Fact-checked by Grok 2 weeks ago

Mesolimbic pathway

The mesolimbic pathway, also referred to as the mesolimbic dopaminergic system, is a major neural circuit in the mammalian brain composed primarily of dopaminergic neurons that originate in the ventral tegmental area (VTA) of the midbrain and project to key limbic and forebrain structures, including the nucleus accumbens (NAc) in the ventral striatum, amygdala, ventral pallidum, and olfactory tubercle.^[1] This pathway serves as a critical mediator of reward processing, motivation, and reinforcement learning by releasing dopamine in response to salient stimuli, thereby driving appetitive behaviors and the "SEEKING" emotional disposition that promotes goal-directed actions essential for survival, such as foraging and social interaction.^[1]^[2] Beyond its role in natural rewards like food and sex, the mesolimbic pathway is heavily implicated in the neurobiology of addiction, where drugs of abuse such as cocaine and amphetamines hijack the system by inducing supraphysiological dopamine surges in the NAc, enhancing incentive salience and leading to compulsive drug-seeking behaviors, craving, and relapse vulnerability.^[2] Dysregulation in this pathway contributes to context-dependent sensitization, where environmental cues associated with rewards or drugs trigger heightened dopaminergic activity, perpetuating addictive cycles and influencing individual susceptibility to substance use disorders.^[1] Additionally, the pathway modulates broader motivational functions, including effort-based decision-making and responses to stress.^[1] Research highlights the mesolimbic pathway's involvement in psychiatric conditions beyond addiction, such as schizophrenia, depression, and attention-deficit/hyperactivity disorder (ADHD), where altered dopamine signaling disrupts reward anticipation and motivational drive.^[1] Neuroplastic adaptations, including changes in receptor density and synaptic strength within the VTA-NAc circuit, underscore its dynamic role in learning and adaptation, making it a primary target for therapeutic interventions aimed at restoring balanced dopaminergic function.^[2]

Anatomy

Origin and Neuronal Composition

The mesolimbic pathway originates from dopaminergic neurons located in the ventral tegmental area (VTA), a key structure in the midbrain tegmentum.^[3] This region, also known as the A10 cell group, was first mapped as a cluster of catecholaminergic neurons by Dahlström and Fuxe in their seminal histochemical studies of monoamine-containing cells in the rat brain.^[4] The VTA is situated dorsally to the interpeduncular nucleus and forms part of the broader midbrain dopaminergic complex. Dopamine serves as the primary neurotransmitter released by these neurons.^[1] Within the VTA, the neuronal population is heterogeneous, with dopaminergic neurons comprising the majority, estimated at approximately 60-65% based on stereological counts in rats.^[5] These tyrosine hydroxylase-positive cells are intermingled with GABAergic neurons, which account for about 30-35% of the total, and a smaller proportion of glutamatergic neurons, around 2-3%.^[5] This composition reflects the VTA's role as a mixed nucleus, though the mesolimbic pathway itself is defined by the projections of its dopaminergic subset. The neurons exhibit diverse morphologies, including fusiform and multipolar shapes, contributing to the pathway's integrated signaling.^[6] The axons of VTA dopaminergic neurons are characteristically unmyelinated or only lightly myelinated, allowing for slower conduction velocities compared to heavily myelinated tracts but enabling fine spatial and temporal control of dopamine release.^[7] These axons typically extend several millimeters in length from the midbrain to forebrain targets, with extensive branching patterns that form dense arborizations, often exceeding 50 mm in terminal fields for individual neurons.^[8] Anatomically, the VTA lies in close proximity to the substantia nigra pars compacta laterally and the red nucleus dorsally, sharing boundaries that facilitate interactions within the midbrain dopaminergic system.^[9]

Major Projections and Terminations

The mesolimbic pathway originates from dopaminergic neurons in the ventral tegmental area (VTA) and extends primary projections to several limbic and cortical structures, forming a key component of the brain's reward circuitry. These projections primarily target the nucleus accumbens (NAc), divided into the shell and core subregions of the ventral striatum, where medial VTA regions such as the central linear nucleus and interfascicular nucleus innervate the medial shell, while lateral VTA areas like the parabrachial pigmented nucleus project to the lateral shell and core.^[10] Additional primary targets include the ventral pallidum, receiving dopaminergic inputs from the VTA that modulate basal ganglia outputs, the basolateral amygdala for emotional processing integration, the ventral hippocampus via sparse dopaminergic fibers to the CA1 region, and with some overlap to prefrontal areas via the mesocortical pathway.^[10]^[11]^[12] Termination patterns of these projections are particularly dense in the NAc, where VTA dopaminergic axons form synaptic contacts predominantly on the dendritic spines of medium spiny neurons (MSNs), the principal GABAergic output cells comprising over 90% of NAc neurons.^[10] These synapses enable precise modulation of glutamatergic inputs from cortical and limbic sources, with medial shell MSNs showing higher dendritic spine density compared to core neurons, supporting differential roles in motivation and action selection.^[10] Collateral projections from the VTA provide minor inputs to the olfactory tubercle, a ventral striatal extension receiving up to 28% of its dopaminergic innervation from medial VTA nuclei like the central linear nucleus, facilitating olfactory-reward associations.^[10] Similarly, sparse collaterals extend to the entorhinal cortex, contributing to memory-related limbic integration as part of broader mesolimbic-mesocortical overlaps.^[13] Anatomical variations exist between rodents and humans, with rodent studies relying on stereotaxic atlases like Paxinos and Watson's rat brain atlas revealing precise VTA-NAc tract coordinates (e.g., NAc shell volume ~3-5 mm³ in adult rats), while human postmortem and MRI data indicate homologous pathways with proportionally larger volumes (e.g., total NAc ~0.4-0.6 cm³) and denser terminations due to expanded cortical folding.^[14]^[15] These differences highlight translational challenges, as lab rodents lack certain primate-specific dopaminergic subdivisions in the ventral midbrain.^[16]

Neurochemistry

Dopamine Synthesis and Transport

Dopamine synthesis in the mesolimbic pathway occurs within dopaminergic neurons originating from the ventral tegmental area (VTA). The process begins with the amino acid L-tyrosine, which is hydroxylated to L-3,4-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis that requires tetrahydrobiopterin as a cofactor and molecular oxygen.^[17] This reaction is tightly regulated to control dopamine production levels. L-DOPA is then rapidly converted to dopamine by aromatic L-amino acid decarboxylase (AADC), also known as DOPA decarboxylase, using pyridoxal phosphate as a cofactor.^[18] Following synthesis in the neuronal cytoplasm, dopamine is sequestered into synaptic vesicles for storage and protection from degradation. This transport is mediated by the vesicular monoamine transporter 2 (VMAT2), a proton antiporter that uses the vesicular pH gradient to accumulate dopamine at high concentrations within the vesicles.^[19] Upon arrival of an action potential at the axon terminal, voltage-gated calcium channels open, leading to calcium influx that triggers calcium-dependent exocytosis of the vesicles, thereby releasing dopamine into the synaptic cleft primarily in target regions such as the nucleus accumbens.^[20] To terminate signaling and recycle dopamine, the neurotransmitter is reabsorbed into the presynaptic neuron via the dopamine transporter (DAT), a sodium- and chloride-dependent symporter embedded in the plasma membrane. DAT operates with an affinity in the micromolar range (Km ≈ 1–5 μM) for dopamine uptake, enabling efficient clearance from the extracellular space.^[21] Dopamine synthesis and release are subject to negative feedback regulation through presynaptic D2 autoreceptors on dopaminergic neurons. Activation of these autoreceptors by extracellular dopamine inhibits TH activity via a G-protein-coupled mechanism, reducing further dopamine production and maintaining homeostasis in the mesolimbic pathway.^[22]

