mesolimbic

When facing an unfamiliar environment, animals need to explore to gain new knowledge about which actions provide reward, but also put the newly acquired knowledge to use as quickly as possible. Optimal reinforcement learning strategies should therefore assess the uncertainties of these action-reward associations and utilise them to inform decision making. We propose a novel model whereby direct and indirect striatal pathways act together to estimate both the mean and variance of reward distributions, and mesolimbic dopaminergic neurons provide transient novelty signals, facilitating effective uncertainty-driven exploration...

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release...

Social behaviours are 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...

Excessive consumption of palatable foods that are rich in fats and sugars has contributed to the increasing prevalence of obesity worldwide. Similar to addictive drugs, such foods activate the brain's reward circuit, involving mesolimbic dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the prefrontal cortex. Neuroadaptations occurring in this circuit are hypothesized to contribute to uncontrolled consumption of such foods, a common feature of most of eating disorders and obesity...

Animals are inherently motivated to explore social novelty cues over familiar ones, resulting in a novelty preference (NP), although the behavioral and circuit bases underlying NP are unclear. Combining calcium and neurotransmitter sensors with fiber photometry and optogenetics in mice, we find that mesolimbic dopamine (DA) neurotransmission is strongly and predominantly activated by social novelty controlling bout length of interaction during NP, a response significantly reduced by familiarity. In contrast, interpeduncular nucleus (IPN) GABAergic neurons that project to the lateral dorsal tegmentum (LDTg) were inhibited by social novelty but activated during terminations with familiar social stimuli...

Over 50 million Americans endure chronic pain where many do not receive adequate treatment and self-medicate to manage their pain by taking substances like opioids and cannabis. Research has shown high comorbidity between chronic pain and substance use disorders (SUD) and these disorders share many common neurobiological underpinnings, including hypodopaminergic transmission. Drugs commonly used for self-medication such as opioids and cannabis relieve emotional, bothersome components of pain as well as negative emotional affect that perpetuates misuse and increases the risk of progressing towards drug abuse...

While there is extensive research on alcohol dependence, the factors that make an individual vulnerable to developing alcoholism haven't been explored much. In this study, we aim to investigate how neonatal exposure to sex hormones affects alcohol intake and the regulation of the mesolimbic pathway in adulthood. The study aimed to investigate the impact of neonatal exposure to a single dose of testosterone propionate (TP) or estradiol valerate (EV) on ethanol consumption in adult rats. The rats were subjected to a two-bottle free-choice paradigm, and the content of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (NAcc) was measured using HPLC-ED...

BACKGROUND: Altered neural haemodynamic activity during decision making and learning has been linked to the effects of inflammation on mood and motivated behaviours. So far, it has been reported that blunted mesolimbic dopamine reward signals are associated with inflammation-induced anhedonia and apathy. Nonetheless, it is still unclear whether inflammation impacts neural activity underpinning decision dynamics. The process of decision making involves integration of noisy evidence from the environment until a critical threshold of evidence is reached...

The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled...

Synthetic exendin-4 (EX4, exenatide), is a GLP-1 receptor agonist used clinically to treat glycemia in Type-2 diabetes mellitus. EX4 also promotes weight loss and alters food reward-seeking behaviors in part due to activation of GLP-1 receptors in the mesolimbic dopamine system. Evidence suggests that GLP-1 receptor activity can directly attenuate cue-induced reward seeking. Here, we tested the effects of EX4 (0.6, 1.2, and 2.4 μg/kg, i.p.) on incentive cue (IC) responding, using a task where rats emit a nosepoke response during an intermittent reward-predictive IC to obtain a sucrose reward...

Midbrain dopaminergic (mDA) neurons are significantly impaired in patients inflicted with Parkinson's disease (PD), subsequently affecting a variety of motor functions. There are four pathways through which dopamine elicits its function, namely, nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular dopamine pathways. SHH and Wnt signalling pathways in association with favourable expression of a variety of genes, promotes the development and differentiation of mDA neurons in the brain. However, there is a knowledge gap regarding the complex signalling pathways involved in development of mDA neurons...

