Dopaminergic System

Dopamine (DA) was originally thought to simply be a precursor of norepinephrine (NE) and epinephrine synthesis, but the demonstration that its distribution in the brain was quite distinct to that of NE led to extensive research demonstrating its role as a unique critical neurotransmitter. DA synthesis requires transport of the amino acid L-tyrosine across the blood-brain barrier and into the cell. Once tyrosine enters the neuron, the rate-limiting step for DA synthesis is conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa) by the enzyme tyrosine hydroxylase (TH); L-dopa is readily converted to dopamine and, hence, is used as a precursor strategy to correct a dopamine deficiency in the treatment of Parkinson's disease (Figure 1-4B). The activity of TH can be regulated by many factors, including the activity of catecholamine neurons; furthermore, catecholamines function as end-product inhibitors of TH by competing with a tetrahydrobiopterin cofactor (Cooper et al. 2001).

In contrast to the widespread 5-HT and NE projections, DA neurons form more discrete circuits, with the nigrostriatal, mesolimbic, tuberoinfundibular, and tuberohypophysial pathways comprising the major CNS dopaminergic circuits (Figure 1-4A). The nigrostriatal circuit is composed of DA neurons from the mesencephalic reticular formation (region A8) and the pars compacta region of the substantia nigra (region A9) of the mesencephalon. These neurons give rise to axons that travel via the medial forebrain bundle to innervate the caudate nucleus and putamen (see Anden et al. 1964; Ungerstedt 1971). The DA neurons that make up the nigrostriatal circuit have been assumed to be critical for maintaining normal motor control, since destruction of these neurons is associated with Parkinson's disease; however, it is now clear that these projections subserve a variety of additional functions. For example, recent evidence from human brain imaging studies indicates that a subject's ability to choose rewarding actions during instrumental learning tasks can be modulated by administration of drugs that enhance or reduce striatal DA receptor activation. This further implies that the DA reward pathway in the brain is likely convergent on many discrete brain circuits and neurotransmitter alterations, and it shows that striatal activity can also account for how the human brain proceeds toward making future decisions based on reward prediction (Pessiglione et al. 2006).

The mesolimbic DA circuit consists of DA neurons located in the midbrain just medial to the A9 cells in an area termed the ventral tegmental area (VTA) (Cooper et al. 2001; Nestler et al. 2001; Squire et al. 2003). This circuit shares some similarities to the nigrostriatal circuit in that it is a parallel circuit consisting of axons that make up the medial forebrain bundle. However, these axons ascend through the lateral hypothalamus and project to the nucleus accumbens, olfactory tubercle, bed nucleus of the stria terminalis, lateral septum, and frontal, cingulate, and entorhinal regions of the cerebral cortex (Cooper et al. 2001). This circuit innervates many limbic structures known to play critical roles in motivational, motor, and reward pathways and has therefore been implicated in a variety of clinical conditions, including psychosis and drug abuse (Cooper et al. 2001). Data also suggest a potential role for dopamine—and, in particular, mesolimbic pathways—in the pathophysiology of bipolar mania as well as bipolar and unipolar depression (Beaulieu et al. 2004; Dunlop and Nemeroff 2007; Goodwin and Jamison 2007; Roybal et al. 2007). It is perhaps surprising that the role of the dopaminergic system in the pathophysiology of mood disorders has not received greater study, since it represents a prime candidate on a number of theoretical grounds. The motoric changes in bipolar disorder are perhaps the most defining characteristics of the illness, ranging from the near-catatonic immobility of depressive states to the profound hyperactivity of manic states. Similarly, loss of motivation is one of the central features of depression, whereas anhedonia and "hyperhedonic states" are among the most defining characteristics of bipolar depression and mania, respectively. In this context, it is noteworthy that the midbrain dopaminergic system is known to play a critical role in regulating not only motoric activity but also motivational and reward circuits. It is clear that motivation and motor function are closely linked and that motivational variables can influence motor output both qualitatively and quantitatively. Furthermore, there is considerable evidence that the mesolimbic dopaminergic pathway plays a crucial role in the selection and orchestration of goal-directed behaviors, particularly those elicited by incentive stimuli (Goodwin and Jamison 2007).

The firing pattern of mesolimbic DA neurons appears to be an important regulatory mechanism; thus, in rats, electrical or glutamatergic stimulation of medial prefrontal cortex elicits a burst firing pattern of dopaminergic cells in the VTA and increases DA release in the nucleus accumbens (Murase et al. 1993; Taber and Fibiger 1993). The burst firing of DA cell activity elicits more terminal DA release per action potential than the nonbursting pacemaker firing pattern (Roth et al. 1987). The phasic burst firing of DA neurons and accompanying rise in DA release normally occur in response to primary rewards (until they become fully predicted) and reward-predicting stimuli. Such a role has also been postulated to provide a neural mechanism by which prefrontal cortex dysfunction could alter hedonic perceptions and motivated behavior in mood disorders (Drevets et al. 2002). Recent studies indicate that the amygdala is important in learning new cocaine drug-seeking responses as well as the habit-forming properties of cocaine (Lee et al. 2005), expanding our knowledge of drug addiction circuits in the brain.

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