Dopamine (A*) Flashcards

Question

A*: Describe the spinal component of the central dopaminergic systems.

Answer 1

- 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).

Answer 2

- 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).

Answer 3

- 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).

Answer 4

- 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.

Answer 5

- 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).

Answer 6

- 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).

Answer 7

- 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).

Answer 8

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).

Answer 9

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.

Answer 10

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.

Answer 11

- 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.

Answer 12

- 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.

Answer 13

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.

Answer 14

- 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.

Answer 15

- 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.

Answer 16

- 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.

Answer 17

- 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).

Answer 18

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.

Answer 19

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.