Dopamine (A*)

Question 1

Where do the central dopaminergic pathways originate?

Answer 1

Central dopaminergic pathways originate in the A8-15 dopaminergic cell groups in the midbrain.

Question 2

List the 4 central dopaminergic pathways.

Answer 2

Central dopaminergic pathways include:

1 - Dorsal mesostriatal (nigrostriatal) system.

2 - Ventral mesostriatal (mesolimbic) system.

3 - Mesocorticolimbic (mesocortical) system.

4 - Mesodiencephalic (mesopontine) system.

Question 3

Describe the pathway of the dorsal mesostriatal (nigrostriatal) system.

List 2 functional implications of the this pathway.

Answer 3

• The dorsal mesostriatal (nigrostriatal) system originates from the A8 and A9 cell groups.
• The A8 cell group is located in the reticular formation.
• The A9 cell group is in the substantia nigra pars compacta of the basal ganglia.
• These cell groups project axons through the medial forebrain bundle.
• These axons synapse at the caudate and putamen in the dorsal striatum of the basal ganglia.

Functional implications include:

1 - Dysfunction of the dorsal mesostriatal (nigrostriatal) system is responsible for Parkinson’s disease.

2 - Influencing voluntary movement through modulation of the basal ganglia.

Question 4

Describe the pathway of the ventral mesostriatal (mesolimbic) system.

List 2 functional implications of the this pathway.

Answer 4

• The ventral mesostriatal (mesolimbic) system originates from the A10 cell group.
• The A10 cell group is located in the ventral tegmental area.
• This cell group projects axons through the medial forebrain bundle.
• These axons synapse at the nucleus accumbens in the ventral striatum.

Functional implications include:

1 - Hyperactivity of the ventral mesostriatal (mesolimbic) system is responsible for the positive symptoms of schizophrenia.

2 - Associated with the reward pathway, and therefore motivation and addiction.

Question 5

Describe the pathway of the mesocorticolimbic (mesocortical) system.

List 3 functional implications of the this pathway.

Answer 5

• Like the ventral mesostriatal (mesolimbic) system, the mesocorticolimbic (mesocortical) system originates from the A10 cell group.
• The A10 cell group is located in the ventral tegmental area.
• This cell group has more widespread connections than the other two systems, projecting axons to many sites such as the:

1 - Prefrontal cortex.

2 - Anterior olfactory nucleus.

3 - Hippocampus.

4 - Lateral habenula (a region involved in dopaminergic communication between the forebrain and the midbrain / hindbrain).

Functional implications include:

1 - Hypofunction of the mesocorticolimbic (mesocortical) system is responsible for the negative symptoms of schizophrenia.

2 - Cognition.

3 - Arousal.

Question 6

Describe the pathway of the mesodiencephalic (mesopontine) system.

What is the functional implication of this pathway?

Answer 6

• The mesodiencephalic (mesopontine) system originates from the A10-14 cell groups.
• The A10 cell group is in the ventral tegmental area.
• The A11 cell group is in the posterior and intermediate periventricular nuclei of the hypothalamus.
• The A12 cell group is in the arcuate nucleus of the hypothalamus.
• The A13 cell group is near the mammillothalamic tract of the hypothalamus.
• The A14 cell group is in the preoptic periventricular nucleus of the hypothalamus.
• Cell groups A12 and A14 project into the pituitary gland, where they are involved in the regulation of prolactin release.
• The mesodiencephalic (mesopontine) system also contributes to the diencephalospinal system, contributing axons from cell groups A11 (see A* card 25).

Question 7

Give an overview of the synthesis pathway of dopamine.

Where, and how, is dopamine transported once it is synthesised?

Answer 7

• The synthesis pathway of dopamine is similar to that of noradrenaline, except it is cut short:

1 - Tyrosine hydroxylase converts L-tyrosine into L-DOPA.

2 - DOPA-decarboxylase (AADC) converts L-DOPA into dopamine.

• A VMAT transporter then transports dopamine into a vesicle for exocytosis.

Question 8

Give an example of a VMAT inhibitor.

What is it used for?

Answer 8

• Reserpine is a VMAT inhibitor.

- Reserpine used to be used as an antihypertensive drug, but it isn’t used anymore because it causes depression.

Question 9

How is dopamine transmission terminated?

Answer 9

Dopamine transmission is terminated by dopamine transporter (DAT), which reuptakes the dopamine back into the presynaptic terminal.

*This is similar to NAT (for noradrenaline) and SERT (for serotonin).

Question 10

List the enzymes that are involved in dopamine breakdown.

List 2 major metabolites of dopamine.

Why might it be useful to measure these metabolites?

Answer 10

• Enzymes involved in dopamine breakdown include:

1 - Monoamine oxidase (MAO).

2 - COMT.

3 - Aldehyde dehydrogenase.

Major metabolites include:

1 - HVA (through action of MAO, COMT and aldehyde dehydrogenase).

2 - DOPAC (through action of MAO and aldehyde dehydrogenase).