Receptor Subtypes and Signaling

The mesolimbic pathway primarily involves dopamine receptors from two major families: the D1-like receptors (D1 and D5), which are coupled to stimulatory G proteins (Gs) and exert excitatory effects, and the D2-like receptors (D2, D3, and D4), which are coupled to inhibitory G proteins (Gi/o) and generally produce inhibitory responses.^[23] In the nucleus accumbens, a key termination site of the mesolimbic pathway, D1 and D2 receptors predominate, with D1 receptors highly expressed in medium spiny neurons (MSNs) of the direct pathway and D2 receptors enriched in those of the indirect pathway.^[24] D3 receptors, part of the D2-like family, show particular enrichment in the ventral striatum, including regions like the nucleus accumbens shell, where they contribute to reward-related modulation.^[25] D5 receptors, while less abundant, are also present in the nucleus accumbens and share signaling properties with D1.^[23] D4 receptors exhibit lower expression in mesolimbic areas compared to D2 and D3 but can influence signaling in select neuronal populations.^[26] Upon activation, D1-like receptors stimulate adenylate cyclase via Gs proteins, elevating intracellular cyclic AMP (cAMP) levels, which in turn activates protein kinase A (PKA).^[27] This cascade leads to PKA-mediated phosphorylation of the transcription factor CREB (cAMP response element-binding protein), promoting gene expression changes that support synaptic plasticity and reward signaling in mesolimbic targets.^[28] In contrast, D2-like receptors inhibit adenylate cyclase through Gi/o proteins, reducing cAMP production and thereby dampening PKA activity; they also directly modulate ion channels, such as potassium channels, to alter neuronal excitability.^[29] These opposing signaling mechanisms allow D1-like and D2-like receptors to balance excitatory and inhibitory influences within the same circuit, with dopamine availability from upstream synthesis influencing binding efficacy.^[23] Receptor crosstalk in the mesolimbic pathway enhances signaling complexity, notably through heterodimerization of D2-like receptors with other G protein-coupled receptors (GPCRs).^[30] For instance, D2 receptors form functional heteromers with adenosine A2A receptors, primarily in striatal MSNs, where A2A activation allosterically modulates D2 signaling to fine-tune inhibitory responses and contribute to reward processing.^[31] This interaction exemplifies how mesolimbic dopamine receptors integrate inputs from multiple neurotransmitter systems to regulate downstream cascades.^[32]

Functions

Reward Processing and Hedonic Response

The mesolimbic pathway plays a central role in processing rewarding stimuli by modulating dopamine release from the ventral tegmental area (VTA) to target regions such as the nucleus accumbens, where it encodes the salience and hedonic value of experiences. Dopamine signaling in this pathway distinguishes between anticipated and unexpected rewards, facilitating the neural representation of pleasure and reinforcement without directly causing the subjective feeling of "liking." This process integrates sensory inputs to prioritize biologically relevant stimuli, ensuring adaptive behavioral responses to environmental cues.^[1] Dopamine release in the mesolimbic pathway occurs in two primary modes: tonic and phasic. Tonic release maintains baseline extracellular dopamine levels at low concentrations (approximately 20-30 nM in the nucleus accumbens), providing a steady modulatory tone that influences overall neuronal excitability and readiness for reward-related activity. In contrast, phasic release involves brief bursts of dopamine neuron firing, triggered by unexpected or salient stimuli, leading to rapid, transient elevations in dopamine concentration that signal immediate reward salience. These phasic bursts, lasting milliseconds to seconds, are particularly prominent in the nucleus accumbens and are essential for detecting and responding to novel rewarding events, as opposed to the sustained tonic mode that supports ongoing homeostasis.^[33] Within the nucleus accumbens shell, specific subregions known as hedonic hotspots mediate the pleasurable or "liking" aspect of rewards through interactions between opioid and dopamine systems. These hotspots, approximately 1 mm³ in volume and located in the rostrodorsal medial shell, amplify sensory pleasure when activated by μ-opioid agonists, enhancing facial and behavioral expressions of hedonia in response to sweet tastes or other palatable stimuli. Dopamine modulates this process indirectly by facilitating opioid signaling, but the core hedonic enhancement arises from local opioid receptor activation, dissociating pure pleasure from motivational drive. Microinjections of opioids into these hotspots increase "liking" reactions without necessarily boosting consumption, highlighting their specialized role in the affective component of reward.^[34]^[35] The mesolimbic pathway also encodes reward prediction errors, discrepancies between expected and actual rewards, through a temporal difference learning mechanism. In this model, phasic dopamine bursts from VTA neurons signal positive prediction errors when rewards exceed predictions, while dips in activity indicate negative errors; fully predicted rewards elicit no net change. This signaling, observed in midbrain dopamine neurons across species, updates value representations in downstream structures like the nucleus accumbens, enabling efficient learning about reward contingencies. The temporal difference framework posits that dopamine acts as a teaching signal, shifting from reward delivery to predictive cues over repeated exposures, thereby refining behavioral associations.^[36]^[37] Sensory integration in the mesolimbic pathway processes natural rewards such as food, sex, and social interactions via VTA activation, where multisensory cues converge to trigger dopamine release. For instance, olfactory, gustatory, and tactile inputs from rewarding stimuli like palatable food or sexual contact excite VTA dopamine neurons, enhancing the perceived value of these experiences in the nucleus accumbens. Social rewards, including affiliation and play, similarly engage this pathway, with VTA projections integrating affiliative cues to promote bonding behaviors. This integration ensures that evolutionarily adaptive stimuli elicit robust hedonic responses, prioritizing survival-related pleasures over neutral sensations.^[38]^[39]

