Two important dopaminergic cell groups are found in the midbrain
In the early 1960s, Swedish researchers first began to map the location of DA- and NE-containing nerve cells and fibers in the brain (Dahlstrom and Fuxe, 1964). They developed a classification system in which the catecholamine cell groups (clusters of neurons that stained for either DA or NE) were designated with the letter “A” plus a number from 1 to 16. According to this system, cell groups Al to A7 are noradrenergic, whereas groups A8 to A16 are dopaminergic. On this website, we will focus only a few catecholaminergic cell groups that are of particular interest to psychopharmacologists. To identify the various systems arising from these cells, we will use both the Swedish classification system and standard anatomical names.
Several dense clusters of dopaminergic neuronal cell bodies are located near the base of the mesencephalon (midbrain). Particularly important is the A9 cell group, which is associated with a structure called the substantia nigra, and the A10 group, which is found in a nearby area called the ventral tegmental area (VTA). Axons of dopaminergic neurons in the substantia nigra ascend to a forebrain structure known as the caudate-putamen or striatum. Nerve tracts in the central nervous system are often named by combining the site of origin of the fibers with their termination site. Hence, the pathway from the substantia nigra to the striatum is called the nigrostriatal tract. This tract is severely damaged in Parkinson’s disease (Box 5.1). Because the most prominent symptoms of Parkinson’s disease reflect deficits in motor function (for example, tremors, postural disturbances, and difficulty in initiating voluntary movements), it is clear that the nigrostriatal DA tract plays a crucial role in the control of movement.
Two other important ascending dopaminergic systems arise from cells of the VTA. Some of the axons from these neurons travel to various structures of the limbic system, including the nucleus accumbens, septum, amygdala, and hippocampus. These diverse projections constitute the mesolimbic dopamine pathway (“meso” represents mesencephalon, which is the site of origin of the fibers; “limbic” stands for the termination of fibers in structures of the limbic system). Other DA-containing fibers from the VTA go to the cerebral cortex, particularly the prefrontal area. This group of fibers is termed the mesocortical dopamine pathway. Together, the mesolimbic and mesocortical pathways are very important to psychopharmacologists because they have been implicated in the neural mechanisms underlying drug abuse and also schizophrenia.
A few other sites of dopaminergic neurons can be mentioned briefly. For example, there is a small group of cells in the hypothalamus that gives rise to the tuberohypophyseal dopamine pathway. This pathway is important in controlling the secretion of the hormone prolactin by the pituitary gland. There are also DA-containing neurons within sensory structures such as the olfactory bulbs and the retina.
To examine the role of catecholamines in behavior, researchers sometimes damage these systems in animals and then evaluate the resulting functional changes. Catcholamine pathways, particularly those using DA, can be lesioned using the substance 6-hydroxydopamine (6-OHDA). This substance is a neurotoxin, which means that it causes injury or death to nerve cells. To lesion the central dopaminergic system, one must administer 6-OHDA directly into the brain, since the drug doesn’t readily cross the blood-brain barrier. The toxin is taken up mainly by the catecholaminergic neurons (thus sparing neurons that use other neurotransmitters) due to its close structural similarity to DA. Once the toxin is inside, the nerve terminals are severely damaged and sometimes
the entire cell dies. Animals with bilateral 6-OHDA lesions of the ascending dopaminergic pathways show severe behavioral dysfunction. They exhibit sensory neglect (that is, they pay little attention to stimuli in the environment), motivational deficits (they show little interest in eating food or drinking water), and motor impairment (like patients with Parkinson’s disease, they have difficulty initiating voluntary movements). It is also possible to damage the nigrostriatal DA pathway on only one side of the brain. In this case, the lesioned animals display a postural asymmetry characterized by leaning and turning toward the damaged side of the brain due to the dominance of the untreated side. The profound abnormalities seen following either bilateral or unilateral lesions of the DA system indicate how important this neurotransmitter is for normal behavioral functioning.
