Functional neuroanatomy of the basal ganglia

Dopamine

It is appropriate to start out the discussion of neurotransmitters with a consideration of dopamine, the most “prominent” neurotransmitter because it is depleted in PD and because we have the means to manipulate this transmitter in therapeutics. The main sources of dopamine are the lateral SNc (A9), the medial ventral tegmental area (VTA, A10), and the retrorubral area (A8) (see Fig. 3.2 ). The SNc innervates the striatum via the nigrostriatal pathway, and the VTA and retrorubal areas give rise to the mesolimbic innervation of the ventral striatum (nucleus accumbens) and the mesocortical innervation of the dorsolateral and ventromedial prefrontal cortex regions ( Fig. 3.4 ) ( ). Less appreciated is that the SNc also innervates the globus pallidus and subthalamic nucleus ( ), and that the thalamus also received dopamine input from a variety of sources ( ).

Dopamine is formed from levodopa (L-dopa) by the enzyme aromatic L-amino acid decarboxylase (AADC), which has been commonly called dopa decarboxylase ( Fig. 3.5 ) ( ). Once synthesized, dopamine is taken up into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2). In vivo, levodopa is synthesized from L-tyrosine by the enzyme tyrosine hydroxylase (TH). L-tyrosine is an essential amino acid in the brain, because it cannot be synthesized from L-phenylalanine, as it can in the rest of the body. Dopamine can be metabolized by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetic acid (DOPAC), by catechol-O-methyltransferase (COMT) to 3-methoxytyramine (3-MT) (also called 3-O-methydopamine), and by both enzymes serially to homovanillic acid (HVA). MAO exists in two forms, MAO-A and MAO-B, both found in the mitochondria of neurons and glia ( ). COMT is a membrane-bound enzyme ( ). Physiologically, dopamine action is terminated by reuptake into the dopaminergic nerve terminal by action of the dopamine transporter (DAT). Once in the cytosol, it can be taken back up into synaptic vesicles by VMAT2. Dopamine neurons have MAO-A (not MAO-B) ( ), but virtually no COMT. Dopamine not taken up into vesicles will therefore be metabolized to DOPAC. If dopamine remains nonmetabolized in the cytosol, it might contribute to oxidative stress, as discussed in Chapter 5 .

DOPAC can diffuse out of the presynaptic terminal, where it might confront COMT on the postsynaptic neuron, endothelial cells, or possibly glial cells and be converted to HVA. MAO-B is prominent in the basal ganglia and is largely in glial cells. Any dopamine not taken up in the presynaptic terminal might diffuse into glial cells (DAT is not necessary in nondopaminergic cells), where it would be converted to HVA. HVA and DOPAC eventually will diffuse out of cells and either into the circulation or into the cerebrospinal fluid via the choroid plexus.

The exact biology of dopamine differs in different parts of the body and even different parts of the brain. For example, in the cerebral cortex there is not much DAT so that after dopamine release, COMT is much more important in terminating dopamine action ( ).

There are five subtypes of dopamine receptors, D1 to D5, in two families, D1-like and D2-like ( ; ; ). The D1-like family, composed of D1 and D5, activates adenyl cyclase and causes conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Raising the concentration of cAMP is typically excitatory. The D2-like family, composed of D2, D3, and D4, inhibits adenyl cyclase and reduces the concentration of cAMP. Lowering cAMP is typically inhibitory. Some D2 receptors, called autoreceptors, are on the presynaptic side of dopamine synapses, regulating release by negative feedback. The dopamine receptors are G protein coupled and give rise to downstream effects in the postsynaptic cell in addition to modulating adenyl cyclase ( ).

