Electronic Reviews |
|
|
A BRIEF GUIDE TO NEUROTRANSMITTER SYSTEMS
This review was written for basic
level educational purposes only, and is not intended to serve as a current peer
level review
The catecholamines [epinephrine (adrenalin), norepinephrine
and dopamine] form the adrenergic systems within the CNS. Some of these adrenergic neurons radiate
from the phylogenetically ancient limbic system (emotional centers) and
discharge catecholamines in a diffuse manner into the frontal cortex. The catecholaminergic pathways are thus
responsible for alertness, mood and stress (fight or flight) responses. In addition catecholamines act peripherally
to modulate blood pressure and other functions.
The catecholamines released from the adrenal, predominantly
adrenaline, form part of a hierarchical neuroendocrine system, with CRF
released from the hypothalamus to induce adrenocorticotropic hormone (ACTH)
release from the pituitary, which in turn stimulates the release of
catecholamines and other compounds from the adrenal. Just prior to waking each morning, the brain secretes ACTH to
stimulate adrenalin release from the adrenal gland in the abdomen.
Serotonin is the primary neurotransmitter modulating
the excitatory catecholamine systems in the CNS. Serotonin neurons control memory, mood, sex drive, appetite etc.
The compound has many other functions including allergic response, and
regulation of vasotension, especially in the meninges and other brain tissue.
Dopamine – essential facts
Dopamine is found exclusively in networks from the frontal area - mostly
the frontal lobes, to the amygdala/hippocampus, which is in the limbic system,
inside the temporal lobes. Dopaminergic
systems dominate the activity of those diffuse systems that couple interactions
between the limbic system and the neocortex.
Dopamine systems are in essence a subset of adrenergic systems, as
dopamine is a precursor to adrenaline.
Dopaminergic networks are associated with "pleasure and movement
centers". When animals have probes
implanted that let them self-stimulate the pleasure pathway (dorsal raphe -
ventral tegmental area – nucleus accumbens (NA)/prefrontal cortex (PFC)), they
will often stimulate dopamine release into the NA/PFC, rather than eat or
sleep, until they starve to death.
Dopaminergic systems are therefore thought to control mood, motivation
and reward. Evolutionary psychologists
suggest we evolved these networks to reinforce appropriate survival
pathways. Many rewards and pleasures
can ‘trip the dopamine pleasure switch’, including sex, food, hugging, kissing,
recreational drugs and even video games.
Dopaminergic neurons within the substantia nigra are responsible for
controlling the initiation of movement, resting muscle tone and targeted
movement, and it is these cells that undergo degeneration in Parkinsons,
resulting in the loss of dopaminergic input.
Dopaminergic
Projections
|
|
The projections of the dopamine system can be separated into five
basic systems, four of which are behaviourally relevant. These include the
mesocortical, mesolimbic, tuberoinfundibular and nigrostriatal systems. In general the nigrostriatal system, which
runs directly from the substantia nigra to the caudate and putamen with a
reciprocal feedback inhibition loop which includes acetylcholine and GABA, is
concerned with the initiation and maintenance of motor behaviours. |
The mesolimbic
and mesocortical systems arise from the ventral tegmentum, which lies in close
proximity to the substantia nigra. The mesolimbic system projects to elements
of the limbic system including the amygdala,
hippocampus, nucleus accumbens and the
septal area, which are in close proximity to the caudate and putamen
leading to the term ‘limbic striatum’.
The mesocortical system projects to the frontal cortex, although there
are likely separate feedback loops from each of these systems. As the cells of origin are intermingled,
feedback within the mesolimbic system will also affect the mesocortical system
and vice versa.
The
tuberoinfundibular tract has a major role in the regulation of some
hypothalamic and pituitary peptides including prolactin, with inhibition of
dopamine activity within this tract leading to an increase in prolactin
release. As this system is inhibited in
acute stress, prolactin is regarded as a ‘stress hormone’. This is the reverse of pattern of activity
in the mesocortical and mesolimbic systems, which are activated in stress. It is interesting to note that there is a
lack of autoreceptors on the presynaptic terminals in the tuberoinfundibular
system. Which thus shows profound differences pharmacologically.
The
mesolimbic and mesocortical systems both appear important in the initiation and
maintenance of goal-directed and reward-mediated behaviours. This therefore
includes the proper maintenance of cognitive sets (i.e. logical thought). A dysfunction in this system alters the normal
association process and leads to a breakdown in the proper perceptual
functioning of the heteromodal areas of the frontal lobe. This results in an
inability to filter out non-meaningful or unwanted stimuli – a central feature
of schizophrenia. Possible consequences
would include such experiences as a loosening of associations, bradyphrenia,
flight of ideas and delusional perceptions.
The dopaminergic system may also play a role in the regulation of
affective expression. Huntington's Chorea is a disease state associated with
increased dopaminergic activity, as Parkinson's disease is associated with
dopamine deficiency. Although these diseases are usually considered movement
disorders, they have parallel effects on the limbic striatum as well.
The soma of the
neurons forming the major ascending dopaminergic pathways are located in the
brainstem, in the substantia nigra pars compacta (SNc, A9) and ventral
tegmental area (VTA, A10). The A9 neurones of the SNc project predominantly to
the caudate-putamen or to the dorsal striatum forming the nigrostriatal
dopamine system. However a minor
component of the nigrostriatal system projects from the A8 area to the ventral
putamen. The mesolimbic dopaminergic
pathway is formed by neurons that project from the A10 area to the ventral
striatum, which comprises the nucleus
accumbens, olfactory tubercle and other limbic regions such as the amygdala, hippocampus and septum. In
addition, the A10 area sends axons to the cortical areas such as the medial, prefrontal, entorhinal and
cingulate cortex, a system known as the mesocortical dopaminergic pathway.
There
is good evidence for at least five subtypes of postsynaptic dopamine receptors.
In these innervated brain regions, dopamine receptor are divided into two major
subclasses, termed D1- and D2-like metabotropic
receptors. Each group is divided into
subtypes, i.e. D2, D3 and D4 receptors
belonging to the D2 subclass, and D1 and D5
falling within the D1 subclass. The D1-type and D2-type receptors
(including D4) utilize differing transduction mechanisms. D1 class receptors
appear to be linked to Adenylate Cyclase (AC) activation via a Gs-coupled
mechanism, whilst the D2 class appears to be linked via a Gi-mechanism to AC
inhibition. D2 also inhibits calcium
entry through the voltage-sensitive channels, and possibly also via an increase
in K+ conductance, and therefore D2-type receptors are thought to be
inhibitory. Both D1 and D2 receptors also appear to have an influence on the
PLC system. A subtype of the D2 receptor is the D4 receptor, which is
distributed in the frontal cortex, midbrain and amygdala, but is also present
at low concentrations in the motor striatum.
Rat brain
schematic diagram illustrating the ascending dopaminergic pathways arising
within the substantia nigra (pars compacta, SNc, A9) and the ventral tegmental
area (VTA, A10) depicting main projection areas.
The D1 receptor is expressed in dorsal and ventral
striatum, and within several limbic regions including hypothalamus and
thalamus. In the striatum, D1 receptors are expressed mainly upon GABAergic
medium-size spiny neurons projecting to the SNr. The D5 receptor is expressed within the hippocampus
and some thalamic nuclei.
D2 receptors are expressed in the dorsal and
ventral striatum in GABAergic neurons and are found co localized with
enkephalins. D3 receptors are expressed predominantly within
the ventral striatum, and in particular the nucleus accumbens and olfactory
tubercle, with low levels of detection within the dorsal striatum. In contrast the expression level of D4 receptor is low within the basal ganglia, and
higher within the areas such as frontal cortex, amygdala and hypothalamus.
Since dopamine is
highly concentrated within the striatum, a brain area involved in
extrapyramidal motor activity, it was therefore deduced that dopamine is
involved in the regulation of motor functions.
A deficiency of dopaminergic function underlies the symptoms of
Parkinson's disease, and drugs that modulate dopamine receptor function dictate
extrapyramidal motor function.
The inhibition or
activation of nigrostriatal, mesolimbic and mesocortical projections by lesions
or psychotropic compounds, results in profound and distinct changes in both
spontaneous and drug-induced motor activity.
Activation of nigrostriatal dopaminergic transmission by locally applied
dopamine, amphetamine (an indirect DA receptor agonist) or apomorphine (direct
agonist) induces mainly stereotyped behaviours but not increased
locomotion. In contrast, selective
activation of accumbal dopaminergic transmission augments only locomotor
activity but does not cause stereotyped behaviour.
In the
caudate-putamen, the dopaminergic neurons make synaptic contacts with
medium-size GABAergic spiny neurons, also utilizing enkephalin, substance P and
dynorphin as "cotransmitters".
Dopamine may serve as a modulator of glutaminergic signalling from the
cortical areas through the basal ganglia. The GABAergic neurons projecting from
the dorsal striatum, directly or indirectly, via the globus pallidus and sub
thalamic nucleus to the SNr are central efferents in the regulation of motor
activity. The SNr projects to the
thalamus, which in turn projects to the cortical areas innervating the dorsal
striatum, completing the cortico-striato-pallido-thalamic loop. This circuitry is central in the modulation
of extrapyramidal motor processes, and it is the balance of this circuit which
is disturbed in Parkinson's disease, symptoms of which variously include
tremor, rigidity and difficulties in the initiation of motor (akinesia).
Schematic flow
diagram of the brain structures involved in the regulation of psychomotor and
reinforcement processes and the connections between them (modified from Robbins
and Everitt 1996). CPu = caudate-putamen, GP = globus pallidus, Th = thalamus,
STh = subthalamic nucleus, PPTg = Pedunculopontine Tegmental nucleus, SNc =
substantia nigra pars compacta, VTA = ventral tegmental area, PCF = prefrontal
cortex, VP = ventral pallidum, B = nucleus basalis of Meynert, LH = lateral
hypothalamus, AcbSh = nucleus accumbens, shell; AcbC = nucleus accumbens core.
Similarly to the
caudate-putamen, the nucleus accumbens receives glutaminergic afferents from
some cortical areas and also from the amygdala and hippocampus (Heimer et al.
1995). Stimulation of inputs from the amygdala and hippocampus induces
locomotor stimulation, which can be blocked with dopamine receptor antagonists
(Mogenson 1987). This effect of glutaminergic activation can be enhanced by
direct application of dopamine into the nucleus accumbens.
Similarly to the
dorsal striatum, accumbal dopamine is believed to have a gating function, i.e.
it regulates the information flow from the limbic structures such as amygdala
and hippocampus to the motor nuclei (Mogenson 1987). The nucleus accumbens
sends afferents to the VP, which, in turn projects, to the medial prefrontal
cortex (MPC), thalamus (Th), pedunculopontine tegmental nucleus (PPTg), which
is a part of the mesencephalic locomotor region (Schaefer and Michael 1987),
the medial subthalamic nucleus and SN. In the nucleus accumbens,
dopamine-induced hyperactivity is thought to be caused by its inhibitory effect
on GABAergic neurons projecting to the VP, so that the release of GABA is
decreased following activation of dopamine receptors in the nucleus accumbens
(Bourdelais and Kalivas 1990; Inglis et al. 1994; Mogenson 1987). This is
thought to result in the disinhibition neurons projecting to the mediodoral thalamus
to enhance locomotor activity (Pulvirenti et al. 1991). Another output from the
VP is a pathway to the PPTg, a brain area that could further mediate the
information from forebrain structures to the spinal cord and modulate the motor
behaviour (Mogenson 1987).
The prefrontal
cortex (PFC) is involved in the various cognitive processes such as regulation
of working memory and focused attention and these functions are modulated by mesocortical
dopamine pathway (Barkley 1998; Le Moal and Simon 1991). However, dopamine in
the PFC plays a role in locomotor activity and reinforcement as well. For
instance, attenuation of dopaminergic tone in the PFC by a 6-OHDA lesion
increases the stimulatory effects of amphetamine (Carter and Pycock 1980). These
effects have been suggested to result from disinhibition of the excitatory glutaminergic
afferents projecting from the PFC to the ventral tegmental area and nucleus
accumbens (Taber and Fibiger 1995). Furthermore, rats self-administer cocaine
into the PFC indicating that this brain area could be an important part of the
brain reward circuitry (Goeders and Smith 1983) .
Dopamine, like other
catecholamine neurotransmitters, is synthesized from the amino acid precursor,
tyrosine, which has to be taken up through the blood brain barrier by a
transporter into the dopaminergic cells (Cooper et al. 1986). The first step in
the synthesis of catecholamines is the hydroxylation of tyrosine to DOPA, by
tyrosine hydroxylase, which is also the rate limiting enzyme in the synthetic
cascade (Fig. 2.3.).
In the cytoplasm of
cells, DOPA decarboxylase transforms DOPA to dopamine, which is then carried by
another active transporter to synaptic vesicles, where the molecules are
protected from catabolizing enzymes. The synthesis rate of the dopamine is
dependent on the activity of the tyrosine hydroxylase, an enzyme which is under
the control of many and complex mechanisms (Feldman et al. 1997). The main
short-term regulatory factors are end-product inhibition, firing rate of the
neuron and autoreceptors located in the nerve-endings. The end-product of the
dopaminergic neurons, dopamine, decreases the affinity of the enzyme's pteridine
co-factor for tyrosine hydroxylase, which results in a decrease of enzyme
activity. All of the above-mentioned mechanisms, as well as many other factors
(Feldman et al. 1997), regulate the phosphorylation state of tyrosine
hydroxylase, which is the major factor in controlling its activity.
Figure 2.3. Simplified presentation of the synthesis
of dopamine and its major metabolic routes. COMT =
catechol-O-methyltransferase, MAO = monoamine oxidase, 3-MT =
3-methoxytyramine, HVA = homovanillic acid, DOPAC = 3,4-dihydroxyphenylacetic
acid.
Inside the
dopaminergic cells the cytosolic dopamine is metabolized mainly by two
successive reactions (Fig. 2.3. and Fig. 2.4.). First, monoamine oxidase (MAO)
transforms dopamine to a corresponding aldehyde, which then can serve as a
substrate for aldehyde dehydrogenase to produce 3,4-dihydroxyphenylacetic acid
(DOPAC). DOPAC then diffuses out of the cells and can be either conjugated to
glucuronides or transformed to homovanillic acid (HVA) by catechol-O-methyltransferase
(COMT) (Männistö et al. 1992; Westerink 1979; Westerink 1985). A
portion of MAO is located outside of the dopaminergic neurons, i.e. in the
glial cells, while COMT is found only outside dopaminergic neurons. A
fraction of the released dopamine, the size of which varies in different brain
areas (Karoum et al. 1994) is first O-methylated by COMT to
3-methoxytyramine (3-MT) and then oxidized by MAO to form HVA (Männistö et al.
1992; Westerink 1985; Wood and Altar 1988).
Since COMT
does not exist inside the dopaminergic neurons (Kaakkola et al. 1987; Karhunen
et al. 1995; Rivett et al. 1983; Roth 1992), all 3-MT found in the brain should
be derived from dopamine that is released from the nerve endings (fig 2.4.).
Based on this
scheme, it has been suggested that the 3-MT concentration in the brain tissue
(Di Giulio et al. 1978; Kehr 1976; Kehr 1981; Wood and Altar 1988) or
interstitial fluid (Brown et al. 1991; Kuczensky and Segal 1992) would be an
indicator of dopamine release. Indeed, it has been shown that 3-MT levels in
brain are elevated during electrical stimulation of the dopaminergic neurons
and after drug treatments that increase dopamine release (Wood and Altar 1988).
Fig 2.4. Metabolism of dopamine in the dopaminergic
nerve terminal and synapse. DA = dopamine, COMT = catechol-O-methyltransferase,
MAO = monoamine oxidase, 3-MT = 3-methoxytyramine, HVA = homovanillic acid,
DOPAC = 3,4-dihydroxyphenylacetic acid.
Methods such as
in vivo micro dialysis and voltammetry have enabled the measurement of
concentrations of extracellular neurotransmitters, such as dopamine, in awake,
freely moving animals (Lane and Blaha 1986, Di Chiara 1990). One major benefit
of these methods is that they allow comparison of drug-induced changes in
dopamine release as a function of time in the same animal, which is not
possible when post mortem tissues are studied. However, utilization of
post mortem metabolite analysis from brain samples has some advantages
over the methods mentioned above. For instance, measurement of dopamine
metabolites in post mortem tissues permits the examination of
dopaminergic activity simultaneously in several brain regions.
Measurements of
DOPAC and HVA concentrations have been also used to assess the activity of
dopaminergic neurons (Di Giulio et al. 1978; Roffler-Tarlov et al. 1971;
Westerink 1985; Wood and Altar 1988), but it is evident that after certain drug
treatments dopamine release and formation of these acidic metabolites become
dissociated (Miu et al. 1992). Since MAO exist also inside the dopaminergic
cells, a large portion of DOPAC is formed from newly synthesised dopamine
without release of dopamine to the synaptic cleft. This may occur especially
during elevated dopamine synthesis. For instance, decreasing the impulse flow
in the dopaminergic neurons by infusion of tetrodotoxin into the medial
forebrain bundle elevates DOPAC and HVA concentrations due to increased
dopamine synthesis, although it decreases dopamine release (Miu et al. 1992).
On the contrary, amphetamine, cocaine and other dopamine reuptake inhibitors
induce a robust increase of extracellular dopamine levels but decrease
concentrations of DOPAC and HVA (Brown et al. 1991; Hurd et al. 1989; Westerink
and Spaan 1982).
Utilisation of
tissue 3-MT in measurement of dopamine release is complicated by the rapid and
massive accumulation of 3-MT in brain after death (Carlsson et al. 1974; Damsma
et al. 1990; Gonzales-Mora et al. 1989; Phebus et al. 1986), which may interfere
with drug-induced changes. In order to prevent the effect of post mortem
changes, experimental animals have been sacrificed with brain-focused microwave
irradiation, which rapidly denature brain enzymes and prevents the formation of
3-MT by inactivating COMT (Blank et al. 1983; Ikarashi et al. 1985;
Lenox et al. 1979). Another approach has been rapid freezing of brain tissue,
which, however, is not so suitable at least when rats are being used as
experimental animals (Carlsson et al. 1974; Di Giulio et al. 1978; Ikarashi et
al. 1984; Westerink 1979).
However, despite the
use of the microwave technique, the validity of measurement of steady state
3-MT, especially in the assessment of increased dopamine release, has been
questioned in some situations. In studies on the effects of neuroleptics on
dopamine metabolism, drugs such as haloperidol, which blocks the pre- and
postsynaptic dopamine receptors and thus increase dopamine release, have
sometimes clearly increased 3-MT concentrations (Gropetti et al. 1978; Karoum
and Egan 1992), induced only transient increase (Ponzio et al. 1981; Westerink
and Spaan 1982) or even decreased 3-MT levels (Waldmeier et al. 1981).
Similarly, µ-opioid receptor agonists have caused variable effects on 3-MT
levels in rat striatum (Wood and Rao 1991; Yonehara and Clouet 1984).
Drug-induced changes in extracellular 3-MT levels collected by micro dialysis,
however, are qualitatively similar to changes in extracellular dopamine
indicating that 3-MT levels in brain do reflect dopamine release (Brown et al.
1991; Kuczensky and Segal 1992; Wood et al. 1988; Yonehara and Clouet 1984).
Extensive research
during recent decades has revealed that dopaminergic mechanisms are important
part of the brain reward circuitry (Wise and Rompré 1989). These neuronal
pathways are believed to mediate the reinforcing effects of different stimuli,
which exert control over behaviour. In operant psychology, a reinforcer is
defined as a stimulus that increases the probability of operant or instrumental
responses that precede or are contingent upon the stimulus (Robbins and Everitt
1996; Stolerman 1992). One example is provided by animals, which learn to press
a lever in order to stimulate certain areas of their brain in operant chambers
(Olds and Milner 1954). The neuronal substrates of stimulation are believed to
be, at least partly the neuronal circuitry, which mediates reinforcement (Olds
and Milner 1954; Wise and Rompré 1989). In the "Biological theory of
reinforcement" Glickmann and Schiff (1967) suggested that the same brain
structures e.g. medial forebrain bundle (mfb) that were found to be substrates
for brain stimulation reward also mediate the species specific sequences of
approach behaviour. According to this idea, the positive reinforcement process
is reflected as forward locomotion or as some other approach response towards a
stimulus.
Research also
revealed that several drugs of abuse can serve as reinforcers in an operant
situation, i.e. experimental animals learned to press a lever in order to get
an intravenous infusion of heroin or amphetamine (Ettenberg et al. 1982;
Pickens and Harris 1968; Pickens and Thompson 1968). The major neuronal systems
that form the medial forebrain bundle are dopaminergic and noradrenergic
pathways (Björklund and Lindvall 1984), emphasizing the involvement of these
neurotransmitter systems in the intracranial self-stimulation (ICSS) reward.
The role of these neurotransmitters both in drug reward and ICSS has also been
supported by the observation that psycho stimulants increased release of these
substances in brain, while treatments that decrease noradrenergic and
dopaminergic activity also attenuated ICSS (Fibiger 1978). However, studies,
where the function of certain dopaminergic or noradrenergic pathways were
blocked pharmacologically or with selective lesions, strongly supported the
role of dopaminergic but not that of noradrenergic system as a substrate for
the reinforcing effects of drugs of abuse (Fibiger 1978; Wise and Rompré 1989).
