Dopamine responsiveness in Nucleus Accumbens Shell and Core and Prefrontal Cortex during operant behavior for sucrose

Dopamine is implicated in the responsiveness to rewarding properties of natural and pharmacological stimuli. Conditioned stimuli (CS), linked to rewards such as food or drugs of abuse (uncontidioned stimuli, US), are essential to support the motivated behaviour. The role of mesocortical and mesolimbic DA in response to food CS after instrumental paradigm still remains unclear. The aim of our study was to investigate by microdialysis the impact of instrumental food CSs and US on behaviour and on basal DA in three terminal DA areas: shell and core of nucleus accumbens (NAc) and medial prefrontal cortex (mPFCX), using a food self-administration paradigm. Rats were trained to acquire sucrose self-administration under a Fixed Ratio 1 (FR 1) or FR5 variable time out schedule of responding. After training, animals were able to self-administer sucrose pellets and microdialysis coupled with self-administration experiments were performed.. The main finding of our study was that NAc shell DA has been activated not only by the conditioned cues but also by food after the instrumental conditioning. When both stimuli are presented in the same moment the increase of DA is strengthened and prolonged. DA response was obtained in NAc core only during US presentation. mPFCX has been activated by each component of motivated behaviour, except for the response to CS using a FR5 schedule. We can conclude that DA in the NAc shell plays an important role on the acquisition and expression of motivated behaviour in food consumption, whereas NAc core and PFCX are less implicated. This study provides a robust and reproducible model for a parametric study of the relationship between behaviour and DA transmission in the NAc shell and core and in the mPFCX

Changes in dopamine transmission in the nucleus accumbens shell and core during ethanol and sucrose self-administration

Ethanol, like other substances of abuse, preferentially increases dopamine (DA) transmission in the rat nucleus accumbens (NAc) following passive administration. It remains unclear, however, whether ethanol also increases NAc DA transmission following operant oral self-administration (SA). The NAc is made-up of a ventro-medial compartment, the shell and a dorso-lateral one, the core, where DA transmission responds differentially following exposure to drugs of abuse. Previous studies from our laboratory investigated changes in dialysate DA in the NAc shell and core of rats responding for sucrose pellets and for drugs of abuse. As a follow up to these studies, we recently investigated the changes in NAc shell and core DA transmission associated to oral SA of a 10% ethanol solution. For the purpose of comparison with literature studies utilizing sucrose + ethanol solutions, we also investigated the changes in dialysate DA associated to SA of 20% sucrose and 10% ethanol + 20% sucrose solutions. Rats were trained to acquire oral SA of the solutions under a Fixed Ratio 1 (FR1) schedule of nose-poking. After training, rats were monitored by microdialysis on three consecutive days under response contingent (active), reward omission (extinction trial) and response non-contingent (passive) presentation of ethanol, sucrose or ethanol + sucrose solutions. Active and passive ethanol administration produced a similar increase in dialysate DA in the two NAc subdivisions, while under extinction trial DA increased preferentially in the shell compared to the core. Conversely, under sucrose SA and extinction DA increased exclusively in the shell. These observations provide unequivocal evidence that oral SA of 10% ethanol increases dialysate DA in the NAc, and also suggest that stimuli conditioned to ethanol exposure contribute to the increase of dialysate DA observed in the NAc following ethanol SA. Comparison between the pattern of DA changes detected in the NAc subdivisions under sucrose and ethanol SA likewise suggests that the NAc shell and core DA play different roles in sucrose as compared to ethanol reinforcement

A Novel null homozygous mutation confirms <i>CACNA2D2</i> as a gene mutated in epileptic encephalopathy

Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental

Systemic Administration of Orexin a Loaded Liposomes Potentiates Nucleus Accumbens Shell Dopamine Release by Sucrose Feeding

Orexin neurons originate in the lateral and dorsomedial hypothalamus and perifornical area and produce two different neuropeptides: orexin A (OxA) and orexin B (OxB), which activate OxR1 and OxR2 receptors. In the lateral hypothalamus (LH) orexin neurons are involved in behavior motivated by natural rewards such as palatable food (sugar, high-fat food) and it has been demonstrated similarly that the orexin signaling in the ventral tegmental area (VTA) is implicated in the intake of high-fat food. The VTA is an important area involved in reward processing. Given the involvement of nucleus accumbens (NAc) shell dopamine (DA) in motivation for food, we intended to investigate the effect of OxA on the basal and feeding-activated DA transmission in the NAc shell. OxA is a large peptide and does not cross the blood–brain barrier and for this reason was loaded on two kinds of liposomes: anti-transferrin-monoclonal antibodies (OX26-mAb) and lactoferrin-modified stealth liposomes. The effect of IV administration of both OxA liposomes on NAc shell DA was studied by microdialysis in freely moving rats. OxA, administered using both kinds of liposomes, produced a delayed and transitory increase in dialysate DA in the NAc shell, strongly and lastingly potentiated the increase in dialysate DA elicited by sucrose pellet consumption and increased the number of eaten pellets. These effects of OxA on DA transmission and feeding were prevented by the OxR1 antagonist SB 334867. Hence, OxA acting on VTA OxR1 can facilitate sucrose-stimulated NAc shell DA transmission directly by increasing the basal activity of VTA DA neurons that send their projections to the NAc shell