• Measuring these metabolites can be useful for assessing dopaminergic turnover.

Question 11

List the 2 major modes of dopaminergic transmission.

What is the functional implication of this?

Answer 11

Dopaminergic transmission occurs via:

1 - Directed transmission.

2 - Volume transmission.

• The functional implication of this is that dopaminergic neurones can influence other neurones that are both nearby and over a large area.

Question 12

What type of function does dopamine have at receptors?

How might dopaminergic neurones carry out this function?

Answer 12

• Dopamine has a neuromodulatory function at receptors.
• This can occur by cotransmission of dopamine with the primary neuromodulator at a single synapse (example given in a later card), where dopamine binds directly to a postsynaptic receptor in a synapse.
• Alternatively, some dopamine synapses are separate to that of the primary neurotransmitter, and run down the neck of the dendrite of the postsynaptic neurone at a point closer to the soma.
• This allows for modulation of the action potential generated at the primary synapse.
• This is known as a ‘synaptic triad’ (since there are 3 synaptic processes involved: the primary presynaptic axon, the dopaminergic axon and the dendrite).

Question 13

What is the function of medium spiny neurones in the corpus striatum?

List 2 ways by which dopaminergic signalling can modify the function of medium spiny neurones.

Answer 13

• Medium spiny neurones constitute the striatal output to the cortex in the dorsal mesostriatal (nigrostriatal) dopaminergic pathway.
• They receive glutamatergic input by nigrostriatal neurones.

1 - One way by which dopaminergic signalling can modify the medium spiny neurones is in an indirect manner, by binding to D2 receptors on cholinergic interneurones. The effect is long-term depression.

• Binding of D2 receptors reduces ACh release from cholinergic interneurons, which normally bind to M1 muscarinic receptors on medium spiny neurones.
• The result of reduced M1 receptor activation is enhanced opening of Ca2+ influx in the medium spiny neurones (because M1 receptors usually mediate an inhibitory effect on the medium spiny neurone).
• Ca2+ is used in the medium spiny neurone to bring about retrograde signalling for negative feedback to glutamatergic nigrostriatal neurones.
• This retrograde signalling is achieved by releasing cannabinoids from the medium spiny neurone, which bind to CB1 cannabinoid receptors on the presynaptic terminal of the nigrostriatal neurone.
• If this signalling mechanism is enhanced by reducing activity of cholinergic M1 receptors, there will be more retrograde signalling and therefore more negative feedback and less activity of the dopaminergic pathway.
• This is a form of long-term depression.

2 - Dopaminergic signalling can also directly affect medium spiny neurones by interfering with the integration of glutamatergic signalling in the medium spiny neurones.

• This occurs via signalling cascades mediated by both D1-like and D2-like receptors that are located at synapses on the medium spiny neurone.
• This form of dopaminergic neuromodulation occurs at synaptic triads.

Question 14

List the types of dopamine receptor.

How are they classified?

Answer 14

• Dopamine receptors include D1 through to D5.
• They are classified as D1-like or D2-like:

D1-like receptors:

1 - D1.

2 - D5.

D2-like receptors:

1 - D2.

2 - D3.

3 - D4.

Question 15

Describe the functions of D1-like and D2-like receptors.

Answer 15

• D1-like receptors are Gs-coupled GPCRs that upregulate adenylyl cyclase and PLC.
• D2-like receptors are Gi/o-coupled GPCRs that downregulate adenylyl cyclase and upregulate PLC.

Question 16

Describe the distribution of dopamine receptor subtypes in the brain.

Answer 16

• D1 receptors are located in the corpus striatum.
• D2 receptors are located in the corpus striatum.
• D3 receptors are located in the nucleus accumbens.
• D4 receptors are located in the medulla and prefrontal cortex.
• D5 receptors are located in the hippocampus and hypothalamus.

Question 17

Where are dopamine autoreceptors found?

Which type of dopamine receptors are used as dopamine autoreceptors?

What is the function of dopamine autoreceptors?

Describe the mechanism by which they do this.

Answer 17

• Dopamine autoreceptors are found:

1 - On presynaptic nerve terminals in dopaminergic pathways.

2 - On postsynaptic dendrites in dopaminergic pathways.

3 - On the somata of dopaminergic neurones.

• D2 and D3 receptors constitute the majority of dopamine autoreceptors.
• This isn’t the only function of D2 and D3. They just also happen to be the dopamine autoreceptors.
• Binding of dopamine to D2 and D3 autoreceptors causes negative feedback by:

1 - Decreasing dopamine synthesis.

2 - Decreasing dopamine release by inhibiting voltage gated Ca2+ channels.

Question 18

List 2 examples of dopaminergic cotransmission.

Answer 18

1 - Dopamine is cotransmitted with glutamate in the ventral mesostriatal (mesolimbic) system.

2 - Dopamine is cotransmitted with GABA in the corpus striatum.

*The evidence for this involved measuring dopamine by fast cyclic voltammetry, which is explained in the next card.