As reviewed above,
there are several dopaminergic systems in the brain and also in the medial
forebrain bundle (Björklund and Lindvall 1984). It is known that the role of
these pathways in the regulation of behaviour is different and that each subsystem
also has several functions, at least partly depending on the functional role of
the neuronal systems they interact with (Amalric and Koob 1993; Le Moal and
Simon 1991; Robbins and Everitt 1996; White 1989).
If one considers the
mesolimbic dopamine system's projection areas, the nucleus accumbens has been
shown to be critically involved in mediation of reinforcing properties of both
drugs of abuse and of natural rewards such as feeding, drinking and sexual
behaviour. Many different kinds of rewards increase dopamine release in that
brain area (Di Chiara and Imperato 1988a; Kiyatkin 1995; Rosaria and Argiolas
1995), and attenuation of dopaminergic signalling in the nucleus accumbens
decreases the reinforcing properties of these stimuli in different animal
models (Ettenberg 1989; Rosaria and Argiolas 1995; Wise and Bozarth 1987).
Based on these findings it has been suggested that accumbal dopaminergic
neurons would be the final common pathway through which different reinforcers
mediate their behavioural effects (Wise and Rompré 1989).
Although the
mesolimbic dopamine system is now generally accepted to be central in the
reinforcing effects of various rewards, during recent years its exact role has
become the subject of intense debate (Bechara et al. 1998; Berridge and
Robinson 1998; Di Chiara 1995; Salamone 1996; Schultz et al. 1997; Wise 1996).
The psychomotor stimulant theory of addiction by Roy Wise and Michael Bozarth
(1987), states that the nucleus accumbens dopamine mediates the rewarding,
pleasurable or hedonistic effect of the reinforcer and blockade of dopamine
receptors antagonizes the hedonistic effects of a given reinforcer. There is,
however, also plenty of evidence in conflict with this idea. For instance, it
seems that dopaminergic mechanisms are not critically involved in alcohol or
opioid-induced reinforcement, since reduction of dopaminergic tone does not
always affect alcohol drinking, opioid self-administration or opioid-induced
conditioned place preference (Ettenberg et al. 1982; Gerrits and Van Ree 1996;
Kiianmaa et al. 1979; Linseman 1990; Mackey and Van Der Kooy 1985). Recent
findings suggest that dopamine does not necessarily play a pivotal role in
intracranial self-stimulation reward (Garris et al. 1999). Therefore, several
other views about the role of dopamine in reinforcement processes have been put
forward.
The theory
formulated by Robinson and Berridge (Robinson and Berridge 1993) proposes that
dopaminergic mechanisms in the nucleus accumbens would not be necessarily
central to the subjective pleasurable effects of reinforcers. According to this
idea, elevated dopaminergic tone "attributes incentive salience" to
those stimuli that are associated with dopamine release, i.e. enhanced
dopaminergic transmission make those events associated with elevated dopamine
transmission salient and wanted. Strong activation and sensitization of the
dopamine system induced by drugs would, therefore, make the drug effects
pathologically attractive and wanted.
A modification from
the theories involving dopamine holds that dopamine mediates incentive
reward-dependent learning (Di Chiara 1995; Schultz et al. 1997). This idea is
based, for instance, on electrophysiological experiments showing that
dopaminergic neurons of the monkey will respond to a novel, rewarding stimulus,
e.g. delivery of juice. However, the activation of the neurones fades when the
animal learns to expect the reward, but subsequently, after the learning, the
environmental cues predicting the reward are able to activate nigral dopamine
neurons (Mirenowicz and Schultz 1996; Schultz et al. 1997). Thus, in the
learning phase, dopamine may serve as signal about the significance of the
event.
Furthermore, van der
Kooy and his associates have suggested that brain dopamine would mediate reinforcement
only in the withdrawal state, i.e. after cessation of repeated opioid treatment
or in food-deprived animals (Bechara et al. 1992; Bechara and van der Kooy
1992). Normally other, non-dopamine mechanisms mediate positive reinforcing
effects of opioids or food etc.
In addition to its
role in the control of motor behaviour, also the nigrostriatal system is known
to be involved in certain memory and learning processes. Dorsal striatum and
its dopaminergic systems have been suggested to be central in the forming of
habits or stimulus-response association, i.e. certain sequences of motor
actions are "built in" the striatal circuitry, which then mediates
learned responses to the appropriate environmental stimuli. This means that the
dorsal striatum mediates "less cognitive" but more "rigid"
learning (White 1997), which is also "impervious to fluctuations in the
value of reinforcer" (Robbins and Everitt 1996). Therefore, also
nigrostriatal dopamine system may have a role in drug reinforcement and the
development of addiction.
It
is, thus, evident that dopaminergic pathways in brain are important in the
regulation of certain learning, motivational and reward processes. However,
their exact role is not known, and it is likely that ascending dopaminergic pathways
have multiple roles in these functions.
Dopamine agonists / facilitators
Amphetamine, cocaine are dopaminergic stimulants acting to inhibit dopamine
reuptake. Dopexamine is a cardiotonic,
whilst the dopamine agonist Fenaldopam is used as an antihypertensive. Metoclopramide is a potent dopaminergic
antagonist employed to alter cholinergic systems, whilst
Pergolide is an ‘ergot’ derivative dopamine agonist employed against
Parkinsonism. Methysergide,
bromolysergide, ergotamine, bromocryptamine and lisuride are all LSD analogs,
which are devoid of hallucinogenic properties, and are used as anti-Parkinson
and anti-Alzheimer's drugs. Naxagolide
is a selective D2 agonist useful in Parkinsonism.
Dopamine antagonists
Dopamine antagonists are used primarily as ant psychotics. Blocking dopamine
systems results in a reduction of spurious, disruptive impulses including
auditory hallucinations endemic to schizophrenia. The main danger with such
drugs involve an induces hypersensitivity to dopamine, particularly a movement
disorder called tardive dyskinesia. Older drugs like Thorazine, which are less
selective for D2, may be less hazardous in this regard than newer, more potent
and more selective agents such as Haldol and Risperdal. Even newer drugs like
clozapine and olanzapine (Zyprexa) also block dopamine but have complications
through non-specific actions at serotonin receptors. The reduction in the
natural reward sensations mediated by these pathways results in a "flattening"
of affect.
Noradrenaline – essential facts
|
|
An idea of the behavioural effects of a transmitter system is at least
partially disclosed by studying the projections of its pathways (releasing
terminals). The fibres of the NE tract sweep over the anterior pole before
proceeding caudally. Thus, lesions along the pathway can result in a
functional decrease in NE activity. Thus anterior strokes result in a state
similar to functional depression. The
fibres from the lateral tegmental neurons proceed caudally into the spinal
cord and anteriorly into the diencephalon and basal forebrain region. The
basal forebrain is the region just inferior to the anterior part of the
corpus callosum. This is an extremely important region behaviourally. It
includes the septal nuclei, which are central in the reward and reinforcement
system. |
There are two major
noradrenergic cell groups in the neuroaxis. (1) The locus ceruleus (LC) in the
caudal pontine grey which spreads anteriorly forming an extensive net
throughout the cortex. (2) Group projecting from the lateral tegmental neurons
caudally to the spinal cord and rostrally into the diencephalon. Axons of the
LC neurons have varicosities that allow a widely distributed release of
norepinephrine suggesting neuromodulatory function. Two noradrenergic tracts
relevant to behaviour project from the LC and lateral tegmental neurons; the
dorsal bundle and the median forebrain bundle. The widespread network that
these neurons create includes an innervation of specific hypothalamic and
thalamic cell groups. The LC is implicated in learning, memory, anxiety and
psychosis. The noradrenergic system is believed to play a role in the
orientation of the brain to stimuli in the environment and viscera, as it is
activated by a range of sensory stimuli, and thus seems to be related to
attention and vigilance. Such a responsivity or attentiveness to environmental
stimuli may play a role in motivation in exploration of the environment, which
potentially leads to reward, and thus another aspect of the ‘vigilance’ system
is its role in reward and reinforcement.