Motivation, Learning, and Reinforcement

The mesolimbic pathway plays a pivotal role in attributing motivational value to environmental cues through the process of incentive salience, as proposed in Kent Berridge's framework. In this model, dopamine release from ventral tegmental area (VTA) neurons enhances the "wanting" aspect of rewards, transforming neutral stimuli into powerful motivators that drive approach behaviors, distinct from the sensory pleasure or "liking" component.^[40] This attribution occurs via mesolimbic projections to the nucleus accumbens, where phasic dopamine signals amplify the salience of reward-predictive cues, promoting persistent pursuit even in the absence of immediate gratification.^[41] Experimental evidence from rodent studies demonstrates that optogenetic stimulation of VTA dopamine neurons selectively boosts cue-directed behaviors, underscoring the pathway's capacity to imbue stimuli with incentive properties.^[42] In Pavlovian and operant conditioning, VTA dopamine neurons facilitate the acquisition of conditioned reinforcement by signaling the predictive relationship between cues and outcomes. During Pavlovian conditioning, dopamine bursts in response to reward-predictive stimuli strengthen associations, enabling cues to elicit anticipatory behaviors that propel goal-oriented actions.^[43] In operant contexts, this dopamine signaling reinforces instrumental responses by encoding the value of actions leading to rewards, with midbrain dopamine modulating the vigor and persistence of behavior through projections to the nucleus accumbens shell and core.^[44] These mechanisms integrate sensory cues with motor outputs, allowing adaptive learning where repeated pairings enhance the reinforcing efficacy of stimuli, as evidenced by increased response rates in dopamine-intact animals compared to those with VTA lesions.^[45] The pathway also contributes to habit formation by mediating the transition from flexible, goal-directed behaviors to rigid, stimulus-response habits, particularly via dopamine signaling in the nucleus accumbens core. Initially, actions are governed by outcome value, but with overtraining, dopamine release in the core diminishes while supporting automated responding, shifting control toward cue-elicited habits insensitive to devaluation.^[46] This plasticity enables efficient routine behaviors but can lead to maladaptive persistence, as shown in studies where core-specific dopamine manipulations disrupt the consolidation of habitual lever-pressing in rats.^[1] Underlying these processes are synaptic plasticity mechanisms, including long-term potentiation (LTP) at excitatory glutamatergic synapses onto VTA dopaminergic neurons. LTP strengthens these inputs following high-frequency stimulation or reward exposure, enhancing dopamine neuron excitability and thereby amplifying motivational signals to downstream targets.^[47] This form of Hebbian plasticity, dependent on NMDA receptor activation and calcium influx, supports associative learning by stabilizing connections that link cues to reinforcement, with bidirectional modulation (including long-term depression) allowing fine-tuned adaptation.^[48] Such changes in the mesolimbic circuit provide the neural basis for enduring behavioral modifications observed in conditioning paradigms.^[49]

Clinical Significance

Dysregulation in Addiction

The mesolimbic pathway undergoes profound dysregulation in addiction, where repeated exposure to drugs of abuse hijacks its core dopamine signaling mechanisms, transforming adaptive reward processing into compulsive drug-seeking behavior. This dysregulation manifests as sensitization, in which chronic drug use amplifies dopamine release in the nucleus accumbens specifically in response to drug-associated cues, rather than the drug itself, thereby intensifying craving and promoting relapse even after prolonged abstinence.^[50] Seminal animal studies have demonstrated this incentive sensitization, showing enhanced phasic dopamine transients to conditioned stimuli following repeated cocaine or amphetamine administration, a process mediated by neuroplastic changes in ventral tegmental area dopamine neurons and their projections.^[51] In humans, neuroimaging evidence corroborates this, with increased striatal dopamine responses to drug cues observed in cocaine-dependent individuals, underscoring the pathway's role in perpetuating addiction vulnerability.^[52] Tolerance and dependence arise from adaptive changes that diminish the pathway's responsiveness to natural rewards, primarily through downregulation of D2 dopamine receptors in the nucleus accumbens. This reduction in D2 receptor density and availability, documented in positron emission tomography studies of individuals with substance use disorders, blunts dopamine signaling to everyday reinforcers like food or social interaction, shifting motivational priority toward drug-related stimuli to achieve comparable activation.^[53] For instance, in methamphetamine and alcohol addiction, lower D2 binding correlates with reduced sensitivity to non-drug rewards, fostering anhedonia during withdrawal and reinforcing dependence.^[54] These alterations reflect a homeostatic imbalance in the mesolimbic system, where compensatory decreases in receptor expression follow excessive dopamine surges from drug exposure. Drug-specific mechanisms further illustrate the pathway's vulnerability, as each substance exploits distinct neurochemical interactions to elevate dopamine transmission. Cocaine acutely blocks the dopamine transporter (DAT) in the nucleus accumbens, preventing reuptake and causing a rapid, supraphysiological increase in extracellular dopamine levels, which reinforces its euphoric effects and drives repeated use.^[55] Opioids, such as morphine, primarily act via mu-opioid receptors on GABAergic interneurons in the ventral tegmental area, disinhibiting dopamine neurons and thereby enhancing phasic dopamine release to the nucleus accumbens.^[56] Alcohol modulates this interplay by potentiating GABA_A receptor activity, which indirectly disinhibits ventral tegmental area dopamine cells while also inhibiting glutamatergic inputs, resulting in elevated nucleus accumbens dopamine that contributes to its reinforcing properties.^[51] Similar dysregulations extend to behavioral addictions, where non-substance rewards elicit aberrant phasic dopamine signaling in the mesolimbic pathway, paralleling substance use disorders. In gambling disorder, for example, anticipatory cues like near-misses or betting opportunities trigger heightened dopamine release in the ventral striatum, akin to drug cues, fostering persistent engagement despite losses; this is evidenced by increased dopamine responses during reward expectation in functional magnetic resonance imaging studies of affected individuals.^[57] Internet addiction shows comparable patterns, with excessive engagement linked to sensitized dopamine transients in response to online stimuli, highlighting the pathway's broad susceptibility to incentive sensitization beyond pharmacological agents.

Role in Psychiatric and Neurological Disorders

The mesolimbic pathway plays a pivotal role in the pathophysiology of schizophrenia, particularly through hyperdopaminergia that contributes to positive symptoms such as hallucinations and delusions. This dysregulation is characterized by excessive dopamine release in the striatum, stemming from aberrant firing of ventral tegmental area (VTA) neurons projecting to limbic regions like the nucleus accumbens, which amplifies salience attribution to irrelevant stimuli. Seminal formulations of the dopamine hypothesis, updated in version III, posit that striatal hyperdopaminergia underlies these psychotic features, supported by evidence from positron emission tomography (PET) studies showing elevated dopamine synthesis and release in untreated patients. Antipsychotic medications that block D2 receptors in this pathway effectively alleviate positive symptoms by normalizing dopamine transmission.^[58]^[59] In major depressive disorder (MDD), hypoactivity of the mesolimbic pathway is implicated in anhedonia, the diminished capacity for pleasure and reward, often linked to reduced VTA dopamine neuron firing rates. Neuroimaging and electrophysiological studies reveal decreased dopamine release in the nucleus accumbens during reward anticipation in depressed individuals, correlating with motivational deficits and emotional blunting. This hypoactivity may arise from stress-induced adaptations, such as impaired burst firing in VTA neurons, which disrupts hedonic processing and reinforces negative mood states. Treatments like bupropion, which enhance dopamine signaling, can mitigate anhedonia by boosting mesolimbic activity.^[60]^[61]^[62] Attention-deficit/hyperactivity disorder (ADHD) involves altered dopamine signaling in the mesolimbic pathway, which impairs motivation, attention, and reinforcement learning. Reduced dopamine transporter density and inefficient dopamine release in the nucleus accumbens contribute to diminished incentive salience, making it harder for individuals to sustain attention on non-rewarding tasks or initiate goal-directed behaviors. Functional MRI studies demonstrate hypoactivation in VTA-nucleus accumbens circuits during reward processing in ADHD patients, linking these deficits to core symptoms like inattention and motivational lapses. Stimulant medications such as methylphenidate ameliorate these issues by increasing extracellular dopamine in the mesolimbic system, enhancing attentional control and reward sensitivity.^[63]^[64] In Parkinson's disease, mesolimbic deficits contribute to non-motor symptoms like apathy and impaired reward processing, distinct from the primary nigrostriatal dopamine loss affecting motor function. Degeneration of VTA dopamine neurons leads to reduced signaling in limbic targets, resulting in blunted reward anticipation and motivational deficits that manifest as apathy, where patients exhibit diminished initiative despite preserved motor ability. PET imaging confirms lower dopamine binding in the ventral striatum of apathetic Parkinson's patients, correlating with impaired incentive salience and effort-based decision-making. Dopamine agonists targeting D2/D3 receptors in this pathway can partially alleviate apathy, highlighting the mesolimbic system's role in these neuropsychiatric features.^[65]^[66]

Mesocortical Pathway

The mesocortical pathway originates in the ventral tegmental area (VTA) of the midbrain, where dopaminergic neurons project primarily to various regions of the prefrontal cortex (PFC), including the dorsolateral prefrontal cortex (dlPFC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC).^[67] These projections emphasize cognitive processing areas, with dense innervation in the dlPFC supporting higher-order functions, while sparser terminals in the OFC and ACC modulate emotional evaluation and conflict monitoring.^[68] Like the mesolimbic pathway, it shares a common origin in the VTA.^[69] This pathway plays a key role in executive functions, including working memory, decision-making, and attentional control, primarily through dopaminergic modulation of PFC circuitry.^[68] Tonic dopamine release in the PFC, characterized by low-frequency firing (1–6 Hz) and sustained extracellular levels (0.3–15 nM), enhances signal-to-noise ratios in neural networks, facilitating persistent activity for sustained attention and stabilizing working memory representations via D1 receptor activation.^[70] Optimal dopamine levels follow an inverted U-shaped curve, where intermediate concentrations promote cognitive flexibility and goal-directed behavior, while deviations impair performance.^[68] In contrast to the mesolimbic pathway, which targets limbic structures like the nucleus accumbens for affective reward processing, the mesocortical pathway is predominantly cortical, focusing on prefrontal regions for cognitive integration.^[67] Hypofunction in this pathway is implicated in the negative and cognitive symptoms of schizophrenia, such as avolition and impaired executive function, distinct from mesolimbic hyperactivity underlying positive symptoms.^[71] The mesocortical and mesolimbic pathways exhibit reciprocal interactions, with prefrontal projections back to the VTA enabling the integration of cognitive evaluation with reward signals to guide motivated behavior.^[72] This connectivity allows the dlPFC to modulate VTA dopamine release, linking decision-making processes with hedonic reinforcement for adaptive learning.^[73]

Nigrostriatal and Tuberoinfundibular Pathways

The nigrostriatal pathway originates from dopaminergic neurons in the substantia nigra pars compacta, designated as the A9 cell group, and projects primarily to the dorsal striatum, including the caudate nucleus and putamen.^[74] This pathway plays a crucial role in motor control, facilitating smooth and coordinated movements through modulation of basal ganglia circuits, and is also involved in habit learning and procedural memory formation.^[75] Degeneration of these neurons, leading to dopamine depletion in the striatum, is a hallmark of Parkinson's disease, resulting in bradykinesia, rigidity, and tremors.^[76] In contrast, the tuberoinfundibular pathway arises from dopaminergic neurons in the arcuate nucleus of the hypothalamus, known as the A12 cell group, and extends to the median eminence, where it releases dopamine into the pituitary portal system.^[77] This pathway primarily regulates prolactin secretion by inhibiting lactotroph cells in the anterior pituitary through activation of D2 dopamine receptors, thereby suppressing prolactin release under normal physiological conditions.^[78] Disruption of this inhibitory tone, such as in hyperprolactinemia, can lead to elevated prolactin levels and associated endocrine disorders.^[79] Among the major dopaminergic pathways, the nigrostriatal system exhibits the highest dopamine concentrations, accounting for approximately 80% of total brain dopamine, reflecting its extensive axonal arborization in the striatum.^[71] The tuberoinfundibular pathway, by comparison, is the shortest in length and is specialized for endocrine regulation rather than broad neural modulation, with lower overall dopamine output tailored to hypothalamic-pituitary interactions.^[79] These pathways exhibit cross-talk with the mesolimbic system through indirect mechanisms involving basal ganglia loops, where nigrostriatal projections to the dorsal striatum influence ventral striatal activity via reciprocal connections, thereby modulating reward-related outputs without direct overlap.^[80] Dopamine synthesis and transport mechanisms in these pathways parallel those in other dopaminergic systems, involving tyrosine hydroxylase and vesicular monoamine transporter 2 for storage and release.^[74]