Question 19

What is fast cyclic voltammetry?

Answer 19

• Fast cyclic voltammetry is a method used to measure the release of catecholamines.
• Some catecholamines (like dopamine) are particularly prone to oxidation when held at an electrode that is set to a particular voltage.
• In fast cyclic voltammetry, an electrode is placed in a catecholamine-dense region of the brain.
• When dopamine is released at this region, it is oxidised and generates a current.
• The electrode can be oscillated to drive more oxidation.

Question 20

Which structures of the brain are responsible for processing reward and punishment?

Answer 20

Reward and punishment are processed by the limbic system. Structures include:

1 - Amygdala.

2 - Septum.

3 - Ventral striatum (e.g. nucleus accumbens in the mesolimbic pathway).

4 - Prefrontal cortex.

5 - Brainstem catecholamine nuclei.

6 - Ventral tegmental area-nucleus accumbens neurones of the ventral mesostriatal (mesolimbic) system.

• The medial forebrain bundle is a hotspot for transmission of reward and punishment information.

Question 21

How do amphetamines bring about a rewarding effect?

Answer 21

Amphetamines bring about reward by stimulating dopaminergic pathways:

1 - Amphetamines are dopamine receptor agonists.

2 - Amphetamines elevate extracellular dopamine.

3 - Amphetamines prolong dopamine receptor signalling in the corpus striatum.

Question 22

What is 6-hydroxydopamine (6-OHDA)?

What is it used for?

Answer 22

• 6-hydroxydopamine (6-OHDA) is a toxic inhibitor for the dopamine transporter that prevents nerve terminals from releasing dopamine (since no more dopamine can be loaded into vesicles).
• It is used experimentally to deplete dopamine and cause neurodegeneration in dopaminergic neurones.

Question 23

Describe the mechanism that underlies addiction, relapse and acquisition of drug taking in substances of abuse such as cocaine, amphetamine, morphine, nicotine and alcohol.

Answer 23

1 - Substances of abuse can cause addiction by inducing long-term potentiation in dopaminergic neurones of the ventral tegmental area.

2 - Long-term depression in the nucleus accumbens underpins acquisition of drug-taking.

3 - The relapse-prone addictive phase of drug abuse involves synaptic plasticity of neocortical input to the dorsal striatum:

• The dorsal striatum contains the caudate and putamen, which have no bearing on the mesolimbic system (and therefore have no bearing on addiction). The ventral striatum contains the nucleus accumbens, which does.
• Therefore, this plasticity reflects reduced reward and de-emphasis of the role of the nucleus accumbens (contained in the ventral striatum) in this dopaminergic pathway.
• This induces motor habits (because the caudate and putamen are involved motor control) and reduced reward (because the nucleus accumbens is involved in the mesolimbic pathway).

Question 24

How do dopaminergic drugs affect motor behaviour?

Answer 24

• Dopaminergic agonists such as amphetamine stimulate motor activity.
• Dopamine antagonists / depletion inhibit motor activity / cause catalepsy.

Question 25

A*:

Describe the spinal component of the central dopaminergic systems.

Answer 25

• The spinal component of the central dopaminergic systems is derived from the diencephalospinal system, which is a component of the mesodiencephalic (mesopontine) system.
• The diencephalospinal system arises from the A11 dopaminergic cell group, which is in the posterior and intermediate periventricular nuclei of the hypothalamus.
• These axons mostly synapse in the dorsal horn. In mice, these dopaminergic synapses have been shown to:

1 - Exert an analgesic effect, as dopamine receptors reduce the excitability of ascending pain neurones in the dorsal root ganglion and dorsal horn (Puopolo, 2019).

2 - Induce spinal flexion reflexes (see A* card 40 for more details on movement).

Question 26

A*:

How does dopamine reach the periphery?

List the roles of dopamine in the periphery.

Answer 26

• Dopamine cannot cross the blood-brain barrier, therefore peripheral dopamine must be synthesised in:

1 - The adrenal medulla.

2 - Peripherally projecting dopaminergic neurones.

3 - Other endocrine cells such as APUD cells (which are found in various peripheral organs).

• These sources of dopamine together together regulate plasma dopamine.
• Peripheral functions of dopamine include:

1 - Regulation of the respiratory system (see A* card 33).

2 - Regulation of blood pressure (see A* card 34).

3 - Regulation of gastrointestinal motility (see A* card 35).

4 - Regulation of the circadian rhythm by responding to light in the retina.

5 - Regulation of plasma glucose (see A* card 38).

Question 27

A*:

Describe the mechanism of action for L-type Ca2+ channel blockers as a treatment for Parkinson’s disease.

