Investigating the influence of PFC transection and nicotine on dynamics of AMPA and NMDA receptors of VTA dopaminergic neurons

<p>Abstract</p> <p>Background</p> <p>All drugs of abuse, including nicotine, activate the mesocorticolimbic system that plays critical roles in nicotine reward and reinforcement development and triggers glutamatergic synaptic plasticity on the dopamine (DA) neurons in the ventral tegmental area (VTA). The addictive behavior and firing pattern of the VTA DA neurons are thought to be controlled by the glutamatergic synaptic input from prefrontal cortex (PFC). Interrupted functional input from PFC to VTA was shown to decrease the effects of the drug on the addiction process. Nicotine treatment could enhance the AMPA/NMDA ratio in VTA DA neurons, which is thought as a common addiction mechanism. In this study, we investigate whether or not the lack of glutamate transmission from PFC to VTA could make any change in the effects of nicotine.</p> <p>Methods</p> <p>We used the traditional AMPA/NMDA peak ratio, AMPA/NMDA area ratio, and KL (Kullback-Leibler) divergence analysis method for the present study.</p> <p>Results</p> <p>Our results using AMPA/NMDA peak ratio showed insignificant difference between PFC intact and transected and treated with saline. However, using AMPA/NMDA area ratio and KL divergence method, we observed a significant difference when PFC is interrupted with saline treatment. One possible reason for the significant effect that the PFC transection has on the synaptic responses (as indicated by the AMPA/NMDA area ratio and KL divergence) may be the loss of glutamatergic inputs. The glutamatergic input is one of the most important factors that contribute to the peak ratio level.</p> <p>Conclusions</p> <p>Our results suggested that even within one hour after a single nicotine injection, the peak ratio of AMPA/NMDA on VTA DA neurons could be enhanced.</p

Open Access

Nicotine exposure increases the complexity of dopamine neurons in the parainterfascicular nucleus (PIF) sub-region of VT

The impact of psychostimulant administration during development on adult brain functions controlling motivation, impulsivity and cognition.

ADHD pharmacotherapy uses methylphenidate (MPH), D-amphetamine (D- amph), two psychostimulants targeting dopamine transporters, or atomoxetine (ATX), specifically targeting norepinephrine transporters. We have assessed the pharmacological mechanisms of these three drugs on the in vitro efflux of neurotransmitters in rat prefrontal cortex (PFC) and striatal slices as well as on the in vivo electrical activities of PFC pyramidal neurons, striatal medium spiny neurons, ventral tegmental area dopamine neurons or dorsal raphe nucleus serotonin neurons, using single cell extracellular electrophysiological recording techniques. We have also tested whether chronic methylphenidate treatment, during either adolescence or adulthood, could have long-lasting consequences on body growth, depression and neuronal functions. Release experiments showed that all ADHD drugs induce dose-dependent dopamine efflux in both the PFC and striatum, with different efficacies, while only D- amph induced cortical norepinephrine efflux. Atomoxetine induced an unexpected massive dopamine outflow in striatal regions, by mechanisms that depend on physiological parameters. Our electrophysiological studies indicate that all three drugs equally stimulate the excitability of PFC pyramidal neurons, in basal and NMDA-evoked conditions, when administered acutely (3 mg/kg). While the electrophysiological effects elicited by psychostimulants may be dependent on D1 receptor activation, those induced by atomoxetine relied on different mechanisms. In the ventral tegmental area (VTA), methylphenidate (2 mg/kg), but not atomoxetine, induced firing and burst activity reductions, through dopamine D2 autoreceptor activation. Reversal of such effects (eticlopride 0.2 mg/kg) revealed an excitatory effect of methylphenidate on midbrain dopamine neurons that appear to be dependent on glutamate pathways and the combination of D1 and alpha-1 receptors. Finally, acute intraperitoneal psychostimulant injections increased vertical locomotor activity as well as NMDA2B protein expression in the striatum. Some animals chronically treated with intraperitoneal administrations (methylphenidate 4 mg/kg/day or saline 1.2 ml/kg/day) showed decreased body weight gain. Voluntary oral methylphenidate intake induces desensitisation to subsequent intravenous methylphenidate challenges, without altering dopamine D2 receptor plasticity. Significant decreases in striatal NMDA2B protein expression were observed in animals chronically treated. After adolescent MPH treatment, midbrain dopaminergic neurons do not display either desensitisation or sensitisation to intravenous methylphenidate re-challenges. However, partial dopamine D2 receptor desensitisation was observed in midbrain dopamine neurons. Using behavioural experiments, cross-sensitisation between adolescent methylphenidate exposure and later-life D-amphetamine challenge was observed. Significant decreases in striatal NMDA2B protein expression were observed in animals chronically treated, while striatal medium spiny neurons showed decreased sensitivities to locally applied NMDA and dopamine. While caffeine is devoid of action on baseline spike generation and burst activity of dopamine neurons, nicotine induces either firing rate enhancement, firing rate reduction, or has no consequences. Adolescent methylphenidate treatment leads to decreased neuronal sensitivities to the combination of nicotine, MPH and eticlopride, compared to controls. Finally, nicotine partially prevented D-amphetamine-induced increase of rearing activities. Our results show that increases in the excitability of PFC neurons in basal conditions and via NMDA receptor activation may be involved in the therapeutic response to ADHD drugs. Long-term consequences were observed after psychostimulant exposure. Such novel findings strengthen the mixed hypothesis in ADHD, whereby both dopamine and glutamate neurotransmissions are dysregulated. Therefore, ADHD therapy may now focus on adequate balancing between glutamate and dopamine

