional selectivity signaling as a promising strategy for discovery and development of better therapeutics.