Nucleus a ccumbens refers to a region in the basal forebrain and located in front of the preoptic area of the hypothalamus . I t is an aggregate of neurons consisting of an outer shell and an inner core . E ach cerebral hemisphere has its own nucleus accumbens. It is usually designated as NAc or NAcc and is also commonly referred to as either accumbens nucleus or nucleus accumbens septi (Scofield et al., 2016; Salgado & Kaplitt, 2015). Together with the olfactory tubercle, they form the ventral striatum . Both the ventral and dorsal striatum form the striatum, a major component of the basal ganglia. Dopaminergic neurons from the mesolimbic pathway project onto the GABAergic neurons of the nucleus accumbens. It is subdivided into sub - regions, each of which is responsible for different cognitive functions. The main cell types in the stri a tum are the GABAergic medium spiny neurons (MSN), which comprise approximately 90-95% of the total neuronal population. T hese types of cells are subdivided into two different sub - populations according to the type of dopamine receptor (D1 or D2) and also according to neuropeptide expression profil es.
N ucleus accumbens is responsible for the cognitive processing of motivation, aversion, reward, reinforcement learning, and induction of slow wave sleep . D ue to these functions , the region plays a vital role in the development of addition. The other lesser function s of this area of the brain include processing of fear, impulsivity, placebo effect and encoding of motor programs. The main inputs to this area are major glutamatergic inputs such as prefrontal cortex, basolateral amygdala, ventral hippocampus, and thalamic nuclei. The main dopaminergic input to the nucleus accumbens is ventral tegmental area via the mesolimbic pathway which modulate s GABAergic neurons . E uphoric drugs such as amphetamine and opiates also activate the neurons. Another major input to the nucleus accumbens is the hippocampus as well as histaminergic projections from the tuberomammillary nucleus (Scofield et al., 2016; Salgado & Kaplitt, 2015).
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The nucleus accumbens is a major structure of input in the basal ganglia . I t integrates information from the cortex and limbic structures in order to mediate goal - directed behavior. Chronic exposure to various classes of addictive drugs results in the disruption of the plasticity in this region . This allows the cues associated with addiction and drug taking to promote a pathologic motivation for the search of addictive drugs to self-administer. Several changes in the transmission of glutaminergic signals become apparent in the nucleus accumbens after withdrawal from a chronic addiction to drugs . T h i s drug - induced adaptation of the neuronic transmission is the molecular basis for addiction . It also increases vulnerability to relapse back to addiction.
Drug A ddiction
This is a pervasive neuropsychiatric disease which is currently associated with immense societal costs . These costs are in the form of impacts on job or learning performance, health, social break down as well as the resources deployed to combat peddling. The main behavioral disturbance that is produced by addition is the probability of relapsing back to addictive use even after long periods of withdrawal. This has significance for the research and development of behavioral therapies against addiction which have acceptable efficacy (Scofield et al., 2016; Salgado & Kaplitt, 2015). A ddiction to drugs can be thought of as a motivational, behavioral disturbanc e in which the underlying driver is the incentives that arise from the conditioning to addictive drugs. This is an abnormality and attempts have been made to explain it through theories such as incentive-sensitization theory and the allostatic – counteradaptive theory. Both t heories explain addiction as the consequence of the action of non - associative mechanisms at the level of incentive motivation expression and responding for drug reinforcement.
There are t wo basic properties of the motivational disturbance of drug addiction which are not explained by these theories. The first one is the focus on drugs rather than other non-drug incentives, and the other one is the virtual irreversibility. To account for these two aspects, an associative learning hypothesis was proposed by Di Chiara et al. (2002) . This hypothesis poses that the foundational disturbance resulting from drug addiction occurs at the level of acquisition of motivation, particularly of the Pavlovian incentive learning type. In drug addiction, the lack of habituation on repeated addictive drug exposure is due to the strengthening of the stimulus drug associations . This is a consequence of repeated, incremental stimulation of dopamine transmission in the nucleus accumbens septi shell by addictive drugs. Hence, the stimuli associated with drug reward takes on a powerful incentive property after a few instances of conditioning and become resistant to reversal.
The N eurobiological P rocesses U nderlying A ddiction
The neurophysiology that underlies the compulsive , uncontrollable behavior that defines drug addicti on entails t he critical changes that are key for the transition to a state of addictive drug use. Previously, only the mesolimbic dopaminergic efflux was associated with drug reward and hence considered the biologic equivalent of pleasure. It is now apparent that dopaminergic activation occurs in the presence of other new and unexpected stimuli that can either be pleasurable or aversive . It also appears to control the motivational state of wanting or expectation. The continuous release of dopamine which is especially associated with continuous drug use has the effect of progressively recruiting limbic brain regions and the prefrontal cortex. This results in the engraving of drug - related cues or signals into the amygdale employing glutaminergic mechanisms . This involves the anterior cingulate, amygdala, orbitofrontal cortex, and the dorsolateral prefrontal cortex during obsessive cravings for drugs. On succeeding occasions, the addicted brain gets primed to seek the use of drugs when triggered by contextual drug cues, a single use of the drug or stress . E ach process is defined by a relatively distinct region of the brain or neuronal pathway.The compulsion to go back to drug use is supported by deficits in impulse control and decision making . These are normally also mediated by the orbitofrontal cortex and the anterior cingulate (Sackett et al., 2017; Salgado & Kaplitt, 2015).
