Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species.

Social behaviour is essential for animal survival, and the hypothalamic neuropeptide oxytocin (OXT) critically impacts bonding, parenting, and decision-making. Dopamine (DA), is released by ventral tegmental area (VTA) dopaminergic neurons, regulating social cues in the mesolimbic system. Despite extensive exploration of OXT and DA roles in social behaviour independently, limited studies investigate their interplay. This narrative review integrates insights from human and animal studies, particularly rodents, emphasising recent research on pharmacological manipulations of OXT or DA systems in social behaviour. Additionally, we review studies correlating social behaviour with blood/cerebral OXT and DA levels. Behavioural facets include sociability, cooperation, pair bonding and parental care. In addition, we provide insights into OXT-DA interplay in animal models of social stress, autism, and schizophrenia. Emphasis is placed on the complex relationship between the OXT and DA systems and their collective influence on social behaviour across physiological and pathological conditions. Understanding OXT and DA imbalance is fundamental for unravelling the neurobiological underpinnings of social interaction and reward processing deficits observed in psychiatric conditions.

Ethanol-induced AMPA alterations are mediated by mGLU5 receptors through miRNA upregulation in hippocampal slices.

Prenatal alcohol exposure (PAE) affects neuronal networks and brain development causing a range of physical, cognitive and behavioural disorders in newborns that persist into adulthood. The array of consequences associated with PAE can be grouped under the umbrella-term 'fetal alcohol spectrum disorders' (FASD). Unfortunately, there is no cure for FASD as the molecular mechanisms underlying this pathology are still unknown. We have recently demonstrated that chronic EtOH exposure, followed by withdrawal, induces a significant decrease in AMPA receptor (AMPAR) expression and function in developing hippocampus in vitro. Here, we explored the EtOH-dependent pathways leading to hippocampal AMPAR suppression. Organotypic hippocampal slices (2 days in cultures) were exposed to EtOH (150 mM) for 7 days followed by 24 h EtOH withdrawal. Then, the slices were analysed by means of RT-PCR for miRNA content, western blotting for AMPA and NMDA related-synaptic proteins expression in postsynaptic compartment and electrophysiology to record electrical properties from CA1 pyramidal neurons. We observed that EtOH induces a significant downregulation of postsynaptic AMPA and NMDA subunits and relative scaffolding protein expression and, accordingly, a decrease of AMPA-mediated neurotransmission. Simultaneously, we found that chronic EtOH induced-upregulation of miRNA 137 and 501-3p and decreased AMPA-mediated neurotransmission are prevented by application of the selective mGlu5 antagonist MPEP during EtOH withdrawal. Our data indicate mGlu5 via miRNA137 and 501-3p expression as key factors in the regulation of AMPAergic neurotransmission that may contribute, at least in part, to the pathogenesis of FASD.

Recency memory is altered in cocaine-withdrawn adolescent rats: Implication of cortical mTOR signaling.

In humans, cocaine abuse during adolescence poses a significant risk for developing cognitive deficits later in life. Among the regions responsible for cognitive processes, the medial prefrontal cortex (mPFC) modulates temporal order information via mechanisms involving the mammalian-target of rapamycin (mTOR)-mediated pathway and protein synthesis regulation. Accordingly, our goal was to study the effect of repeated cocaine exposure during both adolescence and adulthood on temporal memory by studying the mTOR pathway in the mPFC. Adolescent or adult rats underwent repeated cocaine injections for 15 days and, after two weeks of withdrawal, engaged in the temporal order object recognition (TOOR) test. We found that repeated cocaine exposure during adolescence impaired TOOR performance, while control or adult-treated animals showed no impairments. Moreover, activation of the mTOR-S6-eEF2 pathway following the TOOR test was diminished only in the adolescent cocaine-treated group. Notably, inhibition of the mTOR-mediated pathway by rapamycin injection impaired TOOR performance in naïve adolescent and adult animals, revealing this pathway to be a critical component in regulating recency memory. Our data indicate that withdrawal from cocaine exposure impairs recency memory via the dysregulation of protein translation mechanisms, but only when cocaine is administered during adolescence.

