The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum, which is part of the basal ganglia.
Each cerebral hemisphere has its own nucleus accumbens (NAc or NAcc), which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.
As a whole, the nucleus accumbens has a significant role in the cognitive processing of aversion, motivation, reward (i.e., incentive salience, pleasure, and positive reinforcement), and reinforcement learning. It therefore has a significant role in addiction. It plays a lesser role in processing fear (a form of aversion), impulsivity, and the placebo effect. It is involved in the encoding of new motor programs as well.
The nucleus accumbens is an aggregate of neurons which is described as having an outer shell and an inner core.
Major inputs to the nucleus accumbens include the prefrontal cortex, basolateral amygdala, and dopaminergic neurons located in the ventral tegmental area (VTA), which connect via the mesolimbic pathway. Thus the nucleus accumbens is often described as one part of a cortico–basal ganglia–thalamic loop.
Dopaminergic input from the VTA modulate the activity of neurons within the nucleus accumbens. These neurons are activated directly or indirectly by euphoriant drugs (e.g., amphetamine, opiates, etc.) and by participating in rewarding experiences (e.g., sex, music, exercise, etc.).
Another major source of input comes from the CA1 and ventral subiculum of the hippocampus to the dorsomedial area of the nucleus accumbens. The neurons of the hippocampus have a noteworthy correlation to slight depolarizations of cells in the nucleus accumbens, which makes them more positive and therefore more excitable.
The correlated cells of these excited states of the medium spiny neurons in the nucleus accumbens are shared equally between the subiculum and CA1. The subiculum neurons are found to hyperpolarize (increase negativity) while the CA1 neurons “ripple” (fire > 50 Hz) in order to accomplish this priming.
The nucleus accumbens is one of the few regions that receive histaminergic projections from the tuberomammillary nucleus (the sole source of histamine neurons in the brain).
The output neurons of the nucleus accumbens send axonal projections to the basal ganglia and the ventral analog of the globus pallidus, known as the ventral pallidum (VP). The VP, in turn, projects to the medial dorsal nucleus of the dorsal thalamus, which projects to the prefrontal cortex as well as the striatum.
The nucleus accumbens shell is a substructure of the nucleus accumbens. The shell and core together form the entire nucleus accumbens.
The shell is the outer region of the nucleus accumbens, and – unlike the core – is considered to be part of the extended amygdala, located at its rostral pole.
Neurons in the nucleus accumbens are mostly medium spiny neurons (MSNs) containing mainly D1-type (i.e., DRD1 and DRD5) or D2-type (i.e., DRD2, DRD3, and DRD4) dopamine receptors. A subpopulation of MSNs contain both D1-type and D2-type receptors, with approximately 40% of striatal MSNs expressing both DRD1 and DRD2 mRNA. Mixed type NAcc MSNs with both D1-type and D2-type receptors are mostly confined in the NAcc shell.
The neurons in the shell, as compared to the core, have a lower density of dendritic spines, less terminal segments, and less branch segments than those in the core. The shell neurons project to the subcommissural part of the ventral pallidum as well as the ventral tegmental area and to extensive areas in the hypothalamus and extended amygdala.
The shell of the nucleus accumbens is involved in the cognitive processing of reward perception, subjective “liking” reactions to certain pleasurable stimuli, incentive salience for rewarding stimuli (specifically, the NAcc shell determines the value of and assigns the “desire” or “wanting” attribute of a stimulus), and positive reinforcement.
A “hedonic hotspot” or pleasure center which is responsible for the pleasurable or “liking” component of some intrinsic rewards is also located in a small compartment within the NAcc shell.
The subset of ventral tegmental area projection neurons that synapse onto the D1-type medium spiny neurons in the shell appear to be responsible for immediate drug reward (i.e., “wanting"). Addictive drugs have a larger effect on dopamine release in the shell than in the core. D2-type medium spiny neurons in the shell appear to be associated with aversion-related cognition.
The nucleus accumbens core is the inner substructure of the nucleus accumbens.
The nucleus accumbens core is part of the ventral striatum, located within the basal ganglia.
The core of the NAcc is made up mainly of medium spiny neurons containing mainly D1-type or D2-type dopamine receptors. The neurons in the core, as compared to the neurons in the shell, have an increased density of dendritic spines, branch segments, and terminal segments.
From the core, the neurons project to other sub-cortical areas such as the globus pallidus and the substantia nigra. GABA is one of the main neurotransmitters in the NAcc, and GABA receptors are also abundant.
The nucleus accumbens core is involved in the cognitive processing of motor function related to reward and reinforcement. Specifically, the core encodes new motor programs which facilitate the acquisition of a given reward in the future.
Approximately 95% of neurons in the NAcc are GABAergic medium spiny neurons (MSNs) which primarily express either D1-type or D2-type receptors; about 1–2% of the remaining neuronal types are large aspiny cholinergic interneurons and another 1–2% are GABAergic interneurons.
Compared to the GABAergic MSNs in the shell, those in the core have an increased density of dendritic spines, branch segments, and terminal segments.
From the core, the neurons project to other sub-cortical areas such as the globus pallidus and the substantia nigra. GABA is one of the main neurotransmitters in the NAcc, and GABA receptors are also abundant. These neurons are also the main projection or output neurons of the nucleus accumbens.