Research Developments

Neuroimaging and Experimental Techniques

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are pivotal noninvasive techniques for studying dopamine dynamics in the mesolimbic pathway, particularly through the assessment of D2 receptor binding and indirect measurement of dopamine release. In PET imaging, the radioligand [¹¹C]-raclopride is widely employed to quantify D2/D3 receptor availability in the striatum, including the nucleus accumbens, a key mesolimbic target. Displacement of [¹¹C]-raclopride binding by endogenous dopamine provides an indirect measure of dopamine release, as increased synaptic dopamine competes for receptor occupancy during reward-related stimuli or pharmacological challenges.^[81] For instance, studies using [¹¹C]-raclopride PET have demonstrated elevated dopamine release in the ventral striatum in response to morphine infusion, highlighting the pathway's role in opioid reward processing.^[82] SPECT complements PET by utilizing ligands like [¹²³I]-IBZM to visualize D2 receptor density in striatal regions, offering insights into receptor upregulation or downregulation in dopaminergic disorders affecting the mesolimbic system.^[83] Functional magnetic resonance imaging (fMRI), particularly blood-oxygen-level-dependent (BOLD) imaging, enables the mapping of mesolimbic activation patterns during reward anticipation and consumption tasks. BOLD signals in the ventral tegmental area (VTA) and nucleus accumbens reflect phasic dopaminergic responses to unexpected rewards, correlating with subjective value encoding and motivational salience.^[84] In reward paradigms, such as monetary incentive delay tasks, enhanced connectivity between VTA and nucleus accumbens predicts memory formation for high-reward stimuli, underscoring the pathway's integration of reinforcement learning.^[85] Resting-state fMRI further reveals functional coupling along mesolimbic circuits, with age-related declines in VTA-nucleus accumbens synchrony during motivational contexts.^[86] Optogenetics and chemogenetics provide causal insights into mesolimbic function by enabling precise manipulation of VTA neurons in animal models. Optogenetic stimulation of VTA dopaminergic neurons using channelrhodopsin-2 evokes rapid, temporally precise dopamine release in accumbal terminals, sufficient to drive reinforcement behaviors like self-stimulation without extraneous confounds.^[87] This technique has dissected the pathway's role in reward prediction errors, where phasic VTA activation adapts learning rates in operant tasks.^[43] Chemogenetics, employing designer receptors exclusively activated by designer drugs (DREADDs), allows bidirectional control of VTA dopamine neurons; for example, activation enhances cocaine-seeking, while inhibition disrupts cue-motivated relapse, isolating dopaminergic contributions to addiction-like behaviors.^[88] Recent advances post-2020 have refined mesolimbic pathway visualization and modeling using diffusion tensor imaging (DTI) for tractography and CRISPR editing in induced pluripotent stem cell (iPSC)-derived neurons. DTI-based tractography reconstructs the mesolimbic tract's microstructural integrity, revealing age-related fractional anisotropy declines in the VTA-nucleus accumbens projection, indicative of dopaminergic fiber degeneration.^[89] This method quantifies white matter changes in reward circuits, with applications in tracking pathway alterations in aging or neurodegeneration.^[90] Concurrently, CRISPR/Cas9 editing of iPSC-derived midbrain dopaminergic neurons enables subtype-specific modeling of mesolimbic vulnerabilities; for instance, targeted mutations in genes like PPP2R5D alter dopamine homeostasis in A10-like (VTA) neurons, recapitulating pathway dysfunctions observed in neurodevelopmental disorders.^[91] These human cellular models facilitate high-throughput screening of mesolimbic signaling perturbations.^[92] In 2025, studies using advanced imaging and circuit tracing have further elucidated the mesolimbic dopamine system's flexible encoding of positive and negative values, such as in salt and water rewards, enhancing understanding of its role in adaptive behaviors.^[93] Additionally, research has highlighted the pathway's involvement in aversive signaling and opioid dependence, providing new insights into its dual role in reward and avoidance.^[94]

Emerging Therapeutic Approaches

Recent advancements in dopamine modulation have focused on partial agonists such as aripiprazole, which acts as a stabilizer in the mesolimbic pathway to address dysregulation in schizophrenia and co-occurring substance use disorders. By functioning as a partial agonist at D2 receptors, aripiprazole reduces hyperactivity in the mesolimbic dopamine system associated with positive symptoms of schizophrenia while mitigating extrapyramidal side effects through balanced agonism in hypodopaminergic states.^[95] In patients with schizophrenia and substance use disorders, long-acting injectable aripiprazole has demonstrated sustained antipsychotic efficacy and potential reductions in substance cravings by normalizing dopamine signaling in reward circuits.^[96] Similarly, for addiction, dopamine stabilizers like aripiprazole target mesolimbic overactivation to curb reward-seeking behaviors, with clinical trials showing decreased cocaine intake and improved abstinence rates without exacerbating withdrawal symptoms.^[97] Neuromodulation techniques offer non-pharmacological options to directly influence mesolimbic activity in treatment-resistant conditions. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB), a key component of the mesolimbic reward pathway originating from the ventral tegmental area (VTA), has shown promise in alleviating symptoms of treatment-resistant depression by enhancing dopamine release and restoring affective responsiveness.^[98] In clinical studies, MFB-DBS led to significant reductions in depression scores, with over 50% of patients achieving a 47% improvement within weeks, attributed to normalized signaling in VTA-nucleus accumbens projections.^[99] Complementing this, repetitive transcranial magnetic stimulation (rTMS) applied to prefrontal regions modulates downstream mesolimbic circuits, reducing craving and substance use in addiction disorders through indirect enhancement of inhibitory control over reward processing.^[100] A 2025 review highlighted neuroimaging-guided rTMS as particularly effective for substance use disorders, with medium to large effect sizes in decreasing mesolimbic-driven impulsivity.^[101] Pharmacogenomic approaches personalize interventions by targeting genetic variants in the dopamine transporter gene (SLC6A3/DAT), which influences mesolimbic dopamine reuptake and addiction vulnerability. Individuals with higher DAT expression, conferred by specific SLC6A3 alleles like the 10-repeat VNTR, exhibit better responses to disulfiram therapy for cocaine dependence, as elevated transporter levels enhance the drug's inhibitory effects on dopamine clearance in reward pathways.^[102] This variant-guided strategy improves treatment outcomes by up to 50% in genetically stratified patients, underscoring the role of pharmacogenomics in optimizing mesolimbic-targeted therapies for addiction.^[103] Post-2020 developments include psychedelic-assisted therapies and gene interventions that aim to rewire mesolimbic circuits. Psilocybin, administered in controlled psychotherapeutic settings, indirectly modulates VTA dopaminergic activity via serotonin 5-HT2A receptor agonism, promoting neuroplasticity and reducing anhedonia in treatment-resistant depression and addiction by resetting reward sensitivity in the nucleus accumbens.^[104] Clinical trials from 2023-2025 report sustained symptom relief, with psilocybin enhancing positive valence system function in mesolimbic structures like the VTA and ventral striatum. Additionally, glial cell line-derived neurotrophic factor (GDNF) gene therapy targets alcohol use disorder by restoring dopamine function in the mesolimbic pathway, reducing consumption by over 90% in preclinical primate models through VTA-specific delivery.^[106] This one-time intervention normalizes hypodopaminergic states induced by chronic alcohol exposure, offering a potential long-term solution for severe addiction without ongoing pharmacotherapy.^[107] Emerging behavioral strategies, as of 2025, leverage positive experiences like "winning" to reshape mesolimbic dopamine signaling, thereby reducing drug-seeking behaviors and enhancing resilience to addiction.^[108]