Ventral Tegmental Area Regulation Of Stress-Induced Reinstatement Of Cocaine-Seeking Behavior

No FDA approved medications currently exist for the prevention of drug craving, drug seeking, and relapse to cocaine use. Stress is a major factor in causing relapse in cocaine dependent individuals. Cocaine use is positively correlated with stress-induced craving and relapse outcomes. Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide that plays an important role in the stress response and in the reinstatement rodent model of stress-induced relapse. CRF is released during stress in brain regions associated with the effects of drugs of abuse, notably the ventral tegmental area (VTA). This dissertation addresses key unknown mechanisms behind drug-induced neuroplasticity and how that neuroplasticity gates the ability of stress to cause relapse. Chapter two reports that stress and intra-VTA CRF administration produces robust reinstatement in animals allowed extended long-access (LgA) but not short-access (ShA) cocaine self-administration. Moreover, LgA cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF receptor 1 (CRF-R1) dependent regulation of VTA neurocircuitry. Chapter three characterizes VTA dopamine neuron activation under conditions where stress reinstates cocaine seeking. Dopamine neuron activation was significantly increased in ShA but not LgA rats. However, when examined across groups only in rats that display relapse in response to stress is a significant increase in dopamine neuron activation observed. This suggests that stress-induced reinstatement is associated with increased activation of VTA dopamine neurons. Lastly, chapter 4 addresses the necessity of VTA glutamate and GABA receptors in footshock and intra-VTA CRF dependent reinstatement of cocaine seeking. Intra-VTA administration of NMDA, AMPA, and GABAA receptor antagonists fail to block reinstatement. In contrast, GABAB receptor antagonism blocked reinstatement by both footshock and intra-VTA CRF suggesting GABAB activation is necessary for CRF actions in the VTA. The findings from this dissertation provide much needed insight into the neuroadaptations that occur in the VTA to regulate later stressor induced relapse in cocaine addicts. The hope is that these findings will help with the understanding and eventual long-term management of stressor-induced relapse in abstinent cocaine addicts

Reconsolidation of appetitive memory and sleep: functional connectomics and plasticity