Dopamine is related to recreational drugs including amphetamines, cocaine, and morphine, which increase extracellular levels of dopamine in both the NAc shell and the NAc core, but the effect of these increases is more pronounced in the shell. Only amphetamine at high levels increases extracellular levels of dopamine to similar levels in both the shell and the core.
All of this points to a ‘functional heterogeneity’ in the nucleus accumbens between the shell region and the core region.
Similarly to drug rewards, non-drug rewards also increase levels of extracellular dopamine in the NAc shell, but drug induced DA increase is more resilient to habituation when exposed repeatedly to drug-stimuli, unlike non-drug rewarding stimuli induced dopamine increases, which do succumb to habituation.
Studies have shown that the repeated influence of drug-inducing DA projection has an abnormal strengthening effect on stimulus-drug associations and increases the drug-reward stimuli’s resistance to extinction. This may be a contributing factor to addiction. This effect was more pronounced in the NAc shell than in the NAc core.
Phenethylamine And Tyramine
Phenethylamine and tyramine are trace amine compounds which are synthesized in several types of CNS neurons, including all dopamine neurons. Specifically, these neurotransmitters act within the dopaminergic inputs to the NAcc. These substances regulate the presynaptic release of dopamine through their interactions with VMAT2 and TAAR1, analogous to amphetamine.
Glucocorticoids And Dopamine
Glucocorticoid receptors are the only corticosteroid receptors in the nucleus accumbens shell. L-DOPA, steroids, and specifically glucocorticoids are currently known to be the only known endogenous compounds that can induce psychotic problems, so understanding the hormonal control over dopaminergic projections with regards to glucocorticoid receptors could lead to new treatments for psychotic symptoms.
A recent study demonstrated that suppression of the glucocorticoid receptors led to a decrease in the release of dopamine, which may lead to future research involving anti-glucocorticoid drugs to potentially relieve psychotic symptoms.
A recent study on rats that used GABA agonists and antagonists indicated that GABAA receptors in the NAc shell have inhibitory control on turning behavior influenced by dopamine, and GABAB receptors have inhibitory control over turning behavior mediated by acetylcholine.
Studies have shown that local blockade of glutamatergic NMDA receptors in the NAcc core impaired spatial learning. Another study demonstrated that both NMDA and AMPA (both glutamate receptors) play important roles in regulating instrumental learning.
Overall, 5-HT synapses are more abundant and have a greater number of synaptic contacts in the NAc shell than in the core. They are also larger and thicker, and contain more large dense core vesicles than their counterparts in the core.
Reward And Reinforcement
The nucleus accumbens, being one part of the reward system, plays an important role in processing rewarding stimuli, reinforcing stimuli (e.g., food and water), and those which are both rewarding and reinforcing (addictive drugs, sex, and exercise). The nucleus accumbens is selectively activated during the perception of pleasant, emotionally arousing pictures and during mental imagery of pleasant, emotional scenes.
A 2005 study found that it is involved in the regulation of emotions induced by music, perhaps consequent to its role in mediating dopamine release. The nucleus accumbens plays a role in rhythmic timing and is considered to be of central importance to the limbic-motor interface.
In the 1950s, James Olds and Peter Milner implanted electrodes into the septal area of the rat and found that the rat chose to press a lever which stimulated it. It continued to prefer this even over stopping to eat or drink. This suggests that the area is the “pleasure center” of the brain and is involved in reinforcement learning.
In rats, stimulation of the ventral tegmental area causes the release of dopamine in the nucleus accumbens much in the same way as addictive drugs and natural reinforcers, such as water or food, initiate the release of dopamine in the nucleus accumbens. The same results have been seen in human subjects in functional imaging studies.
Activation of D1-type MSNs in the nucleus accumbens is involved in reward, whereas the activation of D2-type MSNs in the nucleus accumbens promotes aversion.
An fMRI study conducted in 2005 found that when mother rats were in the presence of their pups the regions of the brain involved in reinforcement, including the nucleus accumbens, were highly active. Levels of dopamine increase in the nucleus accumbens during maternal behavior, while lesions in this area upset maternal behavior.
When women are presented pictures of unrelated infants, fMRIs show increased brain activity in the nucleus accumbens and adjacent caudate nucleus, proportionate to the degree to which the women find these infants “cute”.
Current models of addiction from chronic drug use involve alterations in gene expression in the mesocorticolimbic projection. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).
ΔFosB is the most significant gene transcription factor in addiction since its viral or genetic overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction; it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, opiates, and substituted amphetamines.
ΔJunD is the transcription factor which directly opposes ΔFosB. Increases in nucleus accumbens ΔJunD expression can reduce or, with a large increase, even block most of the neural alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).
ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Natural rewards, like drugs of abuse, induce ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.
Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards as well; in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.
Research on the interaction between natural and drug rewards suggests that psychostimulants and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess cross-sensitization effects that are mediated through ΔFosB.
In April 2007, two research teams reported on having inserted electrodes into the nucleus accumbens in order to use deep brain stimulation to treat severe depression. In 2010, experiments reported that deep brain stimulation of the nucleus accumbens was successful in decreasing depression symptoms in 50% of patients who did not respond to other treatments such as electroconvulsive therapy.
Activation of the NAcc has been shown to occur in the anticipation of effectiveness of a drug when a user is given a placebo, indicating a contributing role of the nucleus accumbens in the placebo effect.
Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, eds. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. ISBN 978-0-07-148127-4