Answer 27

• Parkinson’s disease is characterised by degeneration of the substantia nigra pars compacta (SNc).
• The SNc must autonomously release a continuous supply of dopamine to other brain structures such as the caudate and putamen.
• L-type Ca2+ channels are thought to contribute to this pacemaker activity, although, like T-type calcium channels, they are not integral to it.
• However, L-type Ca2+ channels have also been shown to increase oxidative stress in neurones of the SNc, contributing to degeneration.
• Therefore, L-type Ca2+ channel blockers can be used to protect the SNc against Ca2+-mediated degeneration (Chan et al., 2007).

Question 28

A*:

What is the advantage of selective D3 receptor agonists for the treatment of Parkinson’s disease over generic dopamine replacement?

Answer 28

• The advantage of selective D3 receptor agonists for the treatment of Parkinson’s disease over generic dopamine replacement is that selective D3 agonists also promote neuroprotection and regeneration of lost dopaminergic pathways.
• The neuroprotective function of D3 receptors is thought to be through inhibition of alpha-synuclein formation in dopaminergic neurones (preventing formation of Lewy neurites - see Parkinson’s lecture).
• Neurogenesis is thought to be stimulated by the activation of D3 receptors on stem cells in the tegmentum.

Question 29

A*:

What is fasudil?

How can it be used to treat depression?

Answer 29

• Fasudil is a Kv7.4 channel activator.
• Kv7.4 channels are voltage gated potassium channels that have been shown to potentiate activity of dopaminergic neurones in the ventral tegmental area.
• These neurones constitute the mesolimbic pathway, which is involved in reward and is thought to be hypoactive in depression (see cards 4 and 17 in the depression lecture).
• Such hypoactivity could be attributable to decreases in expression of Kv7.4 channels, as demonstrated by the improvement in depressive behaviours following administration of Fasudil in mice (Li et al.,2017).

Question 30

A*:

Describe a mechanism for non-canonical dopamine-gaba corelease.

Where does this occur?

Answer 30

• Some dopaminergic neurones in the corpus striatum express the GABA-synthesising enzyme, GAD 65.
• These neurones are able to induce a GABA-mediated inhibitory potential, with concomitant dopamine release.
• The process of GABA transport in these neurones is considered ‘non-canonical’ because removal of the VGATs that normally load GABA into vesicles for exocytosis has no effect on the generation of GABA-induced postsynaptic potentials.
• On the other hand, disabling VMATs prevents the inhibitory postsynaptic potential, suggesting that GABA is loaded into vesicles by VMATs rather than VGATs in striatal neurones (Tritsch et al., 2012).

Question 31

A*:

Describe the evidence for dopamine-glutamate corelease in the mesolimbic pathway.

Answer 31

• Stimulation of the ventral tegmental area leads to the generation of fast excitatory postsynaptic potentials (EPSPs) in the targets of dopaminergic neurones, such as the nucleus accumbens, and concomitant dopamine release.
• Since dopamine acts at GPCRs, a fast EPSP would not be expected.
• Knockout of VGLUT transporters abolishes the fast EPSPs, therefore the fast EPSP is being generated by glutamate, which is being coreleased with dopamine (Koos et al., 2011).
• Furthermore, VGLUT knockout decreases dopamine release, suggesting that glutamate enhances dopamine release in the mesolimbic pathway, perhaps via presynaptic glutamate receptors.
• Blockade of VGLUTs in this pathway was shown to reduce motor symptoms of cocaine and amphetamine, but did not affect the rewarding effect of the drugs.
• This suggests that glutamate is responsible for motor symptoms, whereas dopamine is responsible for reward in these drugs (Koos et al., 2011).

Question 32

A*:

Describe the history of dopamine discovery.

How were the roles of dopamine in the brain identified?

Answer 32

From Yeragani et al. (2010):

