The nucleus accumbens

The NAc is the major component of the ventral striatum, and of the so-called limbic striatum. This striatal region corresponds to the entire anterior and ventromedial sector of the striatum and continues anteriorly into the NAc and the olfactory tubercle (Heimer and Wilson, 1975 Nauta, 1989). In the NAc, the principal neurons, which are the medium spiny projection neurons, make up approximately 90% of the total neuronal population and are generally similar to those of the striatal (i.e., neostriatal) counterpart. The local circuit neurons represent approximately 10% of the NAc neurons and vary greatly in size, 

A compartmental inhomogeneous organization of neuropeptides, DA and calbindin has been demonstrated in the NAc, but overall the chemoarchitecture and connectivity indicated that the NAc is not organized into patch and matrix compartments equivalent to those in the dorsal striatum, but is instead organized in several compartments with different chemoarchitectural features and different input-output relationships (Voorn et al., 1989). 

Intense investigations on the cellular and molecular chemical neuroanatomy of the NAc, as well as on its connections, neuropharmacology and electrophysiology, have identified two main sub territories, namely the shell and the core (initially identified by Herkenham et al., 1984 Zaborsky, 1985) a third subdivision, represented by the rostral pole, has also been recognized (see for review Kelly, 1999 Meredith, 1999 Zham, 1999, 2000). The organization in subregions has led to theories on a modular function of the NAc as a complex of neuronal ensembles (Pennartz et al., 1994). The shell and the core of the NAc have been demarcated also in primates, and calbindin is the most consistent marker for the shell across species (Haber, 1999). 

The NAc core and the shell show differences in their input-output organization. For example, although hippocampal projections reach both the core and the shell, the ventral subiculum projects to the shell, whereas the dorsal subiculum projects to the core. Different regions of the prefrontal cortex also target differentially the shell and core the prelimbic area projects to the core, whereas the infralimbic and piriform cortices project to the shell (Berendse et al., 1992). Amygdaloid fiber subsets are also differentially distributed to the two main NAc territories. 

The NAc shell is a distinct region, not only due to its chemoarchitectural and pharmacological organization, but also on the basis of its preferential projections to 

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Olive MF, Koenig HN, Nannini MA et al (2001) Stimulation of endorphin neurotransmission in the nucleus accumbens by ethanol, cocaine, and amphetamine. J Neurosci 21 1-5... 

The shell of the nucleus accumbens, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala, together referred to as the extended amygdala, may play a role in diug addiction. 

The nucleus accumbens is part of the limbic system. It receives dopaminergic input through the mesolimbic system that originates from cell bodies in the ventral segmental area (A 10 cell group). This mesolimbic dopaminergic pathway is part of the reward pathways. Drugs of abuse (cocaine, amphetamine, opiates or nicotine) have been shown to increase the level of dopamine release in these neurons. 

It has been suggested that modafinil increases wakefulness by activating ai noradrenergic receptors or hypothalamic cells that contain the peptide hypocre-tin [3], or that it may act by modulating the GABAergic tone that might lead to an increased dopamine release in the nucleus accumbens. On the other hand, modafinil does not have any effect in DAT knockout mice. 

Swartz CM, Breen K, Leone F Serum prolactin levels during extended cocaine abstinence. AmJ Psychiatry 147 777—779, 1990 Sziraki I, Sershen H, Hashim A, et al Receptors in the ventral tegmental area mediating nicotine-induced dopamine release in the nucleus accumbens. Neurochem Res 27 253-261, 2002... 

Yan QS Activation of 5-HT2a/2C receptors within the nucleus accumbens increases local dopaminergic transmission. Brain Res Bull 31 75-81, 2000... 

Pontieri FE, Tanda G, Orzi F, et al Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382 235-237, 1996 Pontieri FE, Zocchi A, Orzi F Mapping of functional changes associated with administration of substances of abuse in the rat. Funct Neurol 13 311-326, 1998 Preble E, Laury GV Plastic cement the ten cent hallucinogen. Int J Addict 2 271— 272, 1967... 

In other brain areas which receive a DA input, such as the nucleus accumbens and prefrontal cortex, it appears to be inhibitory and predominently D2-mediated. This is clear from Fig. 7.5 which shows inhibition by apomorphine (mixed D2, Di agonists) of the firing of neurons in the medial prefrontal cortex of the anaesthetised rat and its antagonism by the D2 antagonist haloperidol. 

These are, of course, extracellular recordings but more recent intracellular studies in both rat and guinea pig accumbens slices show that DA produces a D2-mediated depolarisation and a Di hyperpolarisation which appear to be dependent on decreased and increased K+ conductances respectively. This would certainly fit in with the belief that DA mediates the positive effects of schizophrenia by a D2-mediated stimulation of the nucleus accumbens (see Chapter 17). 

As a result of these observations it has been suggested that DA released in the nucleus accumbens is important in motivation by linking reward (especially when it is food) with the motor activity required to achieve it (Mogenson, Jones and Yim 1980). It is difficult, however, to distinguish a pure behavioural role for DA in actually initiating the sense of reward and motivation from its undisputed part in facilitating the motor response necessary to obtain the reward, e.g. a lever press in rats. 

Salamone, Cousins and Snyder (1997) in fact suggest that the function of DA in the nucleus accumbens should not be described by terms such as motivation, reinforcement and reward. Rather it should be considered to mediate the higher-order motor and sensory processes that are important for the activation of aspects of motivation and responsiveness to conditioned stimuli. 

There is some loss (40-60%) of DA in the nucleus accumbens of the mesolimbic system in the ventral tegmentum (AlO) and cortex at post-mortem but nowhere is it as marked as in the striatum. Some loss of NA, 5-HT, CCK and the enkephalins and of the markers GAD and ChAT (for GABA and ACh) have been reported in the striatum, SN and other areas but these rarely exceed 50% and could be secondary to DA loss. 

The mesolimbic from the ventral tegmentum (VTA, AlO) to the nucleus accumbens, olfactory tubercule, amygdala and pyriform cortex... 

Although there is no evidence that the DA afferents to DLPFC are damaged in schizophrenics, if the cortical pathology does reduce the ability of DA to function there, this would be equivalent to deafferentation and, as in the experimental studies, lead to increased subcortical mesolimbic activity and positive symptoms (Fig. 17.3). Unfortunately there is no good evidence that the nucleus accumbens is more active in schizophrenics or is even the origin of positive symptoms (but see Animal models ). Nevertheless it is a useful working hypothesis. 

Measuring the expression of the early-immediate gene c-fos supports the striatal role of neuroleptics in the induction of EPSs because although all neuroleptics induce such expression in both the nucleus accumbens and striatum, the atypical neuroleptics do so more in the accumbens while clozapine, but not risperidone, also achieve it in the prefrontal cortex (Robertson, Matsumura and Fibiger 1994). How this arises is uncertain but since risperidone is a more potent 5-HT2 antagonist than clozapine, it cannot be through that mechanism. 

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