73
5
The target for cocaine is the dopamine transporter (DAT) (Vaughan and Foster 2013);
see . Fