Since its discovery, and more importantly the discovery of its role as a neurotransmitter, dopamine systems have become the focus of a mass of research, particularly in the past 30 years, due to the link between serious CNS disorders and irregular dopamine transmission. The abundance of research has enabled the mass development of pharmaceuticals to help alleviate symptoms (Missale et al, 1998). For example, DA receptor antagonists have successfully blocked hallucinations and delusions of many schizophrenic patients (Angrist et al 1980), whilst agonists at these same receptors have reduced hypokinesia amongst Parkinson's disease patients (Lieberman et al, 1982). However, despite the success of these drugs, the treatment often comes with severe side effects; antipsychotics can lead to extrapyramidal effects (Casey & Keepers, 1988), similar to those displayed in PD, and vice versa. A major target of the last 10Â years has been to discover selective dopaminergic drugs which are equally as successful at treating the disorder, but do not result in adverse effects.Â This has led to the development of new agents that, although have not completely resolved the aetiology of the disorders, have supplied an increase in the knowledgeÂ of the dopaminergic system.
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However, even with the vast research of the dopamine system, there is very little focusing on extrastriatal regions of the brain, particularly of the thalamus (Takahashi et al, 2006). Plenty of recent research has demonstrated the presence of dopamine receptors in the thalamus, along with electrophysiological research of the direct actions of dopamine on the excitability of dopamine innervated neurons. Yet the functions, if any, of these receptors are still unknown.
In order to discover the role of dopamine within the thalamus, it is necessary to review its mechanisms of actions and functions elsewhere in the brain, including its role in healthy versus patients with CNS disorders, in order to consider its potential purpose within the thalamus.
Dopamine, like all members of the catecholamine family is derived from tyrosine and is an essential part of the sympathetic nervous system. (Hornykiewicz, 1966) It was first recognized as a precursor for Noradrenaline, but later detected as having its own neurotransmitter properties. It is synthesized in several areas of the brain including the substantia nigra and the ventral tegmental area (VTA) and stored in presynaptic vesicles until released upon arrival of an action potential (Elsworth & Roth 1997). This molecule has numerous functions in the mammalian brain; including motor activity, emotion, cognition and endocrine regulation, but also has important roles in the peripheral nervous system, for example secretion of hormones and cardiovascular function.
2.1 Dopamine Receptors
Dopamine receptors are members of the rhodopsin family of G-protein coupled receptors (GPCRs), characterised by seven transmembrane helices and connected by both intracellular and extracellular loops with a binding site located within a water accessible crevice (Javitch et al, 1995). Currently there are five types of dopamine receptors recognized; D1 is the most expressed and widespread receptor. Its mRNA has been found in the striatum, nucleus accumbens and olfactory tubercle; whilst further D1 receptors have been located in the limbic system, the hypothalamus and the thalamus. D5 can functionally be paired with D1 receptors, named 'D1-like receptor family). Both involve activation of the Gs protein, leading to the stimulation of adenyl cyclase and upregulation of cAMP, ultimately leading to an increase of intracellular calcium. (Tumova et al, 2003). However D5 is poorly expressed in comparison to D1; and is generally restricted to the hippocampus.
The D2 like receptor family (D2-D4) combines with the Gi protein, therefore inhibiting adenyl cyclase and reducing the production of cAMP. D2 receptors are the most common of the sub-family, and are found in most dopamine rich areas of the brain including the striatum and olfactory tubercle (Ariano et al, 1993), D3 in the limbic areas and D4 in the frontal cortex, amygdala, hippocampus, (Sibley & Monsma 1992) and recent evidence also suggests in the thalamus
Fig 1: The distribution of D2 receptors in the human brain. High binding is found in the striatum, intermediate in the thalamus and low in the cortex.
(Taken from Takahashi et al, 2006)
2.2 The Dopamine Transporter
The dopamine transporter (DAT) is located on the plasma membrane of nerve terminals and is responsible for mediating the reuptake of dopamine into neurons, making it a major target for drugs and toxins (Chen & Reith 2000). DAT is responsible for controlling the concentration of synaptic dopamine, hence is responsible for the intensity and duration of the dopamine signal (Addler, 2007) (Ciliax et al, 1995) and is the primary way of terminating dopaminergic signal (Van Kampen, 2000). Some recreational drugs, such as cocaine, are known to block the transporter, therefore resulting in an increased synaptic concentration of dopamine, whereas others, amphetamine-like, are actively taken up by the transporter into the pre-synaptic terminal. Both result in increased post-synaptic receptor activation therefore increased reward circuit stimulation.
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DAT is frequently used a measure of dopamine innervation as if there are high levels of the transporter it is a good indication that there are high levels of dopamine being released in this region.
2.3 Dopaminergic Pathways in the Central Nervous System
2.3.1 Nigrostriatal Pathway
The Nigrostriatal pathway is the most studied of the brain's dopamine systems. It projects from the Substantia nigra pars compata (SNpc) to the dorsal part of the striatum (CPu). This pathway plays an important role in the initiation and control of movement, including posture control and movement learning (Matsumoto et al 1999). Depletion of dopamine in this tract can lead to disorders such as Parkinson's disease and dystonia.
Dorsal Striatum as a target
The Striatum is the largest part of the basal ganglia, also considered as the 'main receiving area'. (Van Kampen, 2000). Dopamine receptors are present on the spiny neurons and cortical axon terminals. Activation of the receptors by dopamine triggers a second messenger cascade to modulate pre and post synaptic function. The striatum's main role is in the planning and modulation of movement pathways, but also has involvement in other cognitive functions. Evidence has shown that the striatum is activated by reward stimuli, but also by unexpected or intense stimuli. (Zink, 2006)
2.3.2 Mesolimbic Pathway
The Mesolimbic pathway projects from the Ventral tegmental area (VTA) to the ventral striatum- nucleus accumbens (NAc), via the amygdala and hippocampus, and is involved in control of motor behaviour as well as in motivation, emotions and reward. (Janhunen & Ahtee, 2007)
Nucleus Accumbens as a target
The NAc is part of the reward circuit and therefore is a major target for recreational drugs, and has a crucial role in drug addiction, the use of recreational drugs leads to a manifold increase in dopamine levels in the NAc, thought to mediate positive reinforcement effects. (Koob. 1992) It also provides a link between the limbic system and the central grey nuclei, which aid planning and reasoning processes.
2.3.3 Mesocortical Pathway
Mesocortical neurons also originate at the VTA, but instead project to the frontal lobe and surrounding areas; the medial prefrontal, cingulated and entorhinal cortices (Grace, 1993) These areas have a role in higher cognitive functions such as working memory, as well as in learning and reward. (Janhunen & Ahtee, 2007)
2.4 The Relationship with other Neurotransmitters
Critical dopamine functions often involve the regulation of or by other neurotransmitters - including GABA and Glutamate. DA projections may have inhibitory or excitatory effects resulting in either a decrease or increase in transmitter release, depending on the receptor type activated (D1-like/D2-like). The role can also be reversed and dopaminergic cells can be inhibited (by GABA) or excited (by glutamate). It is thought that DA is thought to 'gate' neurotransmitter drive, by facilitation or attenuation of the transmission. (Sesack et al, 2003)(Bernath & Zigmond, 1989)
GABA is the main inhibitory neurotransmitter in the CNS. There are two subtypes of GABA receptors; GABAA receptors are a type of ligand gated ion channel, which when activated allow the flow of chloride out of the cells, resulting in hyperpolarization of the membrane and therefore decreased excitatability of the cell. GABAB receptors are, like dopamine receptors, GPCRs which activate Gi/o. (Akk, 2010)
Glutamate has the opposite effects to GABA, being the major excitatory neurotransmitter in vertebrates. Like GABA, there are two types of glutamate receptors, ligand-gated cation channels, which lead to excitatory post-synaptic currents (EPSC) and GPCRs, which can either activate Gi/o or Gq (leading to activation of PKC)( Danbolt, 2001)
3.0 Thalamic Dopaminergic System
3.1 The Thalamus
The thalamus, consisting of two identical thalamic bodies, is the largest structure in the diencephalon and is located between the cerebral cortex and midbrain of vertebrates. Internally, the structure is divided into anterior, medial, ventral, lateral and posterior nuclear groups and myelinated fibers make up a system of lamellae, which structurally separate the different subparts. Each of these subparts contains thalamic nuclei which each have varying functions. The anterior group, including the anterior nuclei, are part of the limbic system, therefore involved in emotion and motivation. The medial group nuclei connect emotional centres in the hypothalamus to the frontal lobes, therefore enabling awareness of emotional states. The nuclei in the ventral group have a role in motor control, relaying information from the basal nuclei (of the cerebrum and cerebellum) to the cerebral cortex. The lateral group has a role in feedback to the limbic system and parietal lobes, thereby integrating sensory information and affecting emotional states. The final group of nuclei, the posterior, consists of the pulvinar nucleus - also responsible for sensory integration - and the lateral and medial geniculate nuclei, which project to the visual and auditory cortices respectively. (Martini & Nath, 2009)
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Traditionally the thalamus was soley thought of as a relay station for nerve impulses carrying sensory information into the brain; receiving these sensory inputs, as well as inputs from other parts of the brain, such as the basal ganglia and cerebellum, and determining which signals to forward to the cerebral cortex. (Sherman & Guillery 1996). However, it is now believed that the functions of the thalamus are more than just to relay information, but also to feedback and dynamically influence these systems.
Fig 2: Showing the new concept of thalamic connections. The thalamus relays information from the basal ganglia to the cortex, but also receives input from the cortex and relays back to the basal ganglia. Inputs are processed and dynamically altered before being relayed to the destination
3.2 Dopaminergic Innervation of Thalamus
Until recently, dopaminergic innervation of the thalamus was not recognized; potentially because reports have suggested very little dopamine present in rodent thalami (Groenewegen, 1988). Within the last 10 years, it has become apparent that dopamine and dopamine receptors are present, therefore leading to more and more investigation into the area. Post mortem biochemical studies on humans and macaques have indicated the presence of dopamine in the thalamus (Brown et al., 1979; Goldman-Rakic and Brown, 1981), whilst additional receptor binding and in situ hybridization analyses displayed the presence of both D2 and D3-like receptors in human thalamic nuclei (Rieck et al, 2004). The use of position emission tomography (PET) radioligands has also shown that DAT and D2-like receptors are present in both human and macaque thalami
Unlike dopaminergic innervation of the striatum and cerebral cortex, it has been revealed that thalamic innervation has multiple origins; in the hypothalamus, periaqueductal gray matter, mesencephalon and the lateral parabrachial nucleus. The distribution of the dopaminergic axons in the thalamus, when investigated, was found to be uneven throughout, with a high concentration observed in the midline limbic nuclei and the lowest concentration seen in the intralaminar and the primary sensory relay nuclei. (Sánchez-González et al., 2005)
Immunohistochemistry investigations of dopamine and DAT distribution within human and macaque thalami produced similar results, suggesting that thalamic dopamine has a major role in emotion, attention, cognition and complex somatosensory and visual processing, as well as in motor control (Garcia-Cabezas et al 2006). To improve knowledge of the entire system and to establish which dopaminergic tract the neurons identified in previous experiments belonged to; tract-tracing immuno-cytochemistry was performed on macaques. The tracts revealed that the innervation of the parvocellular mediodorsal thalamic nucleus shares anatomical features with the mesocortical pathway, yet not of the nigrostriatal pathway (Melchitzky et al 2006) suggesting that this region is involved in processing cognitive functions, as oppose to motor control. However the same conclusion may not be applied to other thalamic nuclei, which could have a more functional role in motor systems.
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Fig 3: Displaying a comparison of DATir axons within the macaque and rat thalamus. Despite the variations between the two distributions, high concentrations are seen in the the Mediodorsal and ventralmedial regions of both species. (Garcia-Cabezas et al, 2008)
3.3 Direct action of dopamine
With regards to the direct actions of dopamine in the thalamus, electrophysiological studies have shown a broad range of actions the in lateral geniculate nucleus (LGN) (Munsch et al 2005; Govindaiah & Cox, 2005) mediodorsal (MD) (Levin et al, 1998) and Ventrobasal (VB)(Govindaiah et al, 2010) thalamus.
At the dLGN, dopamine modulates inhibitory synaptic transmission, by activating D2-like receptors on GABA interneurons- these are involved in the sharpening of visual contrast information within the visual system (Sherman & Guilery, 2002). This indicates that the dopaminergic system is necessary for visual processing in the LGN, and a fault with this could be a possible contributor to visual hallucinations in schizophrenia.
At the mediodorsal region of the thalamus, D2 specific agonists, but not D1, increased the response of the neuron to depolarization and facilitated occurrence of Low Threshold Spikes.
Faults can be associated with confusion and information processing deficits (Friedberg & Ross, 1993), but alterations in the area have also been associated with sleep deprivation - also linked with schizophrenia.
Fig4 : Increasing levels of dopamine results in increased number of APs in the ventrobasal region of the thalamus. (taken from Govindaiah et al, 2010)
A very recent electrophysiological study of VB thalamocortical neurons has revealed that activation of D1 like receptors, by dopamine agonists, leads to post-synaptic depolarization, whilst D2 like receptors are responsible for an increased action potential discharge. These neurons are located where peripheral sensory information is passed on to other brain structures, including the cerebral cortex, therefore alterations to them could alter processing of sensory information, therefore changing behavioural states (Govindaiah et al, 2010)
5.0 Involvement of Dopamine in Neurological conditions
Schizophrenia is a severe mental illness affecting 1% of the population worldwide, commonly between the age of 15 to 35. The term was invented by Eugene Bleuler in 1908, literally translating as 'split mind'. Symptoms of Schizophrenia can involve a range of psychological malfunctions. They include positive symptoms, which represent changes of thought/ behaviour, such as hallucinations, delusions and/or thought dysfunctions. The negative symptoms, however, appear as a reduction or lack of thoughts/normal functions, for example 'flattening' of emotions, apathy or becoming increasingly uncommunicative. In severe cases a patient might show catatonia, where they may be largely mute, remain motionless or show purposeless agitation. (Kleist, 1960)
Role of dopamine
The Dopamine Hypothesis of Schizophrenia emerged in the 1970s, when it was observed that schizophrenics have an abnormally high level of dopaminergic neurotransmission. Evidence to support this hypothesis have been provided by the role of dopamine and its receptors in
Actions of Antipsychotic drugs at D2 like receptors
Amphetamine induced psychosis
Symptoms and treatments for Parkinson's disease
Carlsson and Lindqvist identified that antipsychotic drugs increased the metabolism of dopamine when administered to animals. Further evidence came from the study of Reserpine, also effective at treating psychosis, was found to block dopamine, plus other monoamines, reuptake leading to their dissipation (Bear, 2009). The clinical effectiveness of these typical antipsychotic drugs directly correlated with their affinity for dopamine receptors, and in addition it has been observed that a D2 occupancy of 80% and over is necessary to induce an anti-psychotic response. However, it was also noted that the prevalence of extrapyramidal side effects (EPS) increases with increasing affinity for D2 leading to the development of new 'atypical' antipsychotic drugs, e.g. Clozapine. These new drugs have proven to have a lower incidence of EPS (Crossley & Constante, 2010), due to a lower D2 affinity, but are still equally effective at depleting psychosis. It is thought this is due to its specific higher affinity for D4 receptors, as well as a faster dissociation from the receptor.
Possible Role of the thalamus
As previously discussed, the thalamus has a very central role within the brain, particularly facilitating making connections between cortical and brain stem regions. Therefore, it is considered that a majority of information is 'filtered' at the thalamus before reaching its target brain area. However, a fault within this gating system could result in and overload of information - making it difficult for the individual to lead a normal life. When considering the symptoms of schizophrenia, particularly positive ones, it seems more than likely that things such as hallucinations or feeling overwhelmed are linked to a fault in this filtering process. Alternatively it could be suggested that negative symptoms are developed as an 'escape' from this input overload (Andreasen, 1997).
Post mortem studies have revealed elevated dopamine levels in the thalamus of schizophrenic patients (Oke and Adams, 1987) suggesting a either a fault with, or fewer numbers of dopamine receptors. More recent research, using PET, has revealed that D2 receptors in the central medial and posterior regions of the thalamus of schizophrenic patients have a lower binding potential for dopamine than normal controls (Yasuno et al 2004), possibly giving an explanation for the defective gating system of the thalamus.
5.2 Parkinson's Disease
Parkinson's is a common, age related, neurodegenerative disorder of the central nervous system that impairs motor skills. It is associated with tremor of the limbs, stiffness and rigidity. A major pathological feature of PD is the loss of dopaminergic neurons in the nigrostriatal pathways, which as mentioned previously, has a major role in the control and initiation of movement. This loss of input to the striatum results in decreased activity of D1-receptor neurons, yet an increase in activity of D2-receptor neurons (Albin et al, 1989)
Levadopa (l-DOPA) is the naturally occurring precursor to dopamine, which is currently synthesised and used world wide as a treatment for PD. Unlike dopamine, is able to cross the blood-brain barrier is later converted in the brain, therefore providing effective treatment for PD symptoms, particularly rigidity and slowness (Hornykiewicz, 1974).
Role of the thalamus
Of the Parkinson's symptoms, there have been marked changes in thalamic neuron activity, yet the cause of them has presumed to be as a result of the basal ganglia malfunction, which then projects through the motor thalamus to the cortex. However more recent evidence shows this presumption could be incorrect, and that there is, in fact, pathology associated within the thalamus of PD patients. Resting tremor is associated with thalamic structural abnormalities, particularly within the ventral posterior and ventral lateral regions (Kassubek et al 2002). More evidence comes in the form of post mortem studies of patients, which displayed overt pathology in the intralaminar and some midline region (Halliday, 2009). When referring back to the dopaminergic mapping of the thalamus, the midline region was the most innervated area, suggesting a link between the pathology and dopamine, yet the intralaminar was revealed as having one of the lowest dopamine concentrations, therefore implying a further cause.
5.3 Drug Addiction
Drug addiction results from a combination of chronic drug administration, with genetic and/or environment variables. Substance use induces euphoria and relieves distress, but repetitive use can lead to changes in the CNS, resulting in tolerance, dependence and desensitization to the drug (Cami & Farre, 2003). Although addiction affects a large percentage of individuals, there is still dispute as to whether it can be classified as a neurological disorder or not. The molecular mechanisms behind addiction are not well known, however it is recognised that dopamine plays an important role. Many addictive drugs block DAT channels, therefore increasing the amount of extracellular dopamine, resulting in an increase in dopamine receptor activation (Giros et al 1996). Regions thought to be involved in drug addiction are the NAc and VTA. Both, as discussed, are part of the mesolimbic system and associated with reward.
Role of the thalamus
Little, if any, research has considered the role of the thalamus in drug addiction, however due to the role of the anterior and lateral nuclei within the limbic system, it could be possible that these play an important role in the disorder.
6.0 Dopamine, the thalamus and creativity
'Creativity' refers to the ability to produce work that is 'novel and meaningful as opposed to trivial or bizarre' (Sternberg & Lubart, 2002). Similarities and/or genetic links between creative thought and psychopathology have been recognized (Hasenfus & Magaro, 1976), particularly because some of the worlds leading artists, such as Vincent van Gogh, have been associated with mental illness, whilst many 'genius' figures such as Albert Einstein, are said to have had closely related family members with schizophrenia (Hare, 1987). Areas of the brain involved in schizophrenia; the striatum, cortex and the thalamus have also been linked with creative thought. Therefore it would seem appropriate to analyse the link between dopamine levels/ receptor binding potential with creativity.
