72
5
5.5 Dopamine Receptors: Neuroleptics and Cocaine
Cocaine does not interact with neurotransmitter receptors directly. It rather blocks the
reuptake, mainly of the neurotransmitter dopamine, from the synaptic cleft into the presynaptic cell. Dopamine is often referred to as “happy hormone” (Glückshormon).
Deregulation in the dopaminergic pathway is implicated in depression and bipolar disorder. Besides mood, cognition and emotion, dopamine also controls motor activity, and the
loss of dopaminergic neurons in the brain is the cause of Parkinson’s disease. Dopamine
acts via pre- or postsynaptic receptors and generally imposes a slow modulation of fast
glutaminergic and GABAergic neurotransmission.
Five dopamine receptor subtypes are expressed in specific neurons and in smooth
muscle cells. Of those, D 1 and D 5 are coupled to G s ; thus, activation leads to an increase in
intracellular cAMP. By activation of K + -channels, D 1 - and D 2 -signalling can inhibit target
neurons. Alternatively, D 1 - and D 5 -signalling can also activate Na + -channels, causing activation of target neurons. The effect of dopamine therefore depends on the nature of the
neurons that are connecting to the respective dopaminergic nerve endings.
D 2 , D 3 and D 4 are coupled to G i , and receptor activation leads to Giα-dependent
decrease in cAMP. Giβ/γ activation of K + channels leads to a stabilizing of the resting
potential in nerve cells. D 2 , D 3 and D 4 receptors at postsynaptic sites thus inhibit neurotransmission. D 2 receptors on presynaptic sites induce a decrease in dopamine release via
Giβ/γ-mediated inhibition of L/N-type Ca 2+ -channels (Beaulieu and Gainetdinov 2011).
In the striatum D 1 activation is involved in a pathway facilitating motor activity. D 2
activation is involved in a pathway inhibiting motor activity. Because the activating pathway via D 1 is coupled to Gs and the inhibiting pathway via D 2 is coupled to Gi, dopamine
increases cAMP via D 1 in the activating pathway, activating “activation”, and decreases
cAMP via D 2 in the inactivating pathway, inactivating inhibition. Therefore the overall
effect of dopamine in the striatum is motor stimulation. D 1 is expressed widely in the
brain including nigrostriatal, mesolimbic and mesocortical areas. It is also expressed outside the brain, for instance, on smooth muscle cells and stimulates dilation of kidney vessels, so more blood goes through the kidney.
D 2 is expressed in specific brain regions and made responsible for symptoms of schizophrenia and nausea. D 3 is expressed in the cerebellum. It is a target for drugs against
depression, addiction and Parkinson’s disease. Finally, D 4 and D 5 are expressed in some
brain regions, including the hippocampus. Dopamine plays a role in the mesolimbic and
mesocortical systems of the mesencephalon and is thereby involved in neurotransmission
for reward and motivation, cognitive control and emotional response. The positive symptoms of schizophrenia, including hallucinations, delusions and thought disorder, have
also been connected to dopaminergic neurotransmission in the mesencephalon. Loss of
dopamine signalling leads to anhedonia (loss of motivation and energy) as it can often be
observed in Parkinson’s disease patients (Boyd and Mailman 2012).
Some drugs, so-called neuroleptica, have been developed to control psychiatric disorders. Of those, the classical neuroleptica haloperidol and clozapine interact with D2dopamine receptors. Clozapine has some special properties in addition and probably also
interacts with other neurotransmitter receptors; however, these are not completely understood yet (Beaulieu and Gainetdinov 2011; Seeman 2014). Apomorphine is an agonist for
D 1 receptors and is used against symptoms of Parkinson’s disease (Stacy and Silver 2008);
see . Fig. 5.8.
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs
5
5.5 Dopamine Receptors: Neuroleptics and Cocaine
Cocaine does not interact with neurotransmitter receptors directly. It rather blocks the
reuptake, mainly of the neurotransmitter dopamine, from the synaptic cleft into the presynaptic cell. Dopamine is often referred to as “happy hormone” (Glückshormon).
Deregulation in the dopaminergic pathway is implicated in depression and bipolar disorder. Besides mood, cognition and emotion, dopamine also controls motor activity, and the
loss of dopaminergic neurons in the brain is the cause of Parkinson’s disease. Dopamine
acts via pre- or postsynaptic receptors and generally imposes a slow modulation of fast
glutaminergic and GABAergic neurotransmission.
Five dopamine receptor subtypes are expressed in specific neurons and in smooth
muscle cells. Of those, D 1 and D 5 are coupled to G s ; thus, activation leads to an increase in
intracellular cAMP. By activation of K + -channels, D 1 - and D 2 -signalling can inhibit target
neurons. Alternatively, D 1 - and D 5 -signalling can also activate Na + -channels, causing activation of target neurons. The effect of dopamine therefore depends on the nature of the
neurons that are connecting to the respective dopaminergic nerve endings.
D 2 , D 3 and D 4 are coupled to G i , and receptor activation leads to Giα-dependent
decrease in cAMP. Giβ/γ activation of K + channels leads to a stabilizing of the resting
potential in nerve cells. D 2 , D 3 and D 4 receptors at postsynaptic sites thus inhibit neurotransmission. D 2 receptors on presynaptic sites induce a decrease in dopamine release via
Giβ/γ-mediated inhibition of L/N-type Ca 2+ -channels (Beaulieu and Gainetdinov 2011).
In the striatum D 1 activation is involved in a pathway facilitating motor activity. D 2
activation is involved in a pathway inhibiting motor activity. Because the activating pathway via D 1 is coupled to Gs and the inhibiting pathway via D 2 is coupled to Gi, dopamine
increases cAMP via D 1 in the activating pathway, activating “activation”, and decreases
cAMP via D 2 in the inactivating pathway, inactivating inhibition. Therefore the overall
effect of dopamine in the striatum is motor stimulation. D 1 is expressed widely in the
brain including nigrostriatal, mesolimbic and mesocortical areas. It is also expressed outside the brain, for instance, on smooth muscle cells and stimulates dilation of kidney vessels, so more blood goes through the kidney.
D 2 is expressed in specific brain regions and made responsible for symptoms of schizophrenia and nausea. D 3 is expressed in the cerebellum. It is a target for drugs against
depression, addiction and Parkinson’s disease. Finally, D 4 and D 5 are expressed in some
brain regions, including the hippocampus. Dopamine plays a role in the mesolimbic and
mesocortical systems of the mesencephalon and is thereby involved in neurotransmission
for reward and motivation, cognitive control and emotional response. The positive symptoms of schizophrenia, including hallucinations, delusions and thought disorder, have
also been connected to dopaminergic neurotransmission in the mesencephalon. Loss of
dopamine signalling leads to anhedonia (loss of motivation and energy) as it can often be
observed in Parkinson’s disease patients (Boyd and Mailman 2012).
Some drugs, so-called neuroleptica, have been developed to control psychiatric disorders. Of those, the classical neuroleptica haloperidol and clozapine interact with D2dopamine receptors. Clozapine has some special properties in addition and probably also
interacts with other neurotransmitter receptors; however, these are not completely understood yet (Beaulieu and Gainetdinov 2011; Seeman 2014). Apomorphine is an agonist for
D 1 receptors and is used against symptoms of Parkinson’s disease (Stacy and Silver 2008);
see . Fig. 5.8.
Chapter 5 · GPCRs as Targets for Plant-Derived Drugs