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.

The role of Dopamine in the Sensitised Locomotor Activating Effects of Methylenedioxymethamphetamine (MDMA) in Rats

<p>Under certain regimens of repeated pre-exposure, psychostimulant drugs show an increase in locomotor activity across days of testing and, after abstinence from the drug, a greater responsiveness to a subsequent challenge dose of the drug. This phenomenon, termed behavioural sensitisation, is thought to underlie certain aspects of drug addiction such as drug seeking and relapse. Repeated administration of +/-3, 4-Methylenedioxymethamphetamine (MDMA, ecstasy) produced sensitised hyperactivity in rats suggesting a lasting neurological change. The present studies sought to evaluate some of the parameters around both the induction and expression of behavioural sensitisation to MDMA and to evaluate if the sensitivity of the dopamine (DA) D1 and D2 receptors had altered under the current pre-exposure regimen of MDMA. Further, following MDMA pre-exposure that results n behavioural sensitisation, changes in potency to the reinforcing effects of MDMA were investigated through the self administration paradigm. Finally, high performance liquid chromatography (HPLC) was used to evaluate changes in brain amine levels following sensitisation to MDMA locomotor activating effects. Rats received a pre-treatment regimen consisting of 5 daily injections of MDMA (0.0, 5.0 or 10mg/kg i.p). MDMA-produced locomotor activity was measured after 2, 9 or 28 days of withdrawal. In other groups, hyperactivity following administration the DA D1 agonist SKF81297 (0.0, 0.5, 1.0, 2.0, 4.0 or 8.0 mg/kg), or the D2-like DA agonist apomorphine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg) was measured in groups that received pre-exposure to MDMA (10.0 4mg/kg) or vehicle. The effects of the D1 antagonist SCH23390 (0.0, 0.01, 0.02, or 0.04 mg/kg), the D2 antagonist eticlopride (0.03, 0.01, 0.003, 0.05, 0.1, or 0.2 mg/kg) or the 5-HT2C antagonist RS102221 (0.0, 0.25, 0.5, or 1.0 mg/kg) on MDMA-produced hyperactivity in MDMA or vehicle pre-treated rats was also measured. In Experiment 3, effects of MDMA or vehicle pre-treatment on latency to acquisition of MDMA (0.5 or 1.0 mg/kg/infusion) selfadministration was measured. In Experiment 4 effects of pre-treatment on brain tissue levels of DA, its metabolite homovanillic acid (HVA), serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were determined. The regimen of 5 daily treatments of 10.0mg/kg produced persistent behavioural sensitisation and cross-sensitisation to hyperactivity produced by DA receptor agonists. These effects were not, however, reflected in sensitised responses to the ability of the antagonists to attenuate MDMA-produced hyperactivity. Pre-treatment with MDMA did not decrease latency to acquisition of self-administration. Rather, there was an increased latency to acquisition of self-administration in the MDMA pre-treated rats. MDMA pretreatment decreased levels of the serotonin metabolite 5-HIAA in the frontal cortex and hippocampus. Following the current pre-treatment regimen, MDMA produced behavioural sensitisation is mediated by neuroadaptations in central dopaminergic substrates. The persistent locomotor sensitisation is similar to that produced by other amphetamine-like stimulants and might underlie use and abuse of this compound.</p>

The role of Dopamine in the Sensitised Locomotor Activating Effects of Methylenedioxymethamphetamine (MDMA) in Rats