Single and Repeated Exposure to Cannabidiol Differently Modulate BDNF Expression and Signaling in the Cortico-Striatal Brain Network.

Cannabidiol (CBD) is a phytocannabinoid contained in the Cannabis sativa plant, devoid of psychotomimetic effects but with a broad-spectrum pharmacological activity. Because of its pharmacological profile and its ability to counteract the psychoactive Δ9-tetrahydrocannabinol (Δ9THC), CBD may be a potential treatment for several psychiatric and neurodegenerative disorders. In this study, we performed a dose-response evaluation of CBD modulatory effects on BDNF, a neurotrophin subserving pleiotropic effects on the brain, focusing on the cortico-striatal pathway for its unique role in the brain trafficking of BDNF. Male adult rats were exposed to single and repeated CBD treatments at different dosing regimen (5, 15, and 30 mg/kg), to investigate the rapid modulation of the neurotrophin (1 h after the single treatment) as well as a potential drug-free time point (24 h after the repeated treatment). We show here, for the first time, that CBD can be found in the rat brain and, specifically, in the medial prefrontal cortex (mPFC) following single or repeated exposure. In fact, we found that CBD is present in the mPFC of rats treated either acutely or repeatedly with the phytocannabinoid, with a clear dose-response profile. From a molecular standpoint, we found that single, but not repeated, CBD exposure upregulates BDNF in the mPFC, while the repeated exposure increased BDNF only in the striatum, with a slight decrease in the mPFC. Together, these data reveal a CBD dose-dependent and anatomically specific modulation of BDNF, which may be functionally relevant and may represent an added value for CBD as a supplement.

Dopamine neurotransmission in the VTA regulates aversive memory formation and persistence.

Dopamine (DA) neurons in the ventral tegmental area (VTA) innervating several limbic and neocortical regions of the mammalian brain have long been implicated in motivation, rewarding and aversive behaviors, and memory processing. Recently, we demonstrated that somatodendritic release of DA in the VTA regulates the formation and maintenance of appetitive long-term memories (LTM). However, less is known about the impact of DA neurotransmission in the VTA on aversive LTM. Here, we describe the modulation of negative-valence memories by D1/D5-type DA (D1R)-receptor-mediated neurotransmission in the VTA. As aversive stimuli elicit both active and passive behavioral responses, we used two single-trial aversive training protocols: inhibitory avoidance task and conditioned place aversion. We bilaterally microinfused SCH23390, an antagonist of D1R, into the VTA immediately after training and found that DA neurotransmission in the VTA modulates LTM consolidation and persistence of aversive experiences. Together with previous findings demonstrating that D1R-mediated DA neurotransmission in the medial prefrontal cortex and hippocampus is involved in the formation and persistence of LTM for aversive events, our present results indicate that memory processing of environmental stimuli with negative-valence depends on the integration of information mediated by D1R activation in both the VTA region and in selected downstream target areas.

Bidirectional role of dopamine in learning and memory-active forgetting.

Dopaminergic neurons projecting from the Substantia Nigra to the Striatum play a critical role in motor functions while dopaminergic neurons originating in the Ventral Tegmental Area (VTA) and projecting to the Nucleus Accumbens, Hippocampus and other cortical structures regulate rewarding learning. While VTA mainly consists of dopaminergic neurons, excitatory (glutamate) and inhibitory (GABA) VTA-neurons have also been described: these neurons may also modulate and contribute to shape the final dopaminergic response, which is critical for memory formation. However, given the large amount of information that is handled daily by our brain, it is essential that irrelevant information be deleted. Recently, apart from the well-established role of dopamine (DA) in learning, it has been shown that DA plays a critical role in the intrinsic active forgetting mechanisms that control storage information, contributing to the deletion of a consolidated memory. These new insights may be instrumental to identify therapies for those disorders that involve memory alterations.