There are five main subtypes of dopamine receptors organized into D1- and D2-like families
In the previous posts, we discussed the concept of receptor subtypes. The neurotransmitter DA uses five main subtypes, designated D1 to D5, all of which are metabotropic receptors. That is, they interact with G proteins and they function, in part, through second messengers. Various studies have shown that the D1 and D5 receptors are very similar to each other, whereas the D2, D3, and D4 receptors represent a separate family. The D1 and D2 receptors were discovered first, and they are also the most common subtypes in the brain. Both types of receptors are found in large numbers in the striatum and the nucleus accumbens, which are major termination sites of the nigrostriatal and mesolimbic DA pathways, respectively. Thus, D2 receptors not only function as autoreceptors, as mentioned earlier, but they also serve an important role as normal postsynaptic receptors. Interestingly, these receptors are additionally found on cells in the pituitary gland that make the hormone prolactin. Activation of D2 receptors by DA from the hypothalamus leads to an inhibition of prolactin secretion, whereas the blockade of these receptors stimulates prolactin release. All current antischizophrenic drugs are D2 receptor antagonists. In older studies, the receptor-blocking activity of these drugs was assessed by monitoring changes in circulating prolactin levels. Now, however, more direct information on receptor occupancy can be obtained by means of modern imaging techniques such as positron emission tomographic (PET) scanning.
In the early stages of research on DA receptors, investigators discovered that D1 and D2 have opposite effects on the second-messenger substance cyclic adenosine monophosphate (cAMP) (Kebabian and Caine, 1979). More specifically, D1 receptors stimulate the enzyme adenylyl cyclase, which is responsible for synthesizing cAMP. Consequently, the rate of cAMP formation is increased by stimulation of D1 receptors. In contrast, D2 receptor activation inhibits adenylyl cyclase, thereby decreasing the rate of cAMP synthesis. These opposing effects can occur because the receptors activate two different G proteins, Gs in the case of D1 receptors and G; in the case of D2 receptors. The resulting changes in the level of cAMP within the postsynaptic cell alter the cell’s excitability (that is, how readily it will fire nerve impulses) in complex ways that are beyond the scope of this discussion. A second important mechanism of D2 receptor function involves the regulation of membrane ion channels for potassium (K+). In some cells, D2 receptor stimulation activates a G protein that subsequently enhances K+ channel opening. Opening of such channels causes a hyperpolarization of the cell membrane, thus decreasing the cell’s excitability and rate of firing.
Dopamine receptor agonists and antagonists affect locomotor activity and other behavioral functions
Many studies of DA pharmacology have used compounds that directly stimulate or block DA receptors. Apomorphine is a widely used agonist that stimulates both D1 and D2 receptors. At appropriate doses, apomorphine treatment causes behavioral activation similar to that seen with classical stimulants like amphetamine and cocaine. There is also a new use for apomorphine in treating erectile dysfunction in men (marketed under the trade name Uprima). At present, the best-known remedy for this disorder is, of course, Viagra. You will recall that the mechanism of action of Viagra, which involves inhibiting the breakdown of cyclic guanosine monophosphate (cGMP) in the penis. In contrast, apomorphine seems to increase penile blood flow (which is necessary for an erection) by acting through DA receptors in the brain. This effect of apomorphine has actually been known for some time, but clinical application for this purpose was previously thwarted by undesirable side effects (particularly nausea) and poor drug availability when taken orally. These problems have been overcome to some extent through the development of a lozenge that is taken sublingually (under the tongue), thereby bypassing the digestive system and delivering the drug directly into the bloodstream.
Psychopharmacologists also make use of drugs that are more selective for members of the D1 or D2 receptor family. Receptor-selective agonists and antagonists are extremely important in helping us understand which behaviors are under the control of a particular receptor subtype. The most commonly used agonist for D1 receptors is a compound known as SKF 38393. Administration of this compound to rats or mice elicits self-grooming behavior. Quinpirole is a drug that activates D2 and D3 receptors, and its effect is to increase locomotion and sniffing behavior. These responses are reminiscent of the effects of amphetamine or apomorphine, although quinpirole is not as powerful a stimulant as the former compounds.
The typical effect of administering a DA receptor antagonist is to suppress spontaneous exploratory and locomotor behavior. At higher doses, such drugs elicit a state known as catalepsy. Catalepsy refers to a lack of spontaneous movement, which is usually demonstrated experimentally by showing that the subject does not change position when placed in an awkward, presumably uncomfortable posture. Nevertheless, the subject is neither paralyzed nor asleep, and in fact it can be aroused to move by strong sensory stimuli such as being picked up by the experimenter. Catalepsy is usually associated with D2 receptor blockers such as haloperidol, but it can also be elicited by giving a D blocker such as SCH 23390. Given the important role of the nigrostriatal DA pathway in movement, it is not surprising that catalepsy is particularly related to the inhibition of DA receptors in the striatum. We mentioned earlier that D2 receptor antagonists are used in the treatment of schizophrenia. The therapeutic benefit of these drugs is thought to derive from their blocking of DA receptors in the limbic system or the cortex. It should be clear from the present discussion, however, that the same drugs are also likely to produce inhibition of movement and other troublesome motor side effects because of the simultaneous interference with dopaminergic transmission in the striatum.