References

[1]
Behavioral Functions of the Mesolimbic Dopaminergic System
The mesolimbic dopaminergic (ML-DA) system has been recognized for its central role in motivated behaviors, various types of reward, and, more recently, ...
[2]
Neurobiologic Processes in Drug Reward and Addiction - PMC
The review highlights the importance of the mesolimbic pathway in the development of an addiction—which thus may be an optimal site for intervention early ...
[3]
Dopaminergic Neurons and Brain Reward Pathways
Midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive ...
[4]
Dopamine anatomy - Scholarpedia
May 15, 2013 · These mesencephalic cell groups are designated as A8, A9, and A10, according to the nomenclature of Dahlström and Fuxe (1964), and generally ...
[5]
Stereological estimates of dopaminergic, GABAergic and ... - NIH
We therefore used unbiased stereological methods to estimate the number of dopaminergic, GABAergic and glutamatergic cells in these regions in the rat.Missing: composition | Show results with:composition
[6]
Glutamatergic and Dopaminergic Neurons in the Mouse Ventral ...
The ventral tegmental area (VTA) comprises dopamine (DA), GABA and glutamate (Glu) neurons. Some rat VTA Glu neurons, expressing vesicular glutamate transporter ...
[7]
Loss of Mitochondrial Fission Depletes Axonal Mitochondria in ...
Oct 22, 2014 · Although VTA DA neurons are also unmyelinated (R. Y. Wang, 1981; Nirenberg et al., 1997), they generally have fewer collaterals (Fallon and ...
[8]
Length of terminal axonal arbors labeled from single VTA neurons.
The length of the terminal axonal arbor that this neuron provided in M2/FrA, Tu and the AStr was of 68.31, 31.92, and 11.99 mm, respectively ( Table 5). ...
[9]
Ventral Tegmental Area - an overview | ScienceDirect Topics
The VTA is located in the ventral midbrain, medial to the substantia nigra (SN) pars compacta and ventral to the red nucleus.Nicotinic, Glutamatergic And... · Neural Correlates And... · 2 Ventral Tegmental Area<|control11|><|separator|>
[10]
Dopamine reward circuitry: two projection systems from the ventral ...
The medial tubercle receives extensive input from the posterior piriform cortex, lateral entorhinal cortex, dorsal peduncular cortex, and ventral tenia ...
[11]
Ventral tegmental area dopamine projections to the hippocampus ...
May 21, 2024 · We show that the stimulation of VTA dopamine terminals in the hippocampus can trigger the encoding of contextual memory while their inhibition ...
[12]
Dichotomous Dopaminergic Control of Ventral Pallidum Neurons
Dopaminergic afferents reach the VP from the ventral tegmental area (VTA). Recent in vivo studies suggest dopamine application increase the firing in the VP.Abstract · Introduction · Materials and Methods · Discussion
[13]
[PDF] efferents and afferents of the ventral tegmental-a10 region studied ...
The VMT-A10 efferents project to DA-rich areas, including mesolimbic and mesostriatal-mesolimbic projections. Descending projections go to the dorsal raphe, ...
[14]
Comparative anatomical analysis of dopamine systems in Mus ... - NIH
However, in common laboratory mice and rats such as Mus musculus and Rattus norvegicus, this anatomical division is absent (Haber and Knutson 2010; Joel and ...
[15]
Translational implications of the anatomical nonequivalence ... - PNAS
Dec 23, 2019 · This of course means that rats and mice are unlikely to be suitable surrogate models for primates (human and nonhuman) in studies of the ...Missing: mesolimbic | Show results with:mesolimbic
[16]
Tyrosine Hydroxylase and Regulation of Dopamine Synthesis - PMC
Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine biosynthesis; it uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to DOPA.
[17]
Dopamine synthesis and transport: current and novel therapeutics ...
May 30, 2024 · In dopaminergic neurons, TH catalyzes the hydroxylation of L-Tyr to L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA by aromatic ...
[18]
Regulation of the Dopamine and Vesicular Monoamine Transporters
DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into ...
[19]
Mechanisms and regulation of dopamine release - PMC
The mesolimbic pathway consists of dopamine neuron somata in the ventral ... exocytosis pathways in dendritic and terminal dopamine release in vivo.
[20]
Protein Kinase A Activity May Kinetically Upregulate the Striatal ...
Dec 15, 1998 · The neuronal dopamine transporter (DAT) plays a key role in terminating dopaminergic chemical neurotransmission; thus, the study of the ...
[21]
The Role of D2-Autoreceptors in Regulating Dopamine Neuron ...
Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine.
[22]
Dopamine Receptor Subtypes, Physiology and Pharmacology
Jul 14, 2020 · The dopaminergic system signals through “D1-like” D1 and D5 receptor subtypes and “D2-like”: D2Short (S), D2Long (L), D3 and D4 receptor ...
[23]
Functional implications of dopamine D1 vs. D2 receptors
Dec 12, 2014 · Cells of the direct pathway predominantly express the D1 DA receptor (D1DR) and the cells of the indirect pathway express the D2 DA receptor ( ...
[24]
Distribution of Dopamine D3 Receptor Expressing Neurons ... - Nature
Jan 1, 1999 · D3 binding sites and D3 mRNA positive neurons were most abundant in the limbic striatum and efferent structures, such as the nucleus accumbens, ...
[25]
Dopamine receptors – IUPHAR Review 13 - PMC - PubMed Central
Five subtypes of dopamine receptors (D1, D2, D3, D4 and D5 receptors, encoded in humans by genes DRD1, DRD2, DRD3, DRD4 and DRD5, respectively) are known to ...Coupling Of Dopamine... · Dopamine Receptor... · New Dopamine Receptor-Based...
[26]
The Signaling and Pharmacology of the Dopamine D1 Receptor
Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can ...Abstract · Introduction to D1R... · Signal Transduction Via the D1R
[27]
Decoding Dopamine Signaling - ScienceDirect.com
Jul 29, 2005 · When dopamine binds to Gαs-coupled D1 and D5 receptors, the enzyme adenylate cyclase is activated and the secondary messenger cAMP is produced.
[28]
Full article: Dopamine Receptor Signaling - Taylor & Francis Online
Sep 20, 2004 · Dopamine receptor signaling is mediated by G proteins. D1-like receptors use Gαs and Gαolf, while D2-like use Gαi and Gαo, activating various ...
[29]
Adenosine A2A-Dopamine D2 Receptor-Receptor Heteromerization
There is evidence for strong functional antagonistic interactions between adenosine A2A receptors (A2ARs) and dopamine D2 receptors (D2Rs).
[30]
Adenosine A2A-dopamine D2 receptor-receptor heteromerization
Nov 21, 2003 · There is evidence for strong functional antagonistic interactions between adenosine A2A receptors (A2ARs) and dopamine D2 receptors (D2Rs).Missing: crosstalk | Show results with:crosstalk
[31]
Evidence for Adenosine/Dopamine Receptor Interactions - Nature
All these findings suggest receptor subtype-specific interactions between adenosine and dopamine receptors that may be achieved by molecular interactions.
[32]
Influence of Phasic and Tonic Dopamine Release on Receptor ... - NIH
Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic ...Missing: seminal | Show results with:seminal
[33]
Hedonic Hot Spot in Nucleus Accumbens Shell: Where Do μ ...