In contrast to addictive drugs, other conventional reinforcers such as food usually stimulate the transmission of dopamine in the nucleus accumbens in phases. This usually involve s the stimuli undergoing a one - time trial habituation to facilitate associative learning as confirmed by place and taste conditioning paradigm experimental models. Additive drugs and conventional reinforcers share the property of stimulation of transmission of dopamine in the nucleus accumbens shell . However, they differ in that as opposed to conventional stimuli that undergo a one - time trial habituation; the additive drugs are resistant to habituation. This peculiar resistance of addictive drugs to habituation imparts them with the ability to continually and repetitively activate dopamine transmission in the nucleus accumbens shell during every instance of their administration. This phenomenon results in a state in which associative learning is abnormal leading to excessive motivational value being attributed to the same stimuli . I n this case , the stimulus is the availability of an addictive drug. Thus , addiction is described as a state in which there is an expression of a much higher than normal control on behavior which is obtained from stimuli related to administration of addictive drugs, resulting from the abnormal intensification of the stimulus - drug relationship. This intensification is attributed to the stimulation of dopamine transmission in the nucleus accumbens due to continuous intake or administration of addictive drugs (Salgado & Kaplitt, 2015; Di Chiara et al., 1999).
The abnormal stimulant properties of dopamine which develop because of conditioning of stimuli by the use of additive drugs are thought to be the genesis of drug dependency or addiction syndromes. For instance, m icrodialysis studies of additive drugs in animal models have shown that the action of these drugs that results in increase d extracellular dopamine has a higher predilection for the nucleus accumbens. In humans , brain imaging studies have found a correlation between increased levels of extracellular dopamine in the striatum as a result of the action of psychostimulants, and the self - reported feeling of euphoria or being ‘high.' In studies involving administration with mixtures of dopamine (D1 and D2) receptor agonists, the nucleus accumbens has been proven to be an ideal site for dopamine reward. In animal models, the central role of dopamine in drug reward has been demonstrated through D2 or a combination of D1 and D2 blockade . This resulted in the abolition of cocaine, amphetamine , and nicotine conditional taste avoidance (CTA). In these animal studies, CTA was used as a correlate of drug reward independent from performance or associative learning (Di Chiara et al., 2004).
Role in Drug A ddiction
There is evidence of the modulating effect of the NAc on the brain ’s natural reward system . This is achieved through changes in the dopamine levels in the nucleus accumbens. All naturally r ewarding stimuli , for instance , food , is accompanied by an increase in dopamine in the Nac . However, t he levels of dopamine release decrease with repeated exposure and this comprises the normal functioning. This natural reward system may get overwhelmed and function abnormally . F or instance, in circumstances of addictive drug use , this system will fail to exhibit the waning dopamine release with repeated exposure to addictive drugs (Salgado & Kaplitt, 2015). Various substances have been shown to influence the nucleus accumbens . These include cocaine, opiates, ethanol, nicotine, tetrahydrocannabinol (THC), heroin, and polychlorophenol (PCP). Give n the NAc's role in conditioned behavioral activation and discrimination of behavioral responses, it has been hypothesized that a dopamine transmission in the NAc regulates the effort used to obtain a goal. As a result, alterations in the levels of dopamine in the NAc may play a critical role in the development of abuse and addiction. Hence, there is a viewpoint that the mesolimbic dopamine system is hypofunctional in the addicted brain, leading to a decrease in the interest in any non-drug related stimuli and an increase in the sensitivity to the drug of choice.
The actual function of dopamine in drug use has been hypothesized for a long time despite the fact that the relationship between dopamine and reward has been extensively researched. It is, however , important to note that addictive drugs, which are often abused, tend to exhibit an increase in dopamine release in the NAc . Also , they may change the synaptic plasticity . On the other hand, non - abused drugs, in general, do not affect the levels of dopamine in the NAc or cause a change in the synaptic plasticity. After an addictive behavior has been learned, groups of dopamine neurons in the NAc fire at differing levels. The firing of these neurons is usually in proportion to the time between drug infusions . T he firing occurs at various times which include the times between drug infusions, commonly referred to as the anticipatory response ; during drug exposure ; and in response to paired sensory stimuli or cue-induced d r ug seeking. Neuroimaging studies with current technology in human brains have made the link between the cue - induced reinforcement and the NAc less obvious . The f inding s have also link ed cues such as paraphernalia and images to increased levels of dopamine in the NAc. This discrepancy is however attributed to technical limitations of using the current technology (Salgado & Kaplitt, 201 5).
References
Di Chiara, G., Bassareo, V., Fenu, S., De Luca, M. A., Spina, L., Cadoni, C., ... & Lecca, D. (2004). Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology , 47 , 227-241.
Di Chiara, G. (2002). Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behavioural brain research , 137 (1-2), 75-114.
Di Chiara, G., Tanda, G., Bassareo, V., Pontieri, F., Acquas, E. L. I. O., Fenu, S., ... & Carboni, E. (1999). Drug addiction as a disorder of associative learning: role of nucleus accumbens shell/extended amygdala dopamine. Annals of the New York Academy of Sciences , 877 (1), 461-485.
Sackett, D. A., Saddoris, M. P., & Carelli, R. M. (2017). Nucleus Accumbens Shell Dopamine Preferentially Tracks Information Related to Outcome Value of Reward. eNeuro , 4 (3), ENEURO-0058. doi: https://doi.org/10.1523/ENEURO.0058-17.2017
Salgado, S., & Kaplitt, M. G. (2015). The nucleus accumbens: a comprehensive review. Stereotactic and functional neurosurgery , 93 (2), 75-93. doi: https://doi.org/10.1159/000368279
Scofield, M. D., Heinsbroek, J. A., Gipson, C. D., Kupchik, Y. M., Spencer, S., Smith, A. C. W., ... & Kalivas, P. W. (2016). The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacological reviews , 68 (3), 816-871.
