Central Functions

It is perhaps easier to identify some of the central functions of DA than that of the other monoamines because not only does it have distinctive central pathways associated with particular brain areas, but it has few peripheral actions. Also the actions of its antagonists reveal its central effects. These are summarised in Table 7.4.

Table 7.4 Summary of dopamine function

Function

Pathways

Effect of DA agonist

Effect of DA antagonist

Receptor

Control of motor function

Initiation of behaviour

Control (inhibition) of prolactin release

Emesis

Nigrostriatal tract from substantia nigra (A9)

Mesolimbic pathway to nucleus accumbens from YTA (AIO) Mesocortical pathways to prefrontal cortex from YTA (AIO) Tuberoinfundibular tract from A12 in the arcuate nucleus of the median eminence to pituitary No distinct pathway DA receptors in chemoreceptor pathway zone

Animals: Stereotypy. Rotation if one tract is lesioned Humans: Induces dyskinesias

Effective in Parkinsonism Animals: Increases locomotor activity and intracranial self-stimulation Humans: Hallucinations, psychoses (reward, reinforcement) Humans: Hypoprolactaemia

Vomiting

Animals: Catalepsy

Humans: Reduces dyskinesias Induces Parkinsonism

Animals: Decreases activity and self-stimulation

Humans: Reduces positive symptoms of schizophrenia

Humans: Hyperprolactaemia Galactorrhoea Amenorrhoea

Anti-emetic (not motion sickness)

DA antagonists are anti-emetic, elevate plasma prolactin and have major motor and behavioural effects. Thus DA must be involved in the initiation of vomiting, the secretion of prolactin and control of motor and behavioural activity. Its role in emesis and as the prolactin release inhibitory factor have been adequately covered above. Its motor and behavioural function will now be considered.

MOTOR ACTIVITY

People with Parkinson's disease show a specific degeneration of the nigrostriatal tract so DA must be linked in some way to the control of motor function. It is also known that an imbalance of DA function on the two sides of the rat brain, either by stimulation or lesion of one SN, causes off-line or rotational movement (Ungerstadt and Arbuthnott 1970). This is best shown some days after 6-OHDA lesion of one substantia nigra and its nigrostriatal pathway when systemic apomorphine (DA agonist) causes animals to turn away from the lesioned side (contraversive), presumably

Dopaminergic Pathway Motor Function

Figure 7.7 Dopamine-induced rotation in the rat in which one (left) nigrostriatal dopamine pathway from the substantia nigra (SN) to the caudate putamen (CP) has been lesioned by a prior injection (14 days) of 6-hydroxydopamine. Amphetamine, an indirectly acting amine, releases DA and so can only act on the right side. Since the animal moves away from the dominating active side it induces ipsilateral rotation (i.e. towards the lesioned side). By contrast, the development of postsynaptic supersensitivity to DA on the lesioned side ensures that apomorphine, a directly acting agonist, is actually more active on that side and so the animal turns away from it (contralateral rotation)

Figure 7.7 Dopamine-induced rotation in the rat in which one (left) nigrostriatal dopamine pathway from the substantia nigra (SN) to the caudate putamen (CP) has been lesioned by a prior injection (14 days) of 6-hydroxydopamine. Amphetamine, an indirectly acting amine, releases DA and so can only act on the right side. Since the animal moves away from the dominating active side it induces ipsilateral rotation (i.e. towards the lesioned side). By contrast, the development of postsynaptic supersensitivity to DA on the lesioned side ensures that apomorphine, a directly acting agonist, is actually more active on that side and so the animal turns away from it (contralateral rotation)

because the denervated striatum has become supersensitive and therefore more responsive than the control side to the DA agonist. Conversely, the indirectly acting amine amphetamine promotes movement towards the lesioned side (ipsiversive) because it can only release DA in the intact striatum (Fig. 7.7). Thus animals move away from the side with the most responsive and active striatum. These drugs also produce other motor activity including increased locomotion and a so-called 'stereotype' behaviour in which rats sniff avidly around the cage and spend much time licking and rearing. It appears that stereotypy is due to activation of the nigrostriatal pathway as it is absent after lesion of the substantia nigra and follows apomorphine and amphetamine injection into the striatum, whereas locomotor responses to amphetamine are reduced by lesions to A10 and can be induced by its injection into the nucleus accumbens.

Another indication of the importance of DA in motor control is the observation that in humans its precursor levodopa, and DA agonists like bromocriptine, not only overcome the akinesia of Parkinsonism but in excess will actually cause involuntary movements, or dyskinesia (Chapter 14). Also it is well known that DA antagonists like chlorpromazine and haloperidol produce Parkinsonian-like symptoms in humans (and catalepsy in animals) and, as indicated above, reduce the dyskinesia of Huntington's Chorea. Thus DA seems to sit on a knife edge in the control of motor function (Fig. 7.8).

PSYCHOSES

The main use clinically of DA antagonists is in the treatment of schizophrenia (Chapter 17) and the control of mania. Since psychotic symptoms are also a side-effect of levodopa therapy in Parkinsonism and as amphetamine causes hallucinations and schizophrenic-like symptoms in humans, presumably by releasing DA, it appears that DA also has an important part to play in the control and induction of psychotic symptoms. It is possible that the role of DA in psychosis is mediated primarily through the mesolimbic and mesocortical pathways and its control of motor function through the striatum, and there is evidence that the neurons from which these pathways arise have different characteristics. Although there is some overlap between the various DA nuclei in respect of the location of the cell bodies of the neurons that give rise to the different DA pathways, neurons can be identified by antidromic activation of their terminal axons in the appropriate projection areas. Recordings from neurons so identified show that they have differing firing patterns. Those cells innervating the prefrontal cortex fire at a much higher rate (9.7 Hz) than those to the cingulate and piriform cortex (5.9 or 4.3) and the striatum (3.1). Unlike the NA neurons they are also remarkably little affected by the state of the animal, i.e. its wake-sleep cycle. The cells in A10 which form the mesocortical pathway are also less easily inhibited by DA agonists suggesting that they probably have fewer autoreceptors. Unfortunately it seems that the DA postsynaptic receptor is the same at both sites so it has been difficult to divorce the antischizophrenic from the extrapyramidal-inducing activity of DA antagonists (see Chapter 16).

REWARD AND REINFORCEMENT

We expect reward to be pleasurable and it is assessed in animals by their willingness to seek and approach something, such as a lever linked to either food dispensing or brain

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