Introduzione: La dipendenza da cibo \ue8 un disturbo comportamentale caratterizzato da modelli maladattativi di consumo alimentare, in cui alimenti ricchi in zuccheri, sale e/o grassi possono indurre una dipendenza tale da essere paragonata ai disturbi relativi all\u2019abuso di sostanze. Alla base di questo processo vi \ue8 l\u2019associazione tra questi cibi altamente palatabili e la sensazione piacevole e rinforzante indotta dal loro consumo, che pu\uf2 essere codificata in una nuova memoria maladattativa sottostante il disturbo di dipendenza. Infatti, le nuove informazioni che riceviamo quotidianamente dall\u2019esterno vengono processate dal nostro cervello tramite un primo stadio di codifica e un secondo stadio di consolidamento, durante il quale vengono stabilizzate in una nuova memoria e integrate nella rete cerebrale di conoscenze preesistenti. Tuttavia, dopo il suo consolidamento, una memoria pu\uf2 essere destabilizzata e riportata ad uno stato di labilit\ue0 che ne permette la modifica e l\u2019eventuale integrazione con nuove informazioni. Infine, un nuovo processo di stabilizzazione chiamato riconsolidamento \ue8 necessario affinch\ue9 la traccia mnemonica aggiornata sia nuovamente stabilizzata. Da recenti studi, \ue8 noto come il sonno sia rilevante sia per il consolidamento che per il riconsolidamento della memoria. Tuttavia, mentre \ue8 chiaro come il consolidamento che avviene durante il sonno permetta la stabilizzazione a lungo termine delle tracce mnemoniche, non \ue8 ancora stato del tutto chiarito il ruolo del sonno nel processo di riconsolidamento. Scopo: Date queste premesse, e nota l\u2019importanza dell\u2019interazione tra amigdala basolaterale (BLA) e ippocampo nel riconsolidamento delle memorie appetitive, gli obiettivi della presente tesi erano: i) valutare come l\u2019amigdala BLA e ippocampo interagiscono in termini di potenziali locali durante la riattivazione della memoria strumentale effettuata o durante la fase di attivit\ue0 o durante la fase di inattivit\ue0 del ciclo circadiano dei roditori; ii) valutare come il richiamo della memoria effettuato durante la fase attiva o quella inattiva possa influenzare il successivo processo di riconsolidamento, e iii) trovare, in-vivo, un marker di riattivazione della memoria appetitiva. Metodi: Sono stati utilizzati 32 ratti maschi, ceppo Sprague Dawley, a cui sono stati impiantati due elettrodi profondi: uno in BLA e uno in ippocampo, per la registrazione dei potenziali locali. I ratti sono stati sottoposti ad un protocollo comportamentale in gabbia operante di auto-somministrazione di saccarosio, composto da quattro stadi: addestramento (i), in cui i ratti imparavano l\u2019associazione tra la pressione di una leva e l\u2019emissione di un pellet di saccarosio; astinenza (ii), durante la quale i soggetti non venivano esposti al contesto di addestramento; riattivazione o non riattivazione (iii) della memoria strumentale in gabbia operante, svolta o durante la fase di attivit\ue0, o durante la fase di inattivit\ue0; test di ricaduta (iv). I potenziali locali sono stati analizzati per lo stadio (iii) in modo da ottenere la potenza delle oscillazioni theta e gamma per i due elettrodi profondi; tali frequenze sono state scelte in quanto rilevanti per i processi mnemonici. Infatti, il richiamo della memoria \ue8 correlato alla sincronizzazione delle onde theta (4-12 Hz) tra BLA e altre aree cerebrali quali l\u2019area CA1 dell\u2019ippocampo, ed \ue8 inoltre correlato alle basse gamma (30-60 Hz) nell\u2019ippocampo. Infine, l\u2019accoppiamento tra le onde theta e gamma nell\u2019ippocampo \ue8 un noto metodo di comunicazione tra sotto-aree ippocampali nel corso dei processi di memoria. Risultati: I risultati hanno mostrato la presenza di una correlazione inversa tra la potenza delle basse gamma nell\u2019area CA1 ippocampale e il tasso di risposta durante lo stadio di richiamo della memoria nella fase di attivit\ue0, indipendentemente dal fatto che i soggetti stessero o meno premendo la leva. Le basse gamma potrebbero quindi rappresentare un marker di correlazione per il richiamo della memoria appetitiva. Inoltre, la potenza di basse e alte gamma ippocampali aumenta durante le epoche di pressione di leva quando il richiamo della memoria viene effettuato nella fase di inattivit\ue0, suggerendo che le onde gamma potrebbero essere dei marker correlazionali specifici per la componente strumentale del richiamo della memoria effettuato durante la fase di inattivit\ue0. Conclusioni e