Dec 14, 2005 · μ-Opioid systems in the medial shell of the nucleus accumbens contribute to hedonic impact (“liking”) for sweetness, food, and drug rewards.
[34]
Opioid Hedonic Hotspot in Nucleus Accumbens Shell: Mu, Delta ...
Mar 19, 2014 · Separable from hedonic impact, μ-opioid stimulation also increases the motivation to eat (“wanting”) both in the shell hotspot and at many ...
[35]
https://www.jneurosci.org/content/34/12/4239
[36]
Dopamine reward prediction error coding - PMC - NIH
Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards.
[37]
The Neuroscience of Natural Rewards: Relevance to Addictive Drugs
May 1, 2002 · Addictive drugs act on brain reward systems, although the brain evolved to respond not to drugs but to natural rewards, such as food and sex.
[38]
The Brain's Reward System in Health and Disease - PMC
Dopamine plays a critical role in mediating the reward value of food, drink, sex, social interaction, and substance abuse (Hernandez and Hoebel 1988; Everitt ...
[39]
[PDF] The debate over dopamine's role in reward: the case for incentive ...
What data indicate that mesolimbic dopamine activation amplifies incentive salience attributed to specific reward stimuli? Or that mesolimbic systems ...
[40]
From prediction error to incentive salience: mesolimbic computation ...
Incentive salience or 'wanting' is a specific form of Pavlovian-related motivation for rewards mediated by mesocorticolimbic brain systems (Figure 1) (Robinson ...Missing: pathway | Show results with:pathway
[41]
Dopamine neurons create Pavlovian conditioned stimuli with circuit ...
These results show that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals.Missing: operant | Show results with:operant
[42]
Mesolimbic dopamine adapts the rate of learning from action - Nature
Jan 18, 2023 · This work provides strong evidence that phasic dopamine activity can regulate direct learning of behavioural policies.
[43]
Anticipation of Appetitive Operant Action Induces Sustained ...
May 24, 2023 · The mesolimbic dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes.
[44]
Adolescent Dopamine Neurons Represent Reward Differently ... - NIH
Dopamine neurons in the VTA and SN have been implicated in operant and Pavlovian conditioning (Schultz, 1998; Dalley et al., 2002; Parkinson et al., 2002 ...
[45]
How Does Dopamine Release in the Nucleus Accumbens Core ...
Jun 19, 2013 · Overtraining of an instrumental response has been shown to favor automaticity of responding (habits), and this automaticity is correlated with a ...
[46]
Properties and Plasticity of Excitatory Synapses on Dopaminergic ...
May 15, 1999 · Because behavioral sensitization and long-term potentiation (LTP) share several features, it has been suggested that synaptic plasticity at ...
[47]
Synaptic plasticity in the mesolimbic dopamine system - Journals
Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that ...
[48]
Synaptic plasticity in the mesolimbic system - NIH
Excitatory synapses on VTA DA neurons exhibit both LTP, and LTD. ... Long-term potentiation at excitatory amino acid synapses on midbrain dopamine neurons.
[49]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2886008/
[50]
https://doi.org/10.1016/0165-0173(93)90013-p
[51]
https://doi.org/10.1073/pnas.85.14.5274
[52]
https://doi.org/10.1176/ajp.156.1.11
[53]
https://doi.org/10.1002/syn.890140210
[54]
https://doi.org/10.1038/386830a0
[55]
https://doi.org/10.1126/science.2820058
[56]
https://doi.org/10.7554/eLife.09275
[57]
The Dopamine Hypothesis of Schizophrenia: Version III—The Final ...
Mar 26, 2009 · Positive symptoms were hypothesized to result from striatal hyperdopaminergia ... schizophrenia are directly involved in dopaminergic pathways.
[58]
Schizophrenia, Dopamine and the Striatum - PubMed Central - NIH
Sep 28, 2018 · Early models of schizophrenia proposed that dysfunction of the mesolimbic pathway underlay positive psychotic symptoms (Box 1) [4]. Related ...
[59]
Dopamine System Dysregulation in Major Depressive Disorders
Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this ...Missing: hypoactivity | Show results with:hypoactivity
[60]
The Neurobiology of Anhedonia and Other Reward-Related Deficits
Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia, and other neuropsychiatric disorders.
[61]
Role of Mesolimbic Brain-Derived Neurotrophic Factor in Depression
(B,C) Chronic mild stress (CMS) decreases Ih and firing rate of VTA-to-NAc DA neurons. Some clinical and preclinical studies show antidepressant-like effect of ...
[62]
Evaluating Dopamine Reward Pathway in ADHD: Clinical Implications
Sep 9, 2009 · A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ...
[63]
ADHD, Altered Dopamine Neurotransmission, and Disrupted ...
Incentive salience, thought to elicit the the 'wanting' component of the reward response, is associated with mesolimbic dopamine release.
[64]
Reward sensitivity deficits modulated by dopamine are associated ...
Jul 24, 2016 · Muhammed et al. report that lack of sensitivity to rewards may underlie apathy, with dopamine playing a modulatory role. The study provides a ...
[65]
Apathy in Parkinson's Disease: Neurophysiological Evidence of ...
Apr 23, 2014 · Recently, defects involving the mesocorticolimbic system and reward processing have been proposed as possible etiopathogenic factors for apathy ...
[66]
Negative Symptoms of Schizophrenia and Dopaminergic ...
Jun 18, 2020 · Negative symptoms (NS) represent a heterogeneous dimension of schizophrenia (SCZ), associated with a poor functional outcome.
[67]
Mesocortical Pathway - an overview | ScienceDirect Topics
Mesocortical pathway From the VTA of the midbrain, mesocortical pathway, projects to the prefrontal cortex, especially the dorsolateral prefrontal cortex.
[68]
The Formation and Function of the VTA Dopamine System - MDPI
Contrarily, VTA dopamine neurons primarily project to the nucleus accumbens (NAc) and prefrontal cortex (PFC) via the mesolimbic and mesocortical pathways, ...<|control11|><|separator|>
[69]
The ability of the mesocortical dopamine system to operate in ...
This review discusses evidence that cells in the mesocortical dopamine (DA) system influence information processing in target areas across three distinct ...
[70]
The Four Dopamine Pathways Relevant to Antipsychotics ...
Jul 9, 2016 · Hypofunction of the mesocortical pathway might in part explain cognitive and negative symptoms of schizophrenia. D2 blockade of the ...
[71]
Dorsolateral Prefrontal Cortex Drives Mesolimbic Dopaminergic ...
Jul 13, 2011 · The dlPFC integrates and transmits representations of reward to the mesolimbic and mesocortical dopamine systems, thereby initiating motivated behavior.Fmri Data Acquisition · Results · Dcm Analysis<|control11|><|separator|>
[72]
Separate mesocortical and mesolimbic pathways encode effort and ...
Aug 14, 2017 · Using functional MRI, we show that the brain exploits separate mesolimbic and mesocortical networks to simultaneously learn about reward and effort attributes.
[73]
Neuroanatomy, Substantia Nigra - StatPearls - NCBI Bookshelf - NIH
The substantia nigra (SN) is a midbrain dopaminergic nucleus, which has a critical role in modulating motor movement and reward functions as part of the basal ...
[74]
Dopamine: Functions, Signaling, and Association with Neurological ...