Metaplastic Effects of Ketamine and MK-801 on Glutamate Receptors Expression in Rat Medial Prefrontal Cortex and Hippocampus.

Ketamine and MK-801 by blocking NMDA receptors may induce reinforcing effects as well as schizophrenia-like symptoms. Recent results showed that ketamine can also effectively reverse depressive signs in patients' refractory to standard therapies. This evidence clearly points to the need of characterization of effects of these NMDARs antagonists on relevant brain areas for mood disorders. The aim of the present study was to investigate the molecular changes occurring at glutamatergic synapses 24 h after ketamine or MK-801 treatment in the rat medial prefrontal cortex (mPFC) and hippocampus (Hipp). In particular, we analyzed the levels of the glutamate transporter-1 (GLT-1), NMDA receptors, AMPA receptors subunits, and related scaffolding proteins. In the homogenate, we found a general decrease of protein levels, whereas their changes in the post-synaptic density were more complex. In fact, ketamine in the mPFC decreased the level of GLT-1 and increased the level of GluN2B, GluA1, GluA2, and scaffolding proteins, likely indicating a pattern of enhanced excitability. On the other hand, MK-801 only induced sparse changes with apparently no correlation to functional modification. Differently from mPFC, in Hipp, both substances reduced or caused no changes of glutamate receptors and scaffolding proteins expression. Ketamine decreased NMDA receptors while increased AMPA receptors subunit ratios, an effect indicative of permissive metaplastic modulation; conversely, MK-801 only decreased the latter, possibly representing a blockade of further synaptic plasticity. Taken together, these findings indicate a fine tuning of glutamatergic synapses by ketamine compared to MK-801 both in the mPFC and Hipp.

Prefrontal cortex nicotinic receptor inhibition by methyllycaconitine impaired cocaine-associated memory acquisition and retrieval.

Cocaine administration has been shown to induce plastic changes in the medial prefrontal cortex (mPFC), which could represent a mechanism by which cocaine facilitates the association between cocaine rewarding effects with contextual cues. Nicotinic acetylcholine receptors (nAChRs) in the mPFC have critical roles in cognitive function including attention and memory and are key players in plasticity processes. However, whether nAChRs in the mPFC are required for the acquisition and maintenance of cocaine-associated memories is still unknown. To assess this question, we used the conditioning place preference (CPP) model to study the effect of intra-mPFC infusion of methyllycaconitine, a selective antagonist of α7 nAChRs, on the acquisition, consolidation and expression of cocaine-associated memory in adult rats. Our findings reveal that mPFC α7 nAChRs activation is necessary for the acquisition and retrieval, but not consolidation, of cocaine induced CPP. Moreover, cocaine-induced sensitization during CPP conditioning sessions was abolished by methyllycaconitine infusion in the mPFC. Together, these results identify mPFC α7 nAChRs as critical players involved in both acquiring and retrieving cocaine-associated memories. Considering that drug seeking often depends on the association between drug-paired cues and the rewarding effects of the drug, α7 nAChRs in the mPFC could be considered as potential targets for the prevention or treatment of cocaine use disorder.

The late consolidation of an aversive memory is promoted by VTA dopamine release in the dorsal hippocampus.