<p>Under certain regimens of repeated pre-exposure, psychostimulant drugs show an increase in locomotor activity across days of testing and, after abstinence from the drug, a greater responsiveness to a subsequent challenge dose of the drug. This phenomenon, termed behavioural sensitisation, is thought to underlie certain aspects of drug addiction such as drug seeking and relapse. Repeated administration of +/-3, 4-Methylenedioxymethamphetamine (MDMA, ecstasy) produced sensitised hyperactivity in rats suggesting a lasting neurological change. The present studies sought to evaluate some of the parameters around both the induction and expression of behavioural sensitisation to MDMA and to evaluate if the sensitivity of the dopamine (DA) D1 and D2 receptors had altered under the current pre-exposure regimen of MDMA. Further, following MDMA pre-exposure that results n behavioural sensitisation, changes in potency to the reinforcing effects of MDMA were investigated through the self administration paradigm. Finally, high performance liquid chromatography (HPLC) was used to evaluate changes in brain amine levels following sensitisation to MDMA locomotor activating effects. Rats received a pre-treatment regimen consisting of 5 daily injections of MDMA (0.0, 5.0 or 10mg/kg i.p). MDMA-produced locomotor activity was measured after 2, 9 or 28 days of withdrawal. In other groups, hyperactivity following administration the DA D1 agonist SKF81297 (0.0, 0.5, 1.0, 2.0, 4.0 or 8.0 mg/kg), or the D2-like DA agonist apomorphine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg) was measured in groups that received pre-exposure to MDMA (10.0 4mg/kg) or vehicle. The effects of the D1 antagonist SCH23390 (0.0, 0.01, 0.02, or 0.04 mg/kg), the D2 antagonist eticlopride (0.03, 0.01, 0.003, 0.05, 0.1, or 0.2 mg/kg) or the 5-HT2C antagonist RS102221 (0.0, 0.25, 0.5, or 1.0 mg/kg) on MDMA-produced hyperactivity in MDMA or vehicle pre-treated rats was also measured. In Experiment 3, effects of MDMA or vehicle pre-treatment on latency to acquisition of MDMA (0.5 or 1.0 mg/kg/infusion) selfadministration was measured. In Experiment 4 effects of pre-treatment on brain tissue levels of DA, its metabolite homovanillic acid (HVA), serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were determined. The regimen of 5 daily treatments of 10.0mg/kg produced persistent behavioural sensitisation and cross-sensitisation to hyperactivity produced by DA receptor agonists. These effects were not, however, reflected in sensitised responses to the ability of the antagonists to attenuate MDMA-produced hyperactivity. Pre-treatment with MDMA did not decrease latency to acquisition of self-administration. Rather, there was an increased latency to acquisition of self-administration in the MDMA pre-treated rats. MDMA pretreatment decreased levels of the serotonin metabolite 5-HIAA in the frontal cortex and hippocampus. Following the current pre-treatment regimen, MDMA produced behavioural sensitisation is mediated by neuroadaptations in central dopaminergic substrates. The persistent locomotor sensitisation is similar to that produced by other amphetamine-like stimulants and might underlie use and abuse of this compound.</p>

Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity… and Return

Binge alcohol consumption among adolescents affects the developing neural networks underpinning reward and stress processing in the nucleus accumbens (NAc). This study explores in rats the long-lasting effects of early intermittent exposure to intoxicating alcohol levels at adolescence, on: (1) the response to natural positive stimuli and inescapable stress; (2) stress-axis functionality; and (3) dopaminergic and glutamatergic neuroadaptation in the NAc. We also assess the potential effects of the non-intoxicating phytocannabinoid cannabidiol, to counteract (or reverse) the development of detrimental consequences of binge-like alcohol exposuredimensions. Our results show that adolescent binge-like alcohol exposure alters the sensitivity to positive stimuli, exerts social and novelty-triggered anxiety-like behaviour, and passive stress-coping during early and prolonged withdrawal. In addition, serum corticosterone and hypothalamic and NAc corticotropin-releasing hormone levels progressively increase during withdrawal. Besides, NAc tyrosine hydroxylase levels increase at late withdrawal, while the expression of dopamine transporter, D1 and D2 receptors xpression is dynamically altered during binge and withdrawal. Furthermore, the expression of markers of excitatory postsynaptic signaling —PSD95; Homer-1 and -2 and the activity-regulated spine-morphing proteins Arc, LIM Kinase 1 and FOXP1—increase at late withdrawal. Notably, subchronic cannabidiol, during withdrawal, attenuates social- and novelty-induced aversion and passive stress-coping and rectifies the hyper-responsive stress axis and NAc dopamine and glutamate-related neuroplasticity. Overall, the exposure to binge-like alcohol levels in adolescent rats makes the NAc, during withdrawal, a locus minoris resistentiae as a result of perturbations in neuroplasticity and in stress-axis homeostasis. Cannabidiol holds a promising potential for increasing behavioural, neuroendocrine and molecular resilience against binge-like alcohol level’s harmful effects.

Dopamine D1 and D2 Receptors Are Important for Learning About Neutral-Valence Relationships in Sensory Preconditioning

Dopamine neurotransmission has been ascribed multiple functions with respect to both motivational and associative processes in reward-based learning, though these have proven difficult to tease apart. In order to better describe the role of dopamine in associative learning, this series of experiments examined the potential of dopamine D1- and D2-receptor antagonism (or combined antagonism) to influence the ability of rats to learn neutral valence stimulus-stimulus associations. Using a sensory preconditioning task, rats were first exposed to pairings of two neutral stimuli (S2-S1). Subsequently, S1 was paired with a mild foot-shock and resulting fear to both S1 (directly conditioned) and S2 (preconditioned) was examined. Initial experiments demonstrated the validity of the procedure in that measures of sensory preconditioning were shown to be contingent on pairings of the two sensory stimuli. Subsequent experiments indicated that systemic administration of dopamine D1- or D2-receptor antagonists attenuated learning when administered prior to S2-S1 pairings. However, the administration of a more generic D1R/D2R antagonist was without effect. These effects remained constant regardless of the affective valence of the conditioning environment and did not differ between male and female rats. The results are discussed in the context of recent suggestions that dopaminergic systems encode more than a simple reward prediction error, and provide potential avenues for future investigation.