The nigrostriatal pathway controls motor function and learning of new motor capabilities; this pathway is also involved in central pain modulation. The ...
[75]
Basal ganglia circuit loops, dopamine and motivation: A review and ...
Human research has emphasized the role of the nigrostriatal DA system and the BG in movement regulation, whose dysfunction leads to disorders such as Parkinson ...
[76]
Dopamine Release Dynamics in the Tuberoinfundibular Dopamine ...
Tuberoinfundibular dopamine (TIDA) neurons located in the dorsomedial arcuate nucleus (dmArc) provide a powerful suppressive influence on pituitary lactotrope ...
[77]
Physiology, Prolactin - StatPearls - NCBI Bookshelf
The specific mechanism involves non-selective D2 dopamine-receptor inhibiting in multiple dopaminergic pathways, including the tuberoinfundibular tract, where ...
[78]
Current Review of the Function and Regulation of ... - PubMed Central
Dec 21, 2023 · The DA then activates D2 receptors to inhibit prolactin (PRL) secretion from lactotrophs. The TIDA neuronal population is the principal ...
[79]
The place of dopamine in the cortico-basal ganglia circuit - PMC
The mesolimbic and nigrostriatal pathways are an integral part of the basal ganglia through its reciprocal connections to the ventral and dorsal striatum ...Iv. Connections · Iv. 1.1 The Striatum · Iv. 2. Afferent Projections
[80]
Toward whole-brain dopamine movies: a critical review of PET ...
Oct 25, 2017 · The positron emission tomography (PET) radiotracer, [C-11]raclopride, has been used widely to image DA receptors and DA changes in the mesolimbic pathway.
[81]
Striatal Dopamine Release in response to Morphine: a [11C]
Sep 1, 2020 · Here we quantify striatal DA release (measured by [ 11 C]-raclopride displacement) in response to an intravenous infusion of morphine.
[82]
SPECT imaging of dopamine D2 receptors with 123I-IBZM - PubMed
IBZM-SPECT has shown to be a suitable means for in vivo imaging of striatal dopamine D2 receptors in controls and various disorders of the dopaminergic system.Missing: mesolimbic pathway
[83]
Mesolimbic Functional Magnetic Resonance Imaging Activations ...
A key mechanism in mesolimbic reward processing is the phasic activity of dopamine-releasing SN/VTA neurons in response to unexpected rewards and reward- ...Missing: terminations | Show results with:terminations
[84]
Mesolimbic Activation Precedes Memory Formation - Cell Press
In the encoding task, high-reward cues preceding remembered but not forgotten scenes activated the ventral tegmental area, nucleus accumbens, and hippocampus.Fmri Results · Experimental Procedures · Fmri Data Analysis
[85]
Age-Related Trajectories of Functional Coupling between the VTA ...
Aug 22, 2018 · We show that in motivational contexts, there is increased state-dependent coupling across mesolimbic systems in preadolescence/early adolescence that decreases ...
[86]
Optogenetic stimulation of VTA dopamine neurons reveals that tonic ...
The results confirmed that optogenetic activation of VTA dopamine neurons can induce dopamine release in accumbal terminal fields with very high temporal and ...
[87]
Chemogenetic Manipulations of Ventral Tegmental Area Dopamine ...
Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors ...
[88]
Aging of the mesolimbic tract in the human brain: A diffusion tensor ...
Oct 14, 2022 · In the current study, we examined the aging of MLT in normal human participants to explain human brain structures using diffusion tensor ...
[89]
Aging of reward dopamine tracts in the human brain: A diffusion
Nov 17, 2023 · In the current study, we examined aging of the MCT and MLT in normal human participants to explain human brain structures using diffusion tensor ...
[90]
Human stem cell-derived A10 dopaminergic neurons specifically ...
Aug 11, 2025 · In this study, we present a new protocol to differentiate hPSCs into A10-like subtype-enriched mDA neurons by treating mDA neural progenitors ...
[91]
de novo missense mutation in PPP2R5D alters dopamine pathways ...
Oct 26, 2024 · Our work revealed that iPSC-derived midbrain neurons from Jordan syndrome patients display significant differences in dopamine-associated ...Missing: mesolimbic | Show results with:mesolimbic
[92]
Complex Pharmacodynamics of Aripiprazole and Haloperidol in ...
Oct 9, 2024 · The hyperactivity of dopamine in the mesolimbic pathway is associated with positive symptoms of schizophrenia, such as hallucinations and ...
[93]
Once-Monthly Long-Acting Injectable Aripiprazole for the Treatment ...
Feb 5, 2020 · Our study suggests that once-monthly LAI-aripiprazole retains its antipsychotic efficacy in patients with schizophrenia and a coexisting SUD.
[94]
[PDF] Aripiprazole, alcohol and substance abuse: a review
Jan 20, 2010 · Abstract. – Aripiprazole is an atypical an- tipsychotic used for schizophrenia, manic and mixed episodes associated with bipolar I disor-.
[95]
Deep brain stimulation for treatment-resistant major depressive ...
Sep 5, 2025 · The MFB shows promise as a DBS target for treatment-resistant depression, possibly a result of its involvement in the mesocortical and ...
[96]
Long-Term Success with Deep Brain Stimulation for Treatment ...
Apr 7, 2025 · After just two weeks of active DBS, over half the patients saw a 47% reduction in depression scores (as measured by the Montgomery-Åsberg ...
[97]
A systematic review and meta-analysis of neuromodulation ... - Nature
Dec 12, 2023 · We found that rTMS reduced substance use and craving, as indicated by medium to large effect sizes (Hedge's g > 0.5). Results were most ...
[98]
Harnessing neuroimaging-guided transcranial magnetic stimulation ...
Apr 16, 2025 · This review explores the neurobiology underlying SUDs, emphasizing the roles of the prefrontal cortex, striatal circuits, and dopaminergic ...<|separator|>
[99]
Pharmacogenetic role of dopamine transporter (SLC6A3) variation ...
We found that patients with genetically higher DAT levels had better treatment outcomes with disulfiram pharmacotherapy of cocaine dependence than those with ...
[100]
Pharmacogenetic Role of Dopamine Transporter (SLC6A3 ...
May 14, 2019 · Disulfiram has been beneficial in treating cocaine addiction in several studies. Patients with two SLC6A3 (DAT1) rs28363170 10-repeat alleles ...
[101]
Limbic System Response to Psilocybin and Ketamine Administration ...
Psilocybin exhibits no affinity for dopamine D2 receptors [21], but it interacts indirectly with mesolimbic dopaminergic pathways, which play a significant role ...
[102]
Effect of Psilocybin on the Positive Valence System in Treatment ...
Aug 18, 2025 · The mesolimbic circuit (VS, VTA) is the anatomical substrate of anticipation of rewarding stimuli (food, sex, drugs). The amygdala also fulfills ...
[103]
GDNF gene therapy for alcohol use disorder in male non-human ...
Aug 14, 2023 · This treatment approach, targeting chronic alcohol-induced deficits in mesolimbic DAergic function, has the potential to circumvent the reliance ...
[104]
Study shows promise of gene therapy for alcohol use disorder
Aug 14, 2023 · A form of gene therapy currently used in clinical trials to treat Parkinson's disease may dramatically reduce alcohol use among chronic heavy drinkers.Missing: mesolimbic | Show results with:mesolimbic