limitazioni: Per concludere, i risultati hanno mostrato l\u2019importanza delle frequenze basse gamma nel richiamo delle memorie appetitive, tuttavia non hanno mostrato alcuna differenza a livello delle onde theta, n\ue9 a livello della BLA. Di conseguenza, si conclude che il protocollo utilizzato nella presente tesi non ha mostrato una sensibilit\ue0 sufficientemente elevata nell\u2019evidenziare i cambiamenti ipotizzati a livello dei potenziali locali. Lo svolgimento di ulteriori esperimenti che andranno a determinare misure di connettomica quali coerenza e accoppiamento, sia intra- che inter- area, aiuter\ue0 a determinare se e come le due aree comunicano tra di loro.Introduction: Food addiction is a behavioural disorder in which individuals develop maladaptive patterns of food consumption. Particularly, food containing processed sugars, salt, fat etc. can be addictive, and refined food consumption behaviours may meet the criteria for substance use disorders. For these characteristics, food addiction can also be considered a memory disorder. Memories in the brain are processed as follows: new information is encoded and then long-term consolidated through a process allowing its integration into already existing knowledge networks. After a memory has been consolidated, it can be destabilized and brought back to a labile state, requiring a new re-stabilization process called reconsolidation. Memory consolidation is known to require sleep. In fact, sleep allows new memory traces to long-term stabilize. Sleep also seems to influence memory reconsolidation; however, its involvement in this process is not yet clear. Aim: Given these premises, the goals of the project were: to evaluate how basolateral amygdala (BLA) and hippocampus interact in terms of local field potentials (LFPs) when appetitive instrumental memory is retrieved either during active or inactive phase of rats circadian rhythm; to evaluate how retrieving the memory in the activity vs inactivity phase influences following memory reconsolidation; and to find an in vivo electrophysiological marker of appetitive memory retrieval. In fact, it has been shown that BLA and dorsal hippocampus interaction is crucial for appetitive memory reconsolidation. Methods: Thirty-two male Sprague Dawley rats were implanted with in-depth electrodes for LFPs recordings in BLA and dorsal hippocampal CA1 and subject to a behavioural protocol apt to induce appetitive memory retrieval. The behavioural procedure consisted of four stages: training (i), in which animals learned lever pressing \u2013 sucrose reward association; abstinence (ii), during which subjects were not exposed to the training context; memory retrieval or no retrieval (iii): instrumental memory reactivation or no reactivation, performed either during active or inactive phase; and relapse test (iv), during which sucrose-seeking behaviour was analysed. Theta and gamma oscillations powers were analysed during stage (iii). In fact, they are known to be involved in memory processes. Memory retrieval has been shown to correlate with theta (4-12 Hz) synchronization between BLA and other brain areas (such as hippocampal CA1) and with low gamma (30-60 Hz) in hippocampus. Particularly, theta-gamma cross-frequency coupling has been shown to be used as a mean of communication between hippocampal sub-areas during memory processing. Results: Results showed an inverse correlation between hippocampal CA1 low gamma power and reactivation rate of responding (either when rats were lever pressing or not) when reactivation was performed during the active phase. This suggests that low gamma may be a correlational marker of instrumental sucrose memory retrieval, independent of whether rats were lever-pressing or not. Moreover, hippocampal CA1 gamma bands increased when lever pressing during instrumental memory reactivation while in the inactive phase, suggesting that both low and high gamma bands may be correlational markers to actual instrumental responding retrieval during the inactive phase. Conclusions and limitations: In conclusion, results showed that low gamma is relevant in sucrose appetitive memory retrieval. However, no difference was observed in the theta frequency band, nor at the level of BLA. Therefore, the current protocol did not have the sensitivity to detect predicted changes in LFPs. Further experiments would help investigating if and how the two areas interact, by determining connectomics measures such as coherence and coupling within and between areas