• In 1910, James Ewens and George Barger were the first to synthesise dopamine, however at this time, dopamine was known only for its role as an intermediate product in noradrenaline synthesis.
• In fact, the physiological relevance of dopamine as a neurotransmitter in its own right was not recognised until 1957, where several works demonstrated the presence of dopamine in the brain and its potential role in the regulation of blood pressure.
• This emergence of dopamine research was largely pioneered by the Swedish pharmacologist, Arvid Carlsson, who, in the following years, identified high concentrations of dopamine in the basal ganglia. Subsequent experiments by Carlsson in 1959 saw that depletion of dopamine using the VMAT inhibitor, reserpine, led to a profile of symptoms akin to that seen in Parkinson’s disease.
• Carlsson continued to make important contributions to the dopamine research, and was largely responsible for the theory of Schizophrenia.
• Another important figure in dopamine research was James Olds, an American psychologist who, in 1954, found that rats would repeatedly self-stimulate electrodes inserted into the nucleus accumbens and septum. He asserted that these brain regions mediate reward, which would become known as the brain’s ‘pleasure centres’. It was soon discovered that these structures are primarily composed of dopaminergic neurones.
• Consequently, the effect of dopamine depletion and enhancement on reward became of immediate interest. Due to the lack of specific dopaminergic agents, dopamine depletion was achieved in numerous studies by the VMAT inhibitor reserpine, and enhancement was generally achieved by amphetamines and TCAs such as imipramine. These investigations, such as those carried out by Axelrod (1961) and Carlsson (1965) were able to identify significant changes in reward-related behaviour in response to these drugs.
• The role of dopamine in reward was not met without controversy. In 1968, Larry Stein suggested that the functions of the identified pleasure centres of the brain were in fact mediated by noradrenaline. This was founded on the basis that the drugs used in earlier research to attenuate dopamine transmission, such as reserpine, also decrease noradrenergic transmission. Similarly, drugs used to increase dopamine transmission, such as amphetamine and imipramine, also potentiate noradrenergic transmission. These considerations, combined with the fact that numerous noradrenergic structures were already known to exist in close relation with the identified ‘dopaminergic’ sites, led Stein to his hypothesis.
• This was evidenced by subsequent experiments by Wise and Stein, which revealed that inhibition of dopamine-beta-hydroxylase, the enzyme responsible for the conversion of dopamine into noradrenaline, attenuated behaviours relating to reward, such as self-stimulation in rats, and that reversal of this process restored these behaviours.
• However, Wise and Stein’s noradrenergic hypothesis of reward was refuted by a number of follow-up studies in the 1970s. One study by Corbett et al. (1977) demonstrated that self-stimulation of pleasure centres was not attenuated by lesioning of noradrenergic fibres. Others argued that the distribution of noradrenergic fibres did not correspond with earlier mapping of central pleasure centres.
• The debate was ultimately resolved when animal models were carried out using newly developed dopamine receptor antagonists, which saw significant reductions in reward-associated behaviours.
• This led Wise to formulate the ‘hedonia hypothesis’, which posits that dopamine mediates sensations of euphoria in response to pleasurable activities. Today, the involvement of dopamine in reward is widely accepted. However, other hypotheses such as the reward learning hypothesis and incentive salience challenge the hedonia hypothesis in explaining the precise role of dopamine in reward (see A8 card 43).

Question 33

A*:

Describe the role of dopamine in the regulation of the respiratory system.

Answer 33

The role of dopamine in the regulation of the respiratory system (From Ciarka et al., 2006):

1 - Circulating dopamine is able to bind to dopamine receptors on glomus cells - the predominant cell type in carotid bodies. Dopamine is thought to inhibit the response of glomus cells to hypoxia, attenuating the increase in ventilation that would normally occur.

2 - Dopamine interferes with ventilation/perfusion matching, hence reduces the rate of gas exchange.

3 - Dopamine reduces pulmonary blood pressure by mechanisms discussed in A* card 34. This, in turn, reduces the rate of gas exchange, but also is useful for treating oedema.

4 - Dopamine promotes Na/K ATPase function in pulmonary epithelia, which is also useful for treating oedema. It does this by activating beta 2 receptors.

5 - Dopamine can influence airway diameter, however the mechanisms are still unclear. One study showed that dopamine can inhibit histamine-mediated bronchoconstriction, demonstrating potential for dopamine as a treatment for respiratory conditions such as allergic asthma. However, dopamine has also been shown to recruit T cells to mediate inflammation in the lungs, causing bronchoconstriction.

Question 34

A*:

Describe the role of dopamine in the regulation of blood pressure.

Answer 34

The role of dopamine in the regulation of blood pressure:

In the kidneys:

• Circulating L-DOPA is taken up by the kidneys, where it is converted into dopamine.
• Dopamine is secreted into the lumen of the proximal and distal tubules, where it binds to D1-like receptors (including D1 receptors and D5 receptors) to cause natriuresis.
• D1-like receptor activation causes natriuresis through both inhibition of Na+ reuptake from the lumen, and also by increasing renal perfusion to raise GFR.
• Natriuresis leads to an increase in urine volume as water follows Na+ movement. The resulting decrease in water reabsorption leads to a decrease in blood volume, which, if sufficient, leads to a decrease in blood pressure. Accordingly, decreased renal dopamine activity can lead to an increase in blood pressure.
• Dopamine synthesis in the kidneys is stimulated by Na+ concentration in the renal epithelium, and hence acts as a means of negative feedback for Na+ homeostasis.

In the blood:

• In high doses, dopamine causes vasoconstriction.
• This is because at high doses it is able to act as an agonist at adrenergic receptors, hence it causes vasoconstriction at alpha1 receptors.
• However, in vessel walls, activation D1-like receptors causes vasodilation. D2-like receptors are also present on vessel walls, however their effects are variable, and likely involves modulation of autonomic innervation.
• Dopamine is also able to influence vessel diameter through its role in regulating ROS production and the inflammatory response:

1 - Circulating dopamine produces an anti-inflammatory effect.

• Inflammation normally mediates local vasodilation.

2 - ROS is generated with dopamine metabolism.

• In most vessels, ROS causes vasodilation, however in precontracted vessels, ROS promotes further vasoconstriction.

In the heart:

• At high doses, dopamine acts as an agonist at beta-1 receptors in the heart, causing a positive inotropic effect and a less intense positive chronotropic effect.
• Hence, dopamine is used to treat shock for its positive inotropic and vasoconstrictor effects.