Differential activation of accumbens shell and core dopamine by sucrose reinforcement with nose poking and with lever pressing

In order to investigate the role of modus operandi in the changes of nucleus accumbens (NAc) dopamine (DA) transmission in sucrose reinforcement, extracellular DA was monitored by microdialysis in the NAc shell and core of rats trained on a fixed-ratio 1 schedule to respond for sucrose pellets by nose poking and lever pressing respectively. After training, rats were tested on three different sessions: sucrose reinforcement, extinction and passive sucrose presentation. In rats responding by nose poking dialysate DA increased in the shell but not in the core under reinforced as well as under extinction sessions. In contrast, in rats responding by lever pressing dialysate DA increased both in the accumbens shell and core under reinforced and extinction sessions. Response non-contingent sucrose presentation increased dialysate DA in the shell and core of rats trained to respond for sucrose by nose poking as well as in those trained by lever pressing. In rats trained to respond for sucrose by nose poking on a FR5 schedule dialysate DA also increased selectively in the NAc shell during reinforced responding and in both the shell and core under passive sucrose presentation. These findings, while provide an explanation for the discrepancies existing in the literature over the responsiveness of shell and core DA in rats responding for food, are consistent with the notion that NAc shell and core DA encode different aspects of reinforcement

DOPAMINE RESPONSIVENESS IN THE NUCLEUS ACCUMBENS SHELL AND CORE DURING ETHANOL AND SUCROSE SELF-ADMINISTRATION

Ethanol is a psychoactive compound of several beverage abused by humans and it is well known that, as well as other drugs of abuse, increases dopamine (DA) transmission preferentially in the nucleus accumbens (NAc) shell. The aim of our study was to investigate by microdialysis the role of the NAc shell and core DA in the response to ethanol and to ethanol-conditioned stimuli (ethanol-CS) using an instrumental conditioning paradigm with fixed-ratio 1 (FR1). Rats were trained to acquire sucrose and ethanol oral self-administration under a FR 1 paradigm (1 nose poke corresponds to 0.25 ml administration of 20% sucrose or 10% ethanol in 20% sucrose solutions). We found that oral ethanol, either self-administered or given passively, produces an increase of DA transmission in the shell and in the core, strengthened during the self-administration session, while ethanol-CS increased DA preferentially in the NAc shell. Sucrose oral self-administration and its conditioned cues affects DA exclusively in the shell, but the passive administration increases DA in the shell and in the core. These data suggest that the two compartments of the NAc are differently implicated in the responsiveness to natural and to pharmacological rewards. While DA transmission in the NAc shell seems to play a key role in the operant responding for both sucrose and ethanol, the DA core appears to be more involved in the responsiveness to ethanol

Nucleus Accumbens and Prefrontal Cortex Dopamine modifications during operant responding for sucrose

Mesolimbic dopamine (DA) plays a key role in the responsiveness to rewarding properties of natural and pharmacological stimuli. These stimuli are able to give rise to motivated behavior, and it is well known that conditioned stimuli (CS), linked with rewards (food, sex, drugs of abuse) (US), are essential to support it. The purpose of this investigation was to clarify the role of mesolimbic and mesocortical DA in the responsiveness to food and food-CS using an instrumental conditioning paradigm with fixed-ratio (FR) 1 (1 nose poke corresponds to 1 sucrose pellet) or 5 (5 nose pokes correspond to 1 sucrose pellet). We have coupled a self administration paradigm with microdialysis technique to study DA transmission in the NAc shell and core and in the prefrontal cortex during: 1) sucrose pellets seeking behavior, 2) extinction phase and 3) non-contingent presentation of sucrose pellets. The main finding of our study was that NAc shell DA has been activated not only by the conditioned cues but also by food after the instrumental conditioning, and that when both stimuli are presented in the same moment the increase of DA is strengthened and prolonged. We can conclude that DA in the NAc shell plays an important role on the acquisition and expression of motivated behavior in food consumption

Mesolimbic Dopamine Encodes Prediction Errors in a State-Dependent Manner

Mesolimbic dopamine encodes the benefits of a course of action. However, the value of an appetitive reward depends strongly on an animal’s current state. To investigate the relationship between dopamine, value, and physiological state, we monitored sub-second dopamine release in the nucleus accumbens core while rats made choices between food and sucrose solution following selective satiation on one of these reinforcers. Dopamine signals reflected preference for the reinforcers in the new state, decreasing to the devalued reward and, after satiation on food, increasing for the valued sucrose solution. These changes were rapid and selective, with dopamine release returning to pre-satiation patterns when the animals were re-tested in a standard food-restricted state. Such rapid and selective adaptation of dopamine-associated value signals could provide an important signal to promote efficient foraging for a varied diet