A complementary and alternative natural antidepressant therapy with emphasis on their mechanisms of action

Medicinal plants can exert antidepressant activity by many mechanisms included neutralization of various stress mediators (regulate the activity of the hypothalamic- pituitary- adrenal axis and reduce CRF, and ACTH and corticosterone) [5], interaction with serotonergic systems (5-HT3, 5HT2A, 5-HT1A), noradrenergic (α1 and α2 receptors) and dopaminergic (D1 and D2) receptors [6],restoring monoamine transmitters and their receptors to normal limits in certain regions of the cortex, in addition to reducing of oxidative stress and amelioration of inflammatory mediators. The current review discussed the antidepressant activity of medicinal plants, with emphasis on their mechanisms of action.

Bacteroides uniformis CECT 7771 Modulates the Brain Reward Response to Reduce Binge Eating and Anxiety-Like Behavior in Rat

Food addiction (FA) is characterized by behavioral and neurochemical changes linked to loss of food intake control. Gut microbiota may influence appetite and food intake via endocrine and neural routes. The gut microbiota is known to impact homeostatic energy mechanisms, but its role in regulating the reward system is less certain. We show that the administration of Bacteroides uniformis CECT 7771 (B. uniformis) in a rat FA model impacts on the brain reward response, ameliorating binge eating and decreasing anxiety-like behavior. These effects are mediated, at least in part, by changes in the levels of dopamine, serotonin, and noradrenaline in the nucleus accumbens and in the expression of dopamine D1 and D2 receptors in the prefrontal cortex and intestine. B. uniformis reverses the fasting-induced microbiota changes and increases the abundance of species linked to healthy metabolotypes. Our data indicate that microbiota-based interventions might help to control compulsive overeating by modulating the reward response.

Direct and Indirect Pathway Neurons in Ventrolateral Striatum Differentially Regulate Licking Movement and Nigral Responses

SUMMARYDrinking behavior in rodents is characterized by stereotyped, rhythmic licking movement, which is regulated by the basal ganglia. It is unclear how direct and indirect pathways control the lick bout and individual lick event. We find that inactivating D1 and D2 receptors-expressing medium spiny neurons (MSNs) in the ventrolateral striatum (VLS) oppositely alters the number of licks in a bout. D1- and D2-MSNs exhibit similar patterns of lick sequence-related activity but different phases of oscillation time-locked to the lick cycle. On timescale of a lick cycle, transient inactivation of D1-MSNs during tongue protrusion reduces lick probability, whereas transient inactivation of D2-MSNs has no effect. On timescale of a lick bout, inactivation of D1-MSNs (D2-MSNs) causes rate increase (decrease) in a subset of basal ganglia output neurons that decrease firing during licking. Our results reveal the distinct roles of D1- and D2-MSNs in regulating licking at both coarse and fine timescales.

The Critical Role of Hippocampal Dopamine in the Pathogenesis of Hepatic Encephalopathy

The pathogenesis of hepatic encephalopathy (HE) has been generally linked to blood ammonia, gamma-aminobutyric acid and serotonin. However, the exact mechanism remains unclear. In the present study, we aimed to explore the role of hippocampal dopamine (DA) and its receptors in the pathogenesis of HE through the use of behavioral testing, western blotting, and immunofluorescence staining in normal rats, HE model rats and rats treated with the DA precursor-levodopa (L-DOPA). HE model rats manifested fibrotic livers and showed serious behavioral disorders. They also had significantly lower hippocampal DA content and increased expression of both D1 and D2 receptors relative to normal rats. After treatment with L-DOPA, the HE model rats showed normal behavior and expression of D1 returned to normal levels. Furthermore, pretreatment with the D1 antagonist SCH23390 blocked the therapeutic effect of L-DOPA on behavior in HE model rats. Taken together, these results clarify that the decrease in hippocampal DA plays a role in the pathogenesis of HE and that this effect is mediated by D1. These findings provide new evidence for the pathogenesis of HE.