Acetylcholine

Cholinergic neurons have two different types of roles ( ; ). One is as an interneuron, and the “giant aspiny interneuron” of the striatum is cholinergic ( ). A second role is as a projection neuron. There are two prominent cholinergic projection systems in the brain. The best known are the neurons of the basal forebrain, such as the nucleus basalis of Meynert, which innervate wide areas of cortex, are involved with functions such as memory, and are deficient in Alzheimer disease. The other is the set of projections from the meso-pontine tegmental complex, which includes the PPN. These are importantly involved in the basal ganglia motor system.

Acetylcholine (ACh) is synthesized in neurons from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme choline acetyltransferase (ChAT). After synthesis it is collected into vesicles by the enzyme vesicular ACh transporter (VAChT). Once released from the nerve terminals it is broken down by acetylcholinesterase (AChE), which is both presynaptic and postsynaptic, and butyrylcholinesterase (BuChE), also called pseudocholinesterase, that resides in glia ( ; ). The resultant choline is taken back up into the presynaptic cell by a choline transporter ( ).

The two broad classes of ACh receptors are nicotinic and muscarinic. Nicotinic receptors (nAChR) are ionotropic and are prominent outside the brain at the neuromuscular junction and autonomic ganglia, but are also in the brain ( ). Activation at an nAChR will open a nonselective cation channel allowing flow of sodium, potassium, and sometimes calcium. Muscarinic receptors (mAChR) are metabotropic and also found both inside and outside the brain. Activation at an mAChR couples to a variety of types of G proteins ( , ). There are many types of nAChR, and these are generally described by their subunit composition ( ). Designations of M ₁ to M ₅ are given to the mAChRs. Both nAChR and mAChR are found in the basal ganglia, and there are both excitatory and inhibitory effects.

Glutamate

Glutamate (Glu) is the primary excitatory neurotransmitter in the brain, and as such it has a prominent role in the excitatory cortical-striatal input and in the excitatory projection from the STN to the globus pallidus interna (GPi). Glu is a central molecule in many cellular processes and is also the precursor for the most important inhibitory neurotransmitter in the brain, GABA. Glu is made from glutamine in mitochondria by glutaminase. It is then taken up into synaptic vesicles by the vesicular glutamate transporter. On release, its action is terminated by its being taken up into glial cells via an excitatory amino acid transporter (EAAT) and then converted to glutamine by glutamine synthetase. Glutamine transporters then move the glutamine from the glial cell into the neuron ( ; ).

Glu receptor biology is very complex, and the details are well beyond this chapter ( ; ). There are three groups of metabotropic glutamate receptors (mGluR), groups I, II, and III, depending on mGluR composition. There are also three classes of ionotropic receptors, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), N-methyl-D-aspartic acid (NMDA) ( ), and the kainate (KA) receptors. Hence, glutamate not only transmits an excitatory signal by opening calcium channels, but also sets many metabolic processes in action, such as creating short- and long-term changes in synaptic excitability. Such changes are thought to be fundamental in brain plasticity ( ; ).

Gamma-amino butyric acid

GABA is the main inhibitory neurotransmitter in the brain, and this includes the major inhibitory connections in the basal ganglia. It is synthesized by glutamic acid decarboxylase (GAD) from glutamate. Once synthesized, it is collected into synaptic vesicles by vesicular inhibitory amino acid transporters. After release, its action is terminated by its being taken back into the presynaptic cell by the GABA transporter (GAT). If the nerve ending has too much GABA in it, it can be broken down by GABA transaminase (GABA-T).

There are three classes of GABA receptors: A, B, and C ( ; ). GABA-A and GABA-C are ionotropic and have inhibitory action by opening chloride and potassium channels. Much is known about GABA-A, but only little about GABA-C. GABA-A channels have many subclasses depending on the subunit makeup. An important distinction between subclasses is whether they are sensitive to benzodiazepines, depending on whether the benzodiazepines bind to them. In the sensitive channels, benzodiazepines can increase the inhibitory action of a GABA-A synapse. GABA-B is a metabotropic receptor ( ) and produces a longer duration inhibition than GABA-A by promoting potassium channels and inhibiting calcium channels.