Measuring how creative an individual might be is quite trivial, and the most successful way of measuring individual differences is with a divergent thinking test. It was hypothesized that individuals with low D2 binding potential in the thalamus, yet high D2BP in the striatum, would score highly on the divergent thinking test (Mazano et al, 2010). The results of this investigation proved this hypothesis, with a strong/weak negative correlation between D2BP in the thalamus/frontal cortex respectively and divergent thinking score (BIS), but a very weak positive correlation within the striatum. These indicate that the thalamus is the most influential region when considering creativity, although it would be necessary to look at different dopamine receptors, before making conclusions.http://brainslab.files.wordpress.com/2010/06/manzanodopaminecreativity.jpg
Fig: Showing a strong negative correlation between D2 receptor binding potential in the thalamus, compared with the striatum and frontal cortex, against BIS (creativity) score. (Mazano et al 2010)
Dopamine has numerous functional roles within the nervous system, including involvement in motor, sensory, cognitive and reward pathways. Not only is it the major neurotransmitter in the Nigrostriatal, Mesolimbic and Mesocortical pathways, but it also is necessary for the regulation, or 'gating' of glutamate and GABA projections. Different DA receptor families also have different functons in the brain; whilst D1-like receptors upregulate the production of cAMP, having excitatory effects, activation D2-like receptors downregulate this production, having inhubiting effect on the cell. There is also evidence to suggest that the individual subtypes of these families also have individual roles/different distributions within the brain. The main evidence for this is the production of 'atypical' antipsychotic drugs - thought to target D4, which have proven to be as efficient as typical neuroeleptics, yet reduce the extrapyramidal side effects associated with these prescription drugs.
Because of this involvement in such a wide range of functions, faults in the dopaminergic can have a huge range of effects on normal functioning. This review has looked at Schizophrenia, Parkinson's Disease and drug addiction, but there are many more disorders linked to dopamine including Attention Deficit Disorder and Dystonia.
The aim of this review was to piece together the known components about the dopaminergic system in order to suggest a possible function for the recently recognized innervation of the thalamus. It was not acknowledged for such a long time due to reports that rodents had little if any dopamine present. In a comparison study between a macaque and rat, it was suggested that although there is a much higher proportion of DAT expressed in primates, a small amount is still present within the rodent thalamus. (Garcia-Cabezas et al 2009). Recent electrophysiological studies have shown that regions of the thalamus are still activated in response to dopamine and DA agonists suggesting that there is still a functional role, despite the small numbers. A possible account for these species differences, which also appears in the cerebral cortex (Berger et al, 1991), is evolution of higher brain capabilities in primates. This is a particularly good explanation since the thalamic nuclei which are most densely populated by dopamine, the midline, mediodorsal and lateral posterior nucleus, are those connected with higher associated cortical regions (Sánchez-González et al., 2005).
Continued investigation into dopamine's actions within the thalamus will enable a deeper insight into the functional roles of dopamine, specifically within disease, but also other human behaviours, such as creativity. Further electrophysiological experiments would enable the discovery of individual thalamic nuclei roles, and also a greater understanding of individual DA receptor subtypes. This information could lead to the development of new pharmaceuticals to aid many severe mental and/or physical disorders of the CNS.
8.0 Aims for Project
A rodent brain slice will be used, in vitro, to investigate and compare the actions of dopamine at individual receptor subtypes, located within the mediodorsal and ventromedial regions of the thalamus. These areas were chosen because imaging studies have revealed that they are the most innervated of the thalamus.
In comparison with the studies previously examined, this project will identify the impact of synaptic inputs, i.e. from stimulation of the prefrontal cortex, on the excitability of the neurons - by the measurement of frequency and intensity of actions potentials. Along with the use of dopamine, it is necessary to use highly selective agonists/antagonists in order to indicate the actions of different receptor subtypes, including D1-like, D2-like and more specific D4 receptor actions - see below for details.
Extracellular recordings will be made to measure the activity of the receptors. This technique was chosen over single cell recordings because, despite being slightly more challenging to interpret, its less demanding methodology results in greater time efficiency.
D1- like receptors
Agonist - SKF38393/ Antagonist - SCH23390
D2- like receptors
Agonist - Quinpirole/ Antagonist - Sulpiride
D4 specific agonist - PD168077/ antagonist - L-745,870