Question 35

A*:

Describe the role of dopamine in the regulation of gastrointestinal motility.

Answer 35

• The mechanisms underlying dopaminergic control of GIT motility are unclear, but it is thought that different distributions of dopamine receptor subtypes in the GIT allow dopamine to mediate different effects at different sites.
• This is based on the finding that dopamine reduces motility in the small intestine, but increases motility in the large intestine.
• Other studies have found that dopamine also stimulates GIT secretions, influences absorption of Na+ and modulates mucosal perfusion.

Question 36

A*:

What is Huntington’s disease?

What is the role of dopamine in Huntington’s disease?

Give an example of a novel dopaminergic therapy for Huntington’s disease.

Answer 36

• Huntington’s disease is an autosomal dominant neuropsychiatric condition characterised by an expansion of CAG repeats in the huntingtin gene.
• Cognitive symptoms are common early in disease, whereas hyperkinetic motor symptoms, such as Huntington’s chorea, typically arise as the disease progresses.
• Various studies have identified elevated dopamine transmission in early Huntington’s disease. Chronically high dopamine is thought to induce cell death in dopaminergic striatal medium spiny neurones (Paoletti et al., 2008) by a huntingtin protein-dependent mechanism that upregulates p38 MAPK signalling.
• This results in hypoactivity of dopaminergic transmission, which is thought to underpin the motor deficits in late stages of disease.
• The traditional view is that this is process occurs to a greater extent in medium spiny neurones in the inhibitory indirect striatal pathway, which express inhibitory D2 receptors and enkephalin, rather than in the medium spiny neurones in the facilitatory direct striatal pathway, which express excitatory D1 receptors and substance P.
• Therefore, motor deficits in Huntington’s disease arise due to decreased basal ganglia outflow, which in turn is due to degeneration of the striatal output neurones in the inhibitory indirect pathway. Classical treatment includes chlorpromazine, a D2 antagonist that decreases inhibitory stimulation of striatal D2 receptors of the indirect pathway. This treatment restores indirect pathway activity, and hence increases inhibitory basal ganglia output back to physiological levels.
• However, it has been suggested that the primary pathology of Huntington’s disease lies in the direct striatal pathway rather than the indirect pathway (Paoletti et al., 2008), as it has been observed that Huntingtin striatal cells are sensitised to excitatory glutamatergic and dopaminergic input. This leads to overactivity of the direct pathway, reducing inhibitory basal ganglia output and resulting in motor symptoms. These findings were substantiated by later electrophysiological studies of the striatum in Huntington’s disease mice (André et al., 2011).
• Following this evidence, subsequent studies found that motor symptoms in Huntington’s disease mice were improved by D1R antagonism and exacerbated by classical dopamine replacement.
• However, a problem with nonselective D1R antagonism is that the ubiquity of D1Rs means that there is potential for many side effects, including sedation and depression.
• In the direct striatal pathway, D1Rs are coexpressed with a subtype of histamine receptors, H3Rs, forming functional heteromers. Therefore, D1 striatal neurones can be selectively targeted using the H3Rs to which they are coupled.
• H3R antagonists have been shown to reduce cognitive and motor symptoms in a mouse model of Huntington’s disease by reducing direct pathway activity (Delgado et al., 2020).
• This novel target has the potential for treating the symptoms of Huntington’s disease without the side effects resulting from non-selective D1R antagonism.
• Taken together, the evidence suggests that both underactivity of the indirect pathway ands overactivity of the direct pathway contribute to the motor symptoms seen in Huntington’s disease. D1R antagonists present a novel therapeutic approach to the treatment of Huntington’s disease, and may prove effective in conjunction with current therapies such as D2R antagonists such as chlorpromazine, VMAT inhibitors such as tetrabenazine and GABA-B agonists such as baclofen.

Question 37

A*:

List 3 disorders involving dopamine transmission that have sex differences.

List 3 possible reasons for these sex differences.

Answer 37

Disorders involving dopamine transmission that have sex differences include:

1 - Women are approximately 2 times more likely to develop depression than men.

2 - Males are approximately 2 times more likely to develop Parkinson’s disease than females.

2 - Women are approximately 2 times more likely to develop anxiety than men.

3 - Women are more susceptible to escalation of drug-taking behaviour and have a greater risk of relapse following drug withdrawal compared to men.

Possible reasons for these sex differences:

1 - Oestradiol and progesterone are able to increase dopamine release from dopaminergic neurones in the dorsal striatum and nucleus accumbens, and have also been shown to modify dopamine receptor binding (Yoest et al., 2018).

• This would explain the results of a study by Cummings et al. (2013), which found that oestradiol enhanced cocaine-induced locomotor symptoms in ovariectomised female rats (since the dorsal striatum is part of the nigrostriatal pathway), and that oestradiol increased cocaine-induced dopamine release in the dorsal striatum and nucleus accumbens in female, but not male rats.
• This might explain sex differences in depression, anxiety and susceptibility to drug-taking behaviour / relapse, since these processes involve the mesolimbic pathway, which includes the nucleus accumbens.