Norepinephrine

NE influence on the basal ganglia comes from the strong projection to it from the LC ( ). NE is made from dopamine (in noradrenergic neurons) by the action of dopamine beta-hydroxylase (DBH). After synthesis, it is stored in vesicles by action of VMAT2 (similar to dopamine). After release, it is taken back up presynaptically by the NE transporter. Like dopamine, it can be metabolized by MAO-A, MAO-B, or COMT, but similar to dopamine, the main enzyme in the presynaptic terminal is MAO-A.

There are a large number of NE receptors; the different classes are alpha 1A, 1B, 1D, alpha 2A, 2B, 2C, and beta 1, 2, and 3 ( ). All can be postsynaptic, and the alpha 2 receptors also can be presynaptic. Activation of the presynaptic receptors inhibits further NE release. The alpha 1 receptors are G protein coupled, and increase levels of phospholipase C, inositol trisphosphate (IP3), and calcium. The alpha 2 receptors are G protein coupled, with an action to inactivate adenylate cyclase and reduce concentrations of cAMP. The beta receptors couple to G proteins that activate adenylate cyclase and increase cAMP.

Serotonin (5-hydroxytryptamine)

Serotonin (5-HT) influence on the basal ganglia comes from the MRN ( ). 5-HT is synthesized from the amino acid tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, and then 5-HTP is converted to 5-HT by aromatic amino acid decarboxylase (AADC). As with dopamine and NE, after synthesis, 5-HT is taken up into vesicles by the action of VMAT2. After release, it is metabolized by MAO-A or taken back up into the serotonergic neuron by the serotonin transporter (SERT). Serotonergic neurons contain both MAO-A and MAO-B.

There are many subtypes of 5-HT receptors ( ), categorized into seven families, 5-HT ₁ to 5-HT ₇ . 5-HT ₃ is a ligand-gated sodium (Na ⁺ ) and potassium (K ⁺ ) channel that depolarizes membranes. The other family members are G protein coupled. 5-HT ₁ and 5-HT _5A decrease cAMP; 5-HT ₄ , 5-HT ₆ , and 5-HT ₇ increase cAMP; 5-HT ₂ increases IP3 and diacylglycerol (DAG). 5-HT _1A and 5-HT _1B/D receptors are presynaptic and act to reduce 5-HT release, a negative feedback influence. Postsynaptic receptors include 5-HT _1A , 5-HT _1B/D , 5-HT _2A , 5-HT _2C , 5-HT ₃ , 5-HT ₄ , 5-HT ₅ , 5-HT ₆ , and 5-HT ₇ . Serotonin actions are complex. Activation of the 5-HT _1A receptor is generally inhibitory but also increases dopamine release. Activation of the 5-HT _2A receptor is generally excitatory but also inhibits dopamine release ( ). Monoamine interactions in general are very complex; for example, NE can influence 5-HT release and 5-HT can influence NE release.

Adenosine

Adenosine is a purine nucleoside and is an endogenous molecule in the brain ( ). Part of ATP, adenosine diphosphate (ADP), and cAMP, adenosine is a critical molecule in cellular energy metabolism, but it also plays a role as a neurotransmitter. Adenosine is found both intracellularly and extracellularly, and the concentration in the synaptic area is regulated by adenosine transporters ( ). There are four subtypes of adenosine receptors, A1, A2A, A2B, and A3, all G protein coupled. Caffeine is an important antagonist at the adenosine receptors. The A1 receptor is generally inhibitory, and the A2 receptors are excitatory, increasing levels of cAMP. Adenosine A2A receptors are colocalized with striatal dopamine D2 receptors on GABAergic medium spiny neurons (MSNs) that project via the “indirect” striatopallidal pathway to the globus pallidus externa (GPe) ( ; ). Adenosine at the A2A receptor reduces binding of dopamine to the D2 receptor, and an antagonist of adenosine, such as caffeine, therefore enhances dopamine binding ( ; ).