Neurotensinergic modulation of glutamatergic neurotransmission in VTA neurons

L’aire tegmentaire ventrale (VTA) contient une forte densité de terminaisons neurotensinergiques ainsi que des récepteurs à la surface des neurones dopaminergiques et non-dopaminergiques. Le VTA a été impliqué dans des maladies comme la schizophrénie, les psychoses et l’abus de substance. Les drogues d’abus sont connues pour induire le phénomène de sensibilisation - un processus de facilitation par lequel l’exposition à un stimulus produit une réponse augmentée lors de l’exposition subséquente au même stimulus. La sensibilisation se développe dans le VTA et implique mécanismes dopaminergiques et glutamatergiques. Il a été montré que les antagonistes neurotensinergiques bloquaient le développement de la sensibilisation et certains mécanismes de récompense et ces effets pourraient être médiés indirectement par une modulation de la neurotransmission glutamatergique. Cependant, on connaît peu les mécanismes de modulation de la transmission glutamatergique par la neurotensine (NT) dans le VTA. Le but de la présente thèse était d’étudier la modulation neurotensinergique de la neurotransmission glutamatergique dans les neurones dopaminergiques et non-dopaminergiques du VTA. Pour ce faire, nous avons utilisé la technique du patch clamp dans la cellule entière dans des tranches horizontales du VTA pour étudier les effets de différents agonistes et antagonistes neurotensinergiques. Les neurones ont été identifié comme Ih+ (présumés dopaminergiques) ou Ih- (présumés non-dopaminergiques) selon qu’ils exprimaient ou non un courant cationique activé par l’hyperpolarisation (Ih). Des techniques d’immunocytochimie ont été utilisées pour marquer les neurones et vérifier leur localisation dans le VTA. Dans une première étude nous avons trouvé que la neurotensine indigène (NT1-13) ou son fragment C-terminal, NT8-13, induisait une augmentation comparable des courants postsynaptiques excitateurs glutamatergiques (CPSEs) dans les neurones Ih+ ou Ih- du VTA. L'augmentation induite dans les neurones Ih+ par la NT8-13 a été bloquée par le SR48692, un antagoniste des récepteurs NTS1, et par le SR142948A, un antagoniste des récepteurs NTS1 et NTS2, suggérant que l'augmentation était médiée par l’activation des récepteurs NTS1. Dans les neurones Ih- l'augmentation n’a été bloquée que par le SR142948A indiquant une implication des récepteurs NTS2. Dans une deuxième étude, nous avons testé les effets de la D-Tyr[11]NT (un analogue neurotensinergique ayant différentes affinités de liaison pour les sous-types de récepteurs neurotensinergiques) sur les CPSEs glutamatergiques dans les neurones Ih+ et Ih- en parallèle avec une série d’expériences comportementales utilisant un paradigme de préférence de place conditionnée (PPC) menée dans le laboratoire de Pierre-Paul Rompré. Nous avons constaté que la D-Tyr[11]NT induisaient une inhibition dépendante de la dose dans les neurones Ih+ médiée par l'activation de récepteurs NTS2. En revanche, la D-Tyr[11]NT a produit une augmentation des CPSEs glutamatergiques médiée par des récepteurs NTS1 dans les neurones Ih-. Les résultats des expériences comportementales ont montré que des microinjections bilatérales de D-Tyr[11]NT dans le VTA induisait une PPC bloquée uniquement par la co-injection de SR142948A et SR48692, indiquant un rôle pour les deux types de récepteurs, NTS1 et NTS2. Cette étude nous a permis de conclure que i) la D-Tyr[11]NT agit dans le VTA via des récepteurs NTS1 et NTS2 pour induire un effet de récompense et ii) que cet effet est dû, au moins en partie, à une augmentation de la neurotransmission glutamatergique dans les neurones non-dopaminergiques (Ih-). Dans une troisième étude nous nous sommes intéressés aux effets de la D-Tyr[11]NT sur les réponses isolées médiées par les récepteurs N-méthyl-D-aspartate (NMDA) et acide α-amino-3- hydroxy-5-méthyl-4-isoxazolepropionique (AMPA) dans les neurones du VTA. Nous avons constaté que dans les neurones Ih+ l’amplitude des CPSEs NMDA et AMPA étaient atténuées de la même manière par la D-Tyr[11] NT. Cette modulation des réponses était médiée par les récepteurs NTS1 et NTS2. Au contraire, dans les neurones Ih-, l’amplitude des réponses NMDA et AMPA étaient augmentées en présence de D-Tyr[11]NT et ces effets dépendaient de l’activation des récepteurs NTS1 localisés sur les terminaisons glutamatergiques. Ces résultats fournissent une preuve supplémentaire que le NT exerce une modulation bidirectionnelle sur la neurotransmission glutamatergique dans les neurones du VTA et met en évidence un nouveau type de modulation peptidergique des neurones non-dopaminergiques