The hippocampus has been implicated in the processing and storage of aversive memories but the precise mechanisms by which these memories persist in time remain elusive. We have demonstrated that dopaminergic neurotransmission in the dorsal hippocampus regulates the long-term storage of both appetitive and aversive memories at a critical time point known as "late consolidation" (12 hr after the learning experience). This modulation appears to have opposite effects depending on the valence of the stimuli, with hippocampal dopamine release peaking immediately and 13-17 hr after a rewarding experience. Here, we determined the release pattern of hippocampal dopamine following an aversive experience, in order to better understand this opposite modulation process. We observed significant increases in dopamine levels at several times (6-8, 11-12, and 15 hr) after subjecting rats to a conditioned place aversion (CPA) task with the aversive agent lithium chloride (LiCl). Early pharmacological blockade of hippocampal DA receptors impaired CPA memory consolidation. In addition and consistent with previous findings showing that late post-training infusions of dopaminergic agents into the hippocampus modulate the long-term storage of aversive memories, we found that the photostimulation of dopaminergic VTA fibers in the dorsal hippocampus 11-12 hr after CPA training was enough to transform a short-lasting long-term memory into a long-lasting one. The fact that the persistence of an aversive memory can still be affected several hours after the learning experience opens new avenues to develop behavioral and pharmacological strategies for the treatment of a variety of mental disorders.

Dopamine Neurotransmission in the Ventral Tegmental Area Promotes Active Forgetting of Cocaine-Associated Memory.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are well-known components of the brain involved in reward-related behaviors and participate in the generation of new memories. Much attention has been focused to understand how DA neurons integrate a diversity of afferent signals with local excitatory and inhibitory influences regulated by somatodendritic release of dopamine. However, the mechanisms that actively forget rewarding information are still terra incognita. Using rodents in the conditioned place preference (CPP) behavioral task, we show that during acquisition D1-type DA receptors (D1R) in the VTA are crucial components of a neural circuit involving the hippocampus that induces active forgetting of cocaine-associated long-term memory, while VTA and nucleus accumbens (NAc) D1R are required for its formation. Inhibition of VTA D1R results in increased activation of VTA ERK1/2 and in prolonging memory storage of cocaine-place association in an ERK-dependent manner. Moreover, intra-VTA infusion of a specific D1 agonist induces forgetting of cocaine-associated consolidated memory. In contrast, D1R in the NAc shell, medial prefrontal cortex, or amygdala appear not to participate in the maintenance of cocaine-associated memory. Our present results suggest that at the moment of learning D1R-mediated neurotransmission in the VTA actively participates in at least two processes affecting the fate of appetitive memory: its consolidation involving NAc shell DA neurotransmission and its forgetting via DA activation of the hippocampus.

Activation of D1/5 Dopamine Receptors in the Dorsal Medial Prefrontal Cortex Promotes Incubated-Like Aversive Responses.

It is well established that neurons of the mammalian medial prefrontal cortex (mPFC) modulate different behavioral outputs, including several memory types. This behavioral modulation is, at least in part, under the control of the D1-like Dopamine (DA) receptor (D1/5R) which comprises D1 and D5-specific subtypes (D1R and D5R, respectively). Here, combining a set of behavioral assays with pharmacology, we determined whether the activation of D1/5R in the mPFC during almost neutral or weak negative-valence experiences induces aversive behaviors. The intra mPFC bilateral infusion of the D1/5R agonist SKF 38393 (6.25 µg/side) immediately after exposing rats to the white compartment of a place conditioning apparatus promotes a incubated-like aversive memory when tested 7 days thereafter, but it was not seen 24 h after conditioning. No signs of fear or changes in the anxiety state were observed after the exposure to the white compartment. This aversive response is observed only when the experience paired with the mPFC D1/5R activation has a context component involved. By using specific agonists for D1R or D5R subtypes we suggest that D5R mediate the induction of the aversive behavior. No aversive effects were observed when the D1/5R agonist was infused into the dorsal hippocampus (HP), the nucleus accumbens (NAcc) or the basolateral amygdala (BLA) of rats exposed to the white compartment. Taken together, our present findings endorse the idea that activation of mPFC D1/5R is sufficient to induce incubated-like aversive memories after exposing rats to an apparent neutral or weak negative-valence environment and that mPFC might be considered a key brain region involved in providing adaptive emotional behaviors in response to an ever-changing environment.