The noradrenergic system also plays a central role in the control of the
autonomic nervous system and in wakefulness. Studies of psychopathology suggest
that over activity of the LC system is associated with anxiety disorders and
drug withdrawal states. It can be seen that dysfunction of the LC circuitry would
result in hypothalamic dysfunction, anxiety, hedonic alterations (i.e. changes
in pleasure-seeking behaviour), autonomic arousal and sleep disturbances. Thus
the LC is a focus of interest in affective and anxiety disorders, and in drug
addiction and withdrawal.
Adrenaline – essential facts
Adrenaline is present in small quantities within the central nervous
system, but its major site of synthesis is the adrenal medulla and thus its major
mode of action is hormonal rather than as a neurotransmitter like
noradrenaline. Adrenaline is thus one
of the outputs of the Hypothalamic-Pituitary-Adrenal (HPA) axis, and is
released is response to a bolus of adrenocorticotropic hormone (ACTH) from the
pituitary, which is in turn released in response to CRH/CRF from the
hypothalamus. Adrenaline not only
increases sympathetic nervous system activity leading to the constriction of
blood vessels, increases in heart rate, but adrenaline also stimulates
norepinephrine binding sites (like a dose of methamphetamine or cocaine) and
stimulates a dopamine and serotonin response.
This leads to fight or flight behaviours and a stress response
systemically and behaviourally.
Serotonin – essential facts
Serotonin is released not only at specific synaptic sites, but also in a
diffuse manner into the central nervous system from sets of "diffuse"
neurons emanating from the emotional centers within the limbic system into the
frontal lobe. This diffuse release sets the biochemical tone of large areas of
neural functioning, controlling mood and motivation. Serotonin's inhibitory
action is however more complex and selective than that of GABA benzodiazepine
class drugs, which appear to have a more global action. Because of their general effects on mood,
serotonin-active drugs are used as antidepressants and anxiolytics
(anti-anxiety) drugs.
Levels of serotonin are elevated within dominant members of hierarchical
animal societies. CNS serotonin systems
may have evolved in parallel with dopaminergic projections during the evolution
of complex social hierarchies and the need to accommodate fight-or-flight
impulses within an increasingly complex cognitive and sensory social
hierarchical environment.
|
|
Serotonin (5-HT) is an indolamine monoamine
neurotransmitter synthesized by a pathway analogous to that of the
catecholamines. However the rate-limiting step for 5-HT synthesis is the
neuronal uptake of tryptophan. This
system allows a multitude of factors to ultimately influence the rate-limiting
step in serotonin synthesis. As
tryptophan is taken up across the blood-brain barrier in competition with
other amino acids in an insulin and glucose concentration-sensitive manner,
and binds to serum albumin at hydrophobic sites. Increases in free fatty acid levels, such as occurs in response
to acute stress which increases the glucocorticoid response, exercise or
acute alcohol consumption displaces tryptophan from albumin and thus
increases tryptophan availability for 5-HT synthesis. Metabolism of 5-HT is
primarily through MAO yielding the principle metabolite 5HIAA.
|
There
are three basic types of serotonin receptors; 5HT-1, 5HT-2, and 5HT-3. The
5HT-3 receptor is notably abundant in the area postrema, which stimulates
emesis. There are at least four major subtypes of 5HT1 receptors, the most
important of which is 5HT-1a autoreceptors, which is expressed within the Raphe
and Hippocampus. This implies that 5-HT1a modulates 5HT release from
presynaptic neurons. 5HT-1a receptors
are G-protein coupled, and play a role in thermoregulation, arteriolar
vasomotor responses, hypotension, sexual behaviour, and sleep. 5HT-2 receptors are prevalent throughout the
cortex and mediate platelet aggregation, vasomotor contraction and again
possibly sleep.
|
|
The projections of the serotonin system arise from
the nuclei of the dorsal raphe and the raphe magnus, which are located so as
to monitor, and process ascending sensory input, and serve to facilitate
information processing. The key position
of these serotonergic nuclei in the processing of sensory inputs underlies
the concepts of sensory gating and directed attention. The Locus Ceruleus is important in arousal
and vigilance, which is in effect a state of increased sensory arousal,
necessary, but not sufficient, for focus or directed attention. Focused attention by definition requires
that incoming sensory information be given a priority according to
importance. Habituation is said to
occur if stimuli are not reinforced. A lack of directed attention can appear
as impaired concentration.
|
Disruption of serotonergic tone can affect the exploratory behaviour of animals, instead directing attention and behavioural importance towards meaningless stimuli. Animals have perseverative responses in serotonin deficient states and behavioural over activity in states of serotonin excess. Atypical neuroleptics are thought to act through a 5HT receptor antagonism to restore a proper sensory gating and ability to direct attention.
5-HT antagonists
Ondansetron serves a selective antagonist for 5-HT3 receptor subtypes
found predominantly upon cholinergic neurons, and when activated it inhibits
ACh release. Along with related compounds such as granisetron and zatosetron it
may become the basis for ‘memory’ enhancing drugs in the aged.
Serotonin
is an indolamine monoamine neurotransmitter. The synthetic pathway is analogous
to the catecholamines in many ways. An important distinction is that the rate-limiting
step is the uptake of tryptophan into the neuron. Tryptophan availability is
the actual rate-limiting factor in the intact animal. Tryptophan crosses the
blood brain barrier via an active transport mechanism in competition with other
neutral amino acids such as leucine, lysine, and methionine. The activity of
this transport mechanism is facilitated by the presence of insulin and glucose.
Another interesting aspect of this system is the fact that tryptophan is one of
the few amino acids which is bound in the plasma to any significant degree. The
actual binding site is the fatty acid binding site of the albumen. This system
allows a multitude of factors to ultimately influence the rate-limiting step in
serotonin synthesis. For example anything which increases free fatty acids
would displace the tryptophan and thus increase the percent free which is able
to cross the BBB. An example of such events includes any acute stressor which
increases glucocorticoid response, exercise, and acute alcohol consumption.
The
metabolism of serotonin is primarily done by MAO. The principle metabolite is
5HIAA. The same statements concerning the CSF measurement of MHPG and HVA
applies to 5HIAA.