RATIONALE: Antipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D2 heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia. OBJECTIVE: The current study sought to explore the use of the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) as a treatment to reduce symptoms related to psychosis and comorbid nicotine use...

Drugs of abuse induce neuroadaptations, including synaptic plasticity, that are critical for transition to addiction, and genes and pathways that regulate these neuroadaptations are potential therapeutic targets. Tropomodulin 2 ( Tmod2 ) is an actin-regulating gene that plays an important role in synapse maturation and dendritic arborization and has been implicated in substance-abuse and intellectual disability in humans. Here we mine the KOMP2 data and find that Tmod 2 knockout mice show emotionality phenotypes that are predictive of addiction vulnerability...

Signaling through nicotinic acetylcholine receptors (nAChRs) plays a role in cocaine reward and reinforcement, suggesting that the cholinergic system could be manipulated with therapeutics to modulate aspects of cocaine use disorder (CUD). We examined the interaction between nAChRs and cocaine reinforcement by expressing a hypersensitive β2 nAChR subunit (β2Leu9'Ser) in the ventral tegmental area of male Sprague Dawley rats. Compared to control rats, β2Leu9'Ser rats acquired (fixed ratio) intravenous cocaine self-administration faster and with greater likelihood...

This paper focuses on Jeffrey Gray's theory of anxiety from the perspective of Fowles' (1980) application of his work to theories of arousal, psychophysiology, and the etiology of psychopathy. Although highly influential, the concept of general arousal failed to find support in terms of between-individuals assessment with multiple physiological measures. Gray's constructs of a behavioral inhibition system (BIS) that mediates anxiety, a behavioral approach or activation system (BAS) that energizes behavior to approach rewards, and a nonspecific arousal system that energized behavior captured aspects of arousal...

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice...

The role of nitrergic system in modulating the action of psychostimulants on reward processing is well established. However, the relevant anatomical underpinnings and scope of the involved interactions with mesolimbic dopaminergic system have not been clarified. Using immunohistochemistry, we track the changes in neuronal nitric oxide synthase (nNOS) containing cell groups in the animals conditioned to intracranial self-stimulation (ICSS) via an electrode implanted in the lateral hypothalamus-medial forebrain bundle (LH-MFB) area...

Evolutionarily conserved, peer-directed social behaviors are essential to participate in many aspects of human society. These behaviors directly impact psychological, physiological, and behavioral maturation. Adolescence is an evolutionarily conserved period during which reward-related behaviors, including social behaviors, develop via developmental plasticity in the mesolimbic dopaminergic "reward" circuitry of the brain. The nucleus accumbens (NAc) is an intermediate reward relay center that develops during adolescence and mediates both social behaviors and dopaminergic signaling...

In males but not in females, brain derived neurotrophic factor (BDNF) plays an obligatory role in the onset and maintenance of neuropathic pain. Afferent terminals of injured peripheral nerves release colony stimulating factor (CSF-1) and other mediators into the dorsal horn. These transform the phenotype of dorsal horn microglia such that they express P2X4 purinoceptors. Activation of these receptors by neuron-derived ATP promotes BDNF release. This microglial-derived BDNF increases synaptic activation of excitatory dorsal horn neurons and decreases that of inhibitory neurons...

The medial prefrontal cortex (mPFC) is associated with various behavioral controls via diverse projections to cortical and subcortical areas of the brain. Dysfunctions and modulations of this circuitry are related to the pathophysiology of schizophrenia and its pharmacotherapy, respectively. Clozapine is an atypical antipsychotic drug used for treatment-resistant schizophrenia and is known to modulate neuronal activity in the mPFC. However, it remains unclear which prefrontal cortical projections are activated by clozapine among the various projection targets...