The various effects of DA receptor agonists and antagonists have given researchers a lot of useful information about the behavioral functions of DA. A newer approach is to manipulate the genes for individual components of the dopaminergic system and determine the behavioral consequences of such manipulations.
We will conclude this post by considering the consequences of administering a D2 receptor antagonist repeatedly rather than just once or twice. When haloperidol is given chronically to rats, the animals develop a syndrome called behavioral supersensitivity. This means that if the haloperidol treatment is stopped (to unblock the D2 receptors) and the subjects are then given a DA agonist like apomorphine, they respond more strongly than control subjects not pretreated with haloperidol. Since the experimental and control animals both received the same dose of apomorphine, this finding suggests that somehow the DA receptors in the experimental group are more sensitive to the same pharmacological stimulation. A similar effect occurs following DA depletion by 6-OHDA. The similarity between haloperidol and 6- OHDA administration is that both treatments persistently reduce the amount of DA stimulation of D2 receptors. Haloperidol accomplishes this by blocking the receptors, whereas 6-OHDA accomplishes the same result by causing a long-lasting depletion of DA. Various studies suggest that the supersensitivity associated with haloperidol or 6- OHDA treatment is related at least partly to an increase in the density of D2 receptors on the postsynaptic cells in the striatum. This phenomenon, which is called receptor up-regulation, is considered to be an adaptive response whereby the lack of normal neurotransmitter (in this case DA) input causes the neurons to increase their sensitivity by making more receptors.
The dopaminergic neurons of greatest interest to neuropsy-chopharmacologists are found near the base of the midbrain in the substantia nigra (A9 cell group) and the VTA (A10 cell group). The neurons in the substantia nigra send their axons to the striatum, thus forming the nigrostriatal tract. This pathway plays an important role in the control of movement. It is severely damaged in the neurological disorder known as Parkinson’s disease. The dopaminergic neurons in the VTA form two major dopaminergic systems. One is the mesolimbic system, which has terminations in several limbic system structures, including the nucleus accumbens, septum, amygdala, and hippocampus. The other is the mesocortical system, which terminates in the cerebral cortex, particularly the prefrontal cortex. The mesolimbic and mesocortical DA systems have been implicated in mechanisms of drug abuse as well as in schizophrenia.
Researchers have identified five main DA receptor subtypes, designated D1 to D5, all of which are metabotropic receptors. These subtypes fall into two families, the first consisting of D1 and D5 and the second consisting of D2, D3, and D4. The most common subtypes are D1 and D2, both of which are found in large numbers in the striatum and the nucleus accumbens. These subtypes can be differentiated partly on the basis that D, receptors stimulate adenylyl cyclase, thus increasing the rate of cAMP synthesis, whereas D2 receptors decrease the rate of cAMP synthesis by inhibiting adenylyl cyclase. Activation of D2 receptors can also enhance the opening of K+ channels in the cell membrane, which hyperpolarizes the membrane and therefore reduces the excitability of the cell.
TABLE 1 Drugs That Affect the Dopaminergic System
|DOPA||Converted to DA in the brain|
|Increases catecholamine levels by inhibiting MAO|
|CC-Methyl-para-tyrosine||Depletes catecholamines by inhibiting|
|Depletes catecholamines by inhibiting vesicular uptake|
|6-Hydroxydopamine (6-OHDA)||Damages or destroys catecholaminergic neurons|
|Cocaine and methylphenidate||Inhibit catecholamine reuptake|
|Apomorphine||Stimulates DA receptors generally (agonist)|
|SKF 38393 ‘||Stimulates Dj receptors (agonist)|
|Stimulates D2 and D3 receptors (agonist)|
|Blocks Dj receptors (antagonist)|
Blocks D2 receptors (antagonist)
Some of the drugs that affect the dopaminergic system, including DA receptor agonists and antagonists, are presented in Table 1. In general, enhancement of dopaminergic function has an activating effect on behavior, whereas interference with DA causes a suppression of normal behaviors ranging from temporary sedation and catalepsy to the profound deficits observed following 6-OHDA treatment. When D2 receptor transmission is persistently impaired either by chronic antagonist administration or by denervation (e.g., 6- OHDA lesions), animals become supersensitive to treatment with a D2 agonist. This response is mediated at least partially by an up-regulation of D2 receptors by postsynaptic neurons in areas such as the striatum.