There
are three basic types of serotonin receptors; 5HT-1, 5HT-2, and 5HT-3. The
5HT-3 receptor is present in the area postrema, which stimulates emesis. The
5HT-1 and 5HT-2 receptors are of a greater interest for psychiatry. The 5HT1
receptors have been sub typed by DNA cloning and differential pharmacology into
four major subtypes. The most important is the 5HT-1a that is located in the
Raphe and Hippocampus. This receptor is implicated as an autoreceptor that
modulates 5HT release from presynaptic neurons. In addition the 5HT-1a
receptors are G-protein linked and have been implicated in thermoregulation,
arteriolar vasomotor responses, hypotension, sexual behaviour, and possibly
sleep. The 5HT-2 receptors are located throughout the cortex and have been
implicated in platelet aggregation, vasomotor contraction, head twitches, and
possibly sleep. Pharmacologically these receptors are important and are
affected by a wide variety of pharmacological agents including butyrophenones,
and phenothiazines.
Disruption
of the normal serotonergic tone in animals can affect their exploratory behaviour.
Animals seem to endow meaningless stimuli with relative behavioural importance.
That is they seem to have perseverative responses in serotonin deficient states
and behavioural over activity in states of serotonin excess. It has been
suggested that some patients with neuroleptic resistant psychosis have a
dysregulated serotonin system. Some of the effects of atypical neuroleptics are
thought to be mediated through a 5HT antagonism. It would seem that these
agents restore a proper sensory gating and ability to direct attention
The catecholamines
that act as neurotransmitters include dopamine and norepinephrine. Epinephrine
is not produced in the central nervous system, but in the peripheral nervous
system (adrenals). The catecholamines share a common synthetic pathway. The rate-limiting
step is tyrosine hydroxylase. The activity of tyrosine hydroxylase can be
modified by phosphorylation. This provides a point of regulation for the
neuron. Clinically there are no agents capable of modulating tyrosine
hydroxylase. However, treatment with agents such as methyldopa can compete with
dopa for further processing. The result is a formation of false
neurotransmitters. The false neurotransmitters are packaged in the synapse as
though they were the catecholamine but when released into the synapse they are
ineffective at the receptor. False neurotransmitters such as octopamine are
also thought to be increased in hepatic encephalopathy. The packaging of false
transmitters in the periphery is thought to be increased by inhibiting MAO.
This is thought to explain the orthostatic blood pressure effects caused by
therapeutic doses of MAO inhibitors.
The
major biochemical difference between the norepinephrine and dopamine neurons is
the presence of a vesicle bound copper-containing enzyme in the neurons of the
norepinephrine neurons. This enzyme is dopamine beta hydroxylase. It catalyses
the synthesis of norepinephrine from dopamine.
The
catecholamines have similar metabolic pathways. The chart below shows these
pathways. A point of potential therapeutic intervention in metabolism is at the
level of monoamine oxidase. MAO is primarily found associated with the
mitochondria. The intracellular site of MAO suggests it is involved in
metabolizing catecholamines once they have been taken back up into the neuron
to prevent repackaging them into the synaptic vesicles. There are two MAO isozymes.
MAO-A appears to be a specific enzyme for serotonin and norepinephrine. MAO-B
is a more broadly active enzyme that acts on phenylethylamines.
Tyramine
and dopamine are equally good substrates for both MAO-A and MAO-B. There is an
anatomic distribution of the isozymes. MAO B is found primarily in the brain.
MAO A is found thought the body and especially in the GI tract where it may
serve to limit the absorption and physiologic effect of dietary monoamines.
There are specific inhibitors of each of these. Non-specific MAO inhibitors
must inhibit all the MAO. Because specific MAO inhibitors only inhibit one of
the isozymes there is always MAO activity present. This has a couple of
consequences; first there is less chance for a tyramine effect, second there is
less orthostatic effect.
As
you see from the chart the catecholamines are also metabolized by
catechol-O-methyl transferase (COMT). COMT is present extracellularly. MAO can
act before or after COMT of the catecholamines. Make note of the metabolic
products as these can reflect the turnover of the neurotransmitters.
Catecholaminergic synapse
The norepinephrine and dopamine synapses are basically analogous. Important extracellular features include the presence of reuptake sites, multiple postsynaptic receptors, and autoreceptors and presynaptic receptor sites. The 'function' of a neurotransmitter depends on a combination of the network it is being used in, and the post-synaptic receptor's behaviours. The autoreceptors modulate the release of neurotransmitter by the presynaptic neuron. The autoreceptors are believed to have a difference in affinity with the neurotransmitter. This is shown by the fact that extremely low doses of a receptor agonist are inhibitor to the release of endogenous transmitter and low dose of a receptor antagonist augments release of neurotransmitter. It is believed that this explains the early increase in HVA that occurs when neuroleptics are first initiated. Some neurons appear to have both presynaptic facilitatory and inhibitory receptors. The presence of both a presynaptic facilitating and presynaptic inhibitory autoreceptor suggest the need for fine-tuning of the release of the neurotransmitter. It should be obvious that the relative proportion of each can adjust the set point of the neurons release of neurotransmitter much like the maxima and minima of a feedback circuit adjust the activity of a domestic process. Enduring changes in activity can be achieved by altering the genetic expression of one or both of the genes for these autoreceptors. In general the mechanism of the effects of these presynaptic autoreceptors are the same as in presynaptic inhibition or facilitation. That is they modulate Ca++ channels or influence the membrane potential of the presynaptic neuron or they influence adenylate cyclase activity.
|
Catecholamines;
synthesis and storage The
catecholamines share a common biosynthetic pathway utilizing the aromatic
amino acids L-Tyrosine and L-Phenylalanine, entry into which is governed
by the activity of tyrosine hydroxylase, which is extensively modulated
at many levels. Epinephrine, the final step in the pathway
is not thought to be produced within the central nervous system outside
of the dorsal and rostral ventrolateral medulla oblongata, but instead
within the peripheral nervous system (adrenals).
The major defining difference between the norepinephrine and
dopamine producing neurons is the presence of a vesicle bound, copper
containing enzyme dopamine beta hydroxylase in the neurons of the norepinephrine
neurons. The catecholamines share metabolic pathways for synthesis and degradation,
and it is at this point, especially at the level of monoamine oxidase
(MAO), that therapeutic intervention may occur. MAO is primarily associated with the mitochondria,
and it mediates the metabolism of catecholamines once they have been
taken back up into the synaptic terminal. MAO exists as two isozymes,
MAO-A preferentially oxidizes serotonin and norepinephrine and the broader
spectrum MAO-B that preferentially oxidizes phenylethylamine (PEA).
MAO isoforms do not discriminate between tyramine and dopamine substrates,
and the two are differentially distributed, with MAO B predominantly
present in brain and MAO A in the body and GI tract, presumably for
the metabolism of dietary monoamines and adrenaline. However, the substrate specificity overlap and the in vivo function of
these two isozymes is not clear. MAO A and B knock out (KO) mice exhibit
distinct differences in neurotransmitter metabolism and behaviour. MAO
A KO mice have elevated brain levels of 5-HT, NE and DA and manifest
aggressive behaviour similar to men with a deletion of MAO A. In contrast,
MAO B KO mice are not aggressive and only levels of PEA are increased.
Both MAO A and B KO mice show increased reactivity to stress. MAO A
and B have distinctly different roles in monoamine metabolism. Catecholamines are also metabolized by catechol-O-methyl transferase
(COMT), which is present extracellularly.
MAO can act before or after COMT in catecholamine catabolism.
The autoreceptor principle Synapses are characterized by the presence of reuptake sites, multiple
postsynaptic receptors, and autoreceptors and presynaptic receptor sites.