qui pourrait être impliqué dans la sensibilisation. En conclusion, la modulation neurotensinergique de la neurotransmission glutamatergique dans les neurones dopaminergiques et non-dopaminergiques du VTA se fait en sens opposé soit, respectivement, par une inhibition ou par une excitation. De plus, ces effets sont médiés par différents types de récepteurs neurotensinergiques. En outre, nos études mettent en évidence une modulation peptidergique de la neurotransmission glutamatergique dans le VTA qui pourrait jouer un rôle important dans les mécanismes de lutte contre la toxicomanie.The ventral tegmental area (VTA) contains a high density of neurotensin (NT) terminals and receptors that are expressed on dopaminergic (DA) and non-DA neurons. This area of the brain is strongly implicated in disorders like schizophrenia, psychosis and drug abuse. Drugs of abuse induce behavioural sensitization- a facilitatory process whereby exposure to a stimulus results in an enhanced response to a subsequent exposure of the same stimulus. Sensitization develops in the VTA and involves glutamatergic neuroadaptations in VTA DA neurons. NT antagonists prevent the development of sensitization and reward mechanisms and this could be mediated through a modulation of glutamatergic neurotransmission in the VTA. However, how NT modulates glutamatergic neurotransmission in VTA neurons remains unclear. The present thesis was aimed at investigating the NTergic modulation of glutamatergic neurotransmission in VTA DA and non-DA neurons. Whole cell patch clamp electrophysiology in acute VTA horizontal slices was used to study the effects of different NTergic agonists on VTA neurons. Neurons were classified as either Ih+ (putative dopaminergic neurons) or Ih- (putative non-dopaminergic neurons) based on the presence or absence of a hyperpolarisation activated cationic current (Ih) respectively. Immunohistochemical techniques were routinely used to label neurons and confirm their location in the medial VTA. In the first study we report that native neurotensin (NT1-13) or its C-terminal fragment, NT8-13 induced comparable increases in the amplitude of glutamatergic excitatory post-synaptic currents (EPSCs) in VTA neurons. The NT8-13 induced augmentation in Ih+ neurons was blocked by SR48692 (NTS1 antagonist) and SR142948A (NTS1/NTS2 antagonist), suggesting that the augmentation effect was mediated by NTS1 receptors. In Ih- neurons, however, only SR142948A blocked the increase in the EPSC amplitude, indicating the involvement of NTS2. In the second study we tested the effects of D-Tyr[11]NT (an active NT analog with differential binding affinities for NT receptor subtypes) on glutamatergic EPSCs in Ih+ and Ih- neurons and conducted (by Romrpe’s Lab) a parallel series of behavioral experiments using a conditioned place preference (CPP) paradigm. We found that D-Tyr[11]NT induced a dose dependent inhibition of EPSCs in Ih+ neurons that was mediated by the activation of NTS2 receptor. In contrast, D-Tyr[11]NT dose dependently enhanced glutamatergic EPSCs through an NTS1 receptor involvement in Ih- neurons. Results from behavioural experiments show that bilateral VTA microinjections of D-Tyr[11]NT induced a CPP that was blocked only by co-injection of SR142948A and SR48692, indicating a role for NTS1. This study allowed us to conclude that i) NT acts on VTA NTS1 receptors to induce a rewarding effect and ii) that this effect is due, at least in part, to an enhancement of glutamatergic inputs to non-dopamine (Ih-) neurons. The third study entailed investigating the effects of D-Tyr[11]NT on isolated n-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated EPSCs in VTA neurons. We found that in Ih+ neurons both NMDA and AMPA EPSC amplitudes were attenuated by D-Tyr[11]NT. This attenuation appeared to be mediated by both NTS1 and NTS2 receptors. In Contrast, in Ih- neurons both NMDA and AMPA EPSC amplitudes were enhanced by an NTS1 dependent mechanism. Additionally, the enhancement effect resulted from a presynaptic potentiation of glutamatergic inputs. These results provide additional evidence that NT exerts a bidirectional modulation on glutamatergic neurotransmission in VTA neurons and highlights a novel peptidergic modulation of non-DA neurons that might be implicated in sensitization mechanisms. Altogether, our studies allowed us to conclude that the NTergic modulation of glutamatergic neurotransmission in VTA DA and non-DA neurons is oppositely regulated by NTS2 and NTS1 receptors respectively. Additionally it highlights a peptidergic modulation of glutamatergic inputs to VTA non-DA neurons that might be crucial for addiction mechanisms