2 - The testis-determining factor (AKA Sry) influences expression of tyrosine hydroxylase in the nigrostriatal pathway (Dewing et al., 2006). Tyrosine hydroxylase is the enzyme responsible for the conversion of tyrosine into DOPA.

• Knockout of TDF in nigrostriatal neurones was shown to impair motor behaviour in male rats, therefore there is likely to be a mechanism in females compensating for the lack of TDF-induced upregulation of tyrosine hydroxylase (since females do not express TDF but do not show impaired motor behaviour compared to males), however no such mechanism is known.
• These biological differences might underlie sex differences in prevalence of Parkinson’s disease.

3 - Glucocorticoid exposure in prenatal rats has been shown to promote neurogenesis in dopaminergic neurones of the ventral tegmental area (VTA), the area responsible for the mesolimbic system, which mediates reward, motivation and addiction.

• N.B. this is strange considering the fact that cortisol is known to inhibit BDNF synthesis in the hippocampus, reducing neurogenesis. The differential effect of cortisol in the prenatal rats reflects the variability of the effect of glucocorticoids on the brain according to the timing and duration of exposure.
• Gillies et al. (2006) found that the effect on prenatal exposure to glucocorticoids had a significantly different effect on VTA size in males compared to females.
• This might explain sex differences in depression, anxiety and susceptibility to drug-taking behaviour / relapse, since these processes involve the mesolimbic pathway, which includes the nucleus accumbens.

Question 38

A*:

Describe the role of dopamine in the regulation of plasma glucose.

Answer 38

• Ikeda et al. (2020) demonstrated that both D2 receptor agonists and antagonists administered separately through the intracerebroventricular route induced hyperglycaemia. This effect was not present in D2 receptor knockout mice, and D1 receptor agents had no effect.
• These agents were found to upregulate enzymes necessary for gluconeogenesis, such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, in the liver.
• In the same study by Ikeda et al., it was found that vagotomy abolished the increase in hepatic gluconeogenesis mediated by D2 receptor agonists, but not D2 receptor agonists.
• Hence, it is thought that parasympathetic nerves mediate the increase in hepatic gluconeogenesis induced by D2 receptor agonists, whereas sympathetic nerves mediate the increase in hepatic gluconeogenesis induced by D2 receptor antagonists.
• Overall, however, reports on the role of D2 receptors on the regulation of plasma glucose show mixed results. It is unlikely that D2 receptor activation mediates either a singular positive or negative influence on plasma glucose, and the process likely involves numerous mechanisms.
• Elucidation of these mechanisms will present a novel target for pharmacological control of plasma glucose, for example in diabetes mellitus.

Question 39

A*:

Describe the mechanisms by which nigrostriatal degeneration occurs in Parkinson’s disease.

Answer 39

• The mechanisms underlying nigrostriatal degeneration in Parkinson’s disease are the subject of debate.
• It is known that Parkinson’s disease pathogenesis is a ‘double hit’ that involves both genetic susceptibility and exposure to environmental factors, resulting in protein misfolding that leads to accumulation of Lewy bodies, Lewy neurites and mitochondrial dysfunction. This contributes to cell death by inducing oxidative stress, inflammation and excitotoxicity. However, the exact mechanisms leading to these cellular events are unclear.

Potential mechanism:

• Two types of VMAT exist: VMAT1 and VMAT2. VMAT1 is primarily extraneural, and is involved in neuroendocrine functions such as in the GIT and adrenal medulla. VMAT2 is primarily neuronal, and hence accounts for the majority of VMATs in the brain.
• It has been found that downregulation of VMAT2 in the rat substantia nigra reversibly induced neuronal degeneration (Bucher et al., 2020), which was accompanied by various hallmarks of Parkinson’s disease, such as accumulation of alpha-synuclein (the protein responsible for the formation of Lewy bodies / neurites) and LRRK2 (a kinase activated by oxidative stress that is characteristic of neuronal degeneration in Parkinson’s disease).
• It is not clear from the results of the study whether the effects of VMAT2 downregulation on neuronal degeneration are mediated by the resulting increase in cytosolic dopamine or by a direct action of VMAT2 itself.
• This study mainly provides a useful model for replicating Parkinson’s disease for future Parkinson’s disease research.

Question 40

A*:

Describe the role of the diencephalospinal system in movement.