The 'function' of a neurotransmitter depends on a combination of the
network it is being used in, and the post-synaptic receptor's behaviours.
The autoreceptors modulate the release of neurotransmitter by the presynaptic
neuron. The autoreceptors are believed to have a difference in affinity
with the neurotransmitter. This is shown by the fact that extremely
low doses of a receptor agonist inhibit the release of transmitter,
and low doses of a receptor antagonist augment the release of neurotransmitter.
Some neurons appear to have both facilitatory and inhibitory presynaptic
autoreceptors. The presence of both a presynaptic facilitating and presynaptic
inhibitory autoreceptor suggest that there is a fine-tuning of neurotransmitter
release. Thus adaptive changes
in synaptic output and activity can be achieved by altering the genetic
expression of one or both of the genes for these autoreceptors. In general
the mechanism of the effects of these presynaptic autoreceptors is to
modulate calcium entry through voltage-gated calcium channels, or to
otherwise influence presynaptic excitability, often through changes
in adenylate cyclase activity.
Acetylcholine, synthesis and release Acetylcholine is one of the oldest and best understood neurotransmitters.
This is likely because of its actions at the neuromuscular junction
and the accessibility of this site to study. Unfortunately the ability
to study the central cholinergic system is relatively new. Unlike the
catecholamines acetylcholine is a relatively simple structure with no
aromatic rings. The ability to measure acetylcholine in body fluids
had to await the development of better assays in the late 60's and 70's.
The synthesis of acetylcholine is relatively simple and straightforward.
It is synthesized from acetyl~CoA + choline by an enzyme known as choline
acetyltransferase (CAT). This enzyme is contained only in cells, which
synthesize acetylcholine. It is a marker enzyme that identifies cholinergic
cells. Recall that Acetyl CoA is derived during the metabolism of glucose.
Choline is derived from dietary sources and from phosphatidylcholines.
After acetylcholine is released into the synapse it ultimately undergoes
hydrolysis to release the choline and acetate. The choline is taken
back up into the presynaptic neuron about 1/3 to 1/2 of the time. The
choline can then be used to resynthesize acetylcholine or can be used
to synthesize phospholipids that can be used as stores of choline. The
diagram below describes the points of pharmacological interventions. Acetylcholine is metabolized by cholinesterases. There are several types
the two most often referred to in reference to acetylcholine metabolism
are acetylcholinesterase and butyrylcholinesterase or pseudocholinesterase.
In the synapse the cholinesterase seems to be intimately related to
the actual receptor. This enzyme is inhibited by physostigmine and organophasphates. Acetylcholine
receptors
There are two major types of cholinergic receptors
based on differential binding. The first type is the nicotinic receptor
and the second is the muscarinic receptor. DNA cloning has identified
five subtypes of muscarinic receptors. All of these muscarinic receptors
are G-protein linked. The muscarinic subtypes also seem to have a differential
distribution in mammalian brain. The nicotinic receptor is a ligand-gated
channel composed of five subunits. It is primarily the responsible for
the peripheral effects of acetylcholine at the autonomic ganglia and
the neuromuscular junction. There may be some nicotinic receptors centrally
but their contribution is uncertain. The nicotinic receptor is composed of 5 subunits. Of interest is the
finding that injection of one of the more lipophilic subunits into the
rabbit results in a syndrome indistinguishable from myasthenia gravis.
This has confirmed suspicions that MG is an autoimmune disease. Nuclear medicine techniques are able to preferentially bind the muscarinic
receptors with an agent known as dexitimide and QNB. Studies are underway
for evaluating the sensitivity of these agents in the evaluation of
Alzheimer's disease.
Acetylcholine
projections
The
chart below illustrates the major central projections of the cholinergic
system. In essence there are three important cholinergic systems for
neuropsychiatry. The first is the nucleus basalis of Meynert. This nucleus
lends projects to the cortex. It is one of the nuclei that is impaired
in senile dementia of the Alzheimer's type. It is suggested that this
nucleus plays a role in learning and memory. In addition the cholinergic
neurons in the basal forebrain are involved in cognitive integration
of vegative and motivationally relevant information. We will discuss
this in more detail when we discuss the dementias. The second system arises from the brainstem. This system sends cholinergic
fibres to the midbrain and thalamus. It is suggested that this system
is related to sleep-wake rhythms and turning on REM. It is felt that
this group of neurons acts as a sensory filter in some way. It has been
shown, (here at UAMS) that schizophrenics has a less CAT in the pontine
cholinergic nucleus. The meaning of this is uncertain. It is of interest
that anticholinergic agents are well known psychotomimetics in high
doses. The third group is the cholinergic neurons in the basal ganglia. GABA receptors
Overview Subtypes of
GABA receptors (GABAA subtype) as well as the antispasmodic amino acid baclofen (GABAB
subtype). There are few selective
GABAC class drugs although
CACA and TACA are relatively selective GABAc agonists. All these are agonists that directly mimic
the action of GABA at the receptor.
Allosteric facilitation of GABA receptors occurs at several distinct
sites; the compounds that bind there are used as sedatives and anxiolytics.
These compounds may act to alter the receptor conformation to favour open
states upon GABA binding. Chemical variants of the beta carbolines
(tetrahydro forms) have been detected in human urine and milk and occur more
plentifully in herbs such as passion flower, yage and B. caapi. GABA synthesis, storage and release
GABA
was identified in the mammalian brain in 1950's and is the one of the
major inhibitory neurotransmitters in the brain together with glycine.
GABA is synthesized from Glutamate, by the GABAergic neuronal marker
Glutamic acid decarboxylase (GAD), which intriguingly is believed to
be the autoantigen in type I diabetes. As GAD is a pyridoxal cofactor
dependent enzyme, one congential form of B-6 vitamin deficiency is known
to predispose to seizures which therefore are, logically, vitamin B6
responsive. Thus L-glutamate is a pivotal amino acid dervied from a-ketoglutarate,
one of the Krebs cycle intermediates, via the addition of an amine group.
L-Glutamate undergoes a second transamination to form L-glutamine by
the addition of another amine group. Glutamine then proceeds to the
liver where it is recycled by deamination to recover L-glutamate which
then returns to the brain effecting the brain’s nitrogen cycle. In situations
where the liver is unable to deaminate L-glutamine the brain must obtain
glutamate by depleting Kreb's cycle intermediates, thus impairing cerebral
energy metabolism.
GABA
reuptake mechanisms in the neurons or by astrocytes terminate the GABA
synaptic signal, rather than by an extracellular synaptic enzymatic
activity such as Acetylcholinesterase. A further control mechanism for
the release of GABA is by presynaptic autoreceptor (GABAB).
GABA is metabolized by the enzyme GABA transaminase to form succinic
acid semialdehyde, which is further metabolized to form succinic acid,
another Kreb's cycle intermediate. As GABA transaminase is inhibited
by valproic acid, this has led to thought that valproic acid is a GABAergic
agent. There are other alternative pathways for GABA metabolism.
GABA receptor subtypes
There are three basic GABA receptor subtypes, GABAA, GABAB and GABAC. GABAA and GABAC receptors belong to a superfamily of ions transmitter operated (ligand-activated) ion channels which includes the nicotinic acetylcholine, serotonin (5-HT3) and glycine receptors. GABAA and GABAC receptor channels are chloride ionophores. Binding of GABA to these receptor increases the permeability to chloride ion which causes a hyperpolarization of the neuron or inhibition where chloride ions are actively excluded to below the Equilibrium Potential for Chloride (ECl). Such receptors are believed to be pentameric, that is five subunits surround a pore.
All members of this receptor superfamily share a common predicted topology, with an N-terminus that contributes towards the ligand binding domain, four TransMembrane spanning domains (TM1-4), an intracellular regulatory loop that receives phosphorylation signals and receptor anchoring, and a pore region contributed by residues of the second transmembrane domain (Sigel, 1995). The considerable functional diversity of GABAA receptor-channels arises not only from the diversity of subunits which coassemble to form ion channels, a repertoire which includes a1-6, b1-4, g1-4, d, e, p and q (Rudolph et al., 2001, Whiting et al., 1999a; 1999b), but also from the alternative splicing and RNA editing of these subunits (Huntsman et al., 1998; Hosie et al., 2001; Quinlan et al., 2000), and post-translational events including receptor clustering (Phillips and Froehner, 2002) and phosphorylation (Sigel, 1995). Functional GABAA
receptors are also known to be present upon adrenal chromaffin cells
(Peters et al., 1989), but at present the subunit expression profile and
biology of GABAA receptors in the adrenal remains unknown. The binding of GABA and its analogues to
GABAA type receptors usually results in an increase in membrane
permeability to chloride ions, typically resulting in membrane hyperpolarization
and a reduction in membrane excitability. However, in the adrenal chromaffin cell,
GABA application elevates free [Ca2+]i (Doroshenko,
1989) by evoking membrane depolarization (Busik et al., 1996) to the activation threshold of voltage-gated Ca2+
channels (Doroshenko, 1989). This
strongly suggests that Cl- is accumulated above equilibrium
in chromaffin cells. Thus an
increase in GABAergic activity might be expected to augment catecholamine
release, and any modulation of GABAergic receptor properties by benzodiazepines
or neuroactive steroids would thus be expected to alter adrenal catecholamine
output.
In addition to
GABA binding sites which are believed to be formed at the interface
contributed by a and b subunits within the N-terminus (Amin and
Weiss, 1993), a number of key neuromodulatory binding sites are thought
to be present within the pentameric receptor-channel complex (Whiting,
1999a; 1999b). Distinct high
and low affinity binding sites for benzodiazepines are present within
the pentameric GABA subunit complex (Walters et
al., 2000), the high affinity site formed within the N-terminus
by residues contributed by both a (Renard et
al., 1999) and g (Kucken et
al., 2000) subunits. The
modulation of GABA-mediated synaptic transmission thus underlies the
pharmacotherapy of various neurological and psychiatric disorders including
anxiety and epilepsy. A
third site is present within the channel pore and is essentially believed
to be a barbiturate binding site.
Binding
to the benzodiazepine site can have three effects, agonism, inverse
agonism, or antagonism. The typical anxiolytic and sedative hypnotic
agents such as diazepam and lorazepam act as agonists at these receptors
increasing the affinity of the GABA binding site for GABA. This results
in an increase in Cl- influx. Inverse agonism occurs with the beta carbolines,
which therefore seem to oppose the actions of the agonist. Binding of
these agents reduces the influx of Cl-, which clinically presents as
anxiety. Antagonists such as flumazenil act to displace
the agonist and inverse agonist, without exerting a direct effect upon
the chloride channel itself, although it is unclear whether flumazenil
will have any use beyond reversing benzodiazepine overdoses. Clinically
agents which act as GABAA agonists are general anticonvulsants
and muscle relaxants. There
is much speculation and evidence for an endogenous benzodiazepine ligand,
or endozepine.
The GABAB (auto) receptor is a G-protein coupled receptor
which is often found presynaptically rather than post-synaptically.
The highest concentrations of GABAB receptors is in the interpeduncular nuclei
and cerebellum. It appears that one of its principle effects is to increase
the efflux of K+ from the cell via the activation of K+
channels, although these receptors also inhibit calcium channels such
as the N-type channel, which again is intuitively an inhibitory action
promoting membrane hyperpolarization. Pharmacologically baclofen is
considered a GABA-B agonist, which is a muscle relaxant.
Interestingly,
a significant relationship between dopamine and GABA exists. In general
GABA acts to reduce the firing of the dopaminergic neurons in the ventral
tegmentum area A10 and in the adjacent substantia nigra. It is for this reason that benzodiazepines
are used in the treatment of psychosis. In addition benzodiazepines
are employed in cases where there is an overactivity of dopamine in
the motor striatum, such as Huntington's Chorea or Tardive Dyskinesia
(by increasing the feedback inhibition of the circuit). The feedback
inhibition from the GABA neurons of the globus pallidus and putamen
to the dopaminergic neurons of the substantia nigra is an important
modulating force on the activity of the dopamine neurons.
Excitatory amino
acids
Glutamate
is considered the principle excitatory amino acid in the CNS. Its role
in cellular metabolism is well known. Glutamate is distributed widely
throughout the neuroaxis. Regions in which it seem particularly important
include the granular cells of the cerebellum, the pyramidal cells of
the hippocampus, the Betz cells of the motor strip, and the projections
of the frontal lobe to the basal ganglia. One of the major difficulties
in recognizing the role of glutamate as a neurotransmitter was the fact
that there is only a small percentage of the glutamate present in synaptic
vesicles. The vast majority of glutamate is present as part of intermediary
metabolism. The ability to define the role of glutamate came as a result
of finding receptors for glutamate and labelling them with various analogs.
There
are four glutamate receptor subtypes of importance. More will undoubtedly
be found and the nomenclature may change in the next few years. The
four receptor subtypes include the NMDA receptor, the quisqualate receptor
(also called the AMPA receptor), the kainate receptor, and the metabotropic
receptor. A common feature of these receptors is depolarization of the
membrane potential. In addition there are some special characteristic
that make this system interesting. First the receptor systems seem to
have a degree of cooperativity. By this I mean that they function most
completely as a group. The diagram below illustrates these receptor
systems.
Note
that the NMDA receptor is present in an inactive state with a Mg++ ion
blocking the calcium channel. For the NMDA receptor to become active
the Mg++ must leave the channel site. This is accomplished by membrane
depolarization brought about by the other glutamate receptors. Once
this is done and the NMDA receptors are active a process known as excitotoxicity
occurs. This may provide the basis for kindling and other long-term
changes which result in neuronal specialization. Excitotoxicity is due
to the opening of the calcium channels, which results in an increase
in free calcium. The degree of damage seems to be limited in most situations
by an energy dependent mechanism of binding the calcium. In situations
of ischaemia or hypoglycaemia there is a loss of this system and an
excessive excitotoxicity.
Neuroscience
has attempted to finding specific NMDA receptor blockers to protect
against ischaemic damage. Some of the compounds found to date include
MK801 and phencyclidine. Each of these compounds has psychotomimetic
activity. This has limited there utility to date. Focus is no on blockers
at other domains of the molecule such as the calcium channel itself.
Another potential site suggested by the diagram is the glycine site.
Glycine acts as an allosteric facilitator. Binding of glycine increases
the ability of glutamate to activate the channel apparently. It is unclear
if this is the site at which Nitric oxide acts.
|
|
|