L’isolamento sociale riduce marcatamente la risposta dei neuroni dopaminergici mesocorticali agli stimoli piacevoli.

The mesolimbic dopaminergic pathway plays an important role in the genesis of emotional arousal and behavioral activation in response to stimuli that provide a reward. This neural circuitry is also active in the early stages of learning and stabilization of addictive behavior due to substances abuse. Isolated animals have a different sensitivity to natural or artificial reinforcers. Accordingly, experimental evidences suggest that exposure to stress can deeply modify eating behavior. In light of these evidences the aim of this study was to investigate the influence of a chronic stress, like social isolation at weaning, on the sensitivity of mesocorticolimbic dopaminergic neurons to anticipation and consumption of food. Rats have been food restricted using a protocol that consists in training the animals to consume their meal for only two hours for day. Using vertical microdialysis, extracellular concentrations of dopamine in response to anticipation and consumption of food were measured both in the mPFC and the NAC. In PFC of GH rats extracellular DA increased (+180%) 80 minutes before food presentation showing the maximal increase (+350%) during food intake. On the contrary, in the NAc of GH rats no significant changes were observed. In SI animals trained to food restriction the increase in mPFC DA output observed in GH animals was completely blunted, while, in the NAc, 40 min before the presentation of the food, a significant increase in extracellular concentrations of DA was observed. Our results show that exposure to chronic stress modified the response of mesocortico-limbic dopaminergic neurons to an enjoyable stimulus and suggest that these changes might be important to explain the greater sensitivity to abuse that is observed in individuals subjected to stressful stimuli. This underlying alteration in brain function might be a crucial mechanism that predisposes individuals to impulsive behavior and increases the risk of developing addiction

L’isolamento sociale riduce marcatamente la risposta dei neuroni dopaminergici mesocorticali agli stimoli piacevoli.

The mesolimbic dopaminergic pathway plays an important role in the genesis of emotional arousal and behavioral activation in response to stimuli that provide a reward. This neural circuitry is also active in the early stages of learning and stabilization of addictive behavior due to substances abuse. Isolated animals have a different sensitivity to natural or artificial reinforcers. Accordingly, experimental evidences suggest that exposure to stress can deeply modify eating behavior. In light of these evidences the aim of this study was to investigate the influence of a chronic stress, like social isolation at weaning, on the sensitivity of mesocorticolimbic dopaminergic neurons to anticipation and consumption of food. Rats have been food restricted using a protocol that consists in training the animals to consume their meal for only two hours for day. Using vertical microdialysis, extracellular concentrations of dopamine in response to anticipation and consumption of food were measured both in the mPFC and the NAC. In PFC of GH rats extracellular DA increased (+180%) 80 minutes before food presentation showing the maximal increase (+350%) during food intake. On the contrary, in the NAc of GH rats no significant changes were observed. In SI animals trained to food restriction the increase in mPFC DA output observed in GH animals was completely blunted, while, in the NAc, 40 min before the presentation of the food, a significant increase in extracellular concentrations of DA was observed. Our results show that exposure to chronic stress modified the response of mesocortico-limbic dopaminergic neurons to an enjoyable stimulus and suggest that these changes might be important to explain the greater sensitivity to abuse that is observed in individuals subjected to stressful stimuli. This underlying alteration in brain function might be a crucial mechanism that predisposes individuals to impulsive behavior and increases the risk of developing addiction