Answer 40

• The diencephalospinal system comprises descending spinal projections containing both D1 and D2 receptors.
• In vitro studies have identified that the influence of dopamine on motor activity depends on both pattern of firing and concentration of dopamine released at the synapse:
• High dopaminergic transmission resulting from phasic activation of these dopaminergic neurones primarily activates D1 receptors, promoting motor activity.
• Low dopaminergic transmission resulting from tonic activation of these dopaminergic neurones primarily activates D2 receptors, inhibiting motor activity (Sharples et al., 2020).
• It is thought that the excitatory component of the diencaphalospinal system is silent under physiological conditions in younger age. This is based on the observation that dopamine concentrations in the spinal cord of young mice is significantly lower than the concentration required to activate spinal D1 receptors. Instead, the effect of D2 receptors predominates, inhibiting motor activity. As the spinal dopamine concentration increases with age, the D1 receptors are able to be activated, facilitating movement. This is thought to be beneficial in young mammals where mobility is not required, but becomes more important with age.
• The role of this system in motor activity was demonstrated in a study by Koblinger et al. (2018), in which activation of the A11 dopaminergic cell group (which is involved in the mesopontine system) was shown to potentiate motor activity in live mice.

Question 41

A*:

What is methylphenidate?

How does it work?

Answer 41

• Methylphenidate is a cognitive enhancement drug used to treat ADHD.
• It is thought to accentuate both the perceived benefits of a cognitive task, and the so-called ‘opportunity cost’ of foregoing the task.
• These effects are brought about by the ability of methylphenidate to increase dopaminergic transmission in the corpus striatum. This, in turn, potentiates activity of the mesolimbic pathway, reducing the cost of mental labour (Hofmans et al., 2020).
• This is a good way of demonstrating the reward learning hypothesis of the mesolimbic system (see A* card 43).

Question 42

A* (not necessarily dopamine related):

List 3 experimental approaches to identify the physiological events that underpin brain functions.

Answer 42

From Berridge (2007):

Experimental approaches to the identify physiological events that underpin brain functions:

1 - Investigating the loss of the brain function when the physiological event is removed (e.g. by lesioning or pharmacological antagonism).

• This type of investigation determines whether the physiological event is necessary for the brain function.

2 - Investigating the enhancement of the brain function when the physiological event is supplemented (e.g. by agonism or electrical stimulation).

• This type of investigation determines whether the physiological event is sufficient in itself to influence the brain function (in the context of the physiological conditions of the brain).

3 - Investigating relationships, e.g. measuring the physiological event whilst carrying out other brain functions.

• This type of investigation determines the way in which the physiological event is coded, and how this coding manifests in the brain function.

Question 43

A*:

Discuss the competing hypotheses that explain the contribution of the mesolimbic pathway to reward.

Answer 43

From Berridge (2006):

Competing hypotheses that explain the contribution of the mesolimbic pathway to reward:

1 - Hedonia hypothesis - ‘liking’.

• This hypothesis suggests that dopamine mediates sensations of euphoria in response to pleasurable activities.
• This was the original hypothesis published by Wise in the early 1980s.
• It is believed by some to be an oversimplification of the role of dopamine in reward. For example, a study by Berridge et al. (1989) found that even severe lesions of striatal dopaminergic neurones does not induce changes to taste reactivity in rats. Such evidence should be taken with caution, as much evidence exists to demonstrate the activation of the mesolimbic pathway in response to pleasurable stimuli, and various drugs affecting mesolimbic dopamine transmission, such as fasudil (see A* card 29), have been shown to reduce anhedonia in animal models of depression. Hence, the findings by Berridge et al. likely reflect the multifaceted nature of reward, and represent an oversimplified model of reward that does not consider the complex, integrated behaviours mediated by the dopamine systems. Models such as drug self-administration provide a more comprehensive insight into motivation. Indeed, many studies have demonstrated reduced self administration following similar lesions to the pleasure centres as was described in the Berridge et al. study.

2 - Reward learning hypotheses, such as prediction error learning models - ‘wanting’.

• Prediction error learning models suggest that dopamine signals anticipate reward, and are able to modulate the synaptic plasticity of (primarily glutamatergic) learning networks, resulting in reinforcement of reward-inducing behaviours.
• The hypothesis therefore states that dopamine itself does not mediate euphoria in response to reward, but is instead involved in generating a learned ‘prediction error’ for the reward derived from a particular stimulus.
• This might explain the role of dopamine in addiction. A prediction error learning model would suggest that addictive substances cause excessive dopaminergic stimulation, resulting in a pathologically high prediction error and, consequently, strong changes to synaptic plasticity that result in high motivation to obtain the addictive substance.
• This hypothesis is substantiated by a number of electrophysiological studies that show activation of the mesolimbic system in anticipation for a rewarding stimulus.
• However, it is challenged by studies that have shown persistence of reward learning in tyrosine hydroxylase knockout mice, such as that carried out by Cannon and Palmiter (2003). This has a number of potential implications. It could suggest that other non-monoaminergic systems are at play in reward learning. Alternatively, it could imply that dopaminergic prediction error signals are simply a consequence of classical, probably glutamatergic, learning, and that dopamine systems simply carry out limited integration of glutamatergic afferent information (Berridge, 2006). It could therefore be conceived that dopamine is sufficient, but not necessary, for reward learning, and instead supplements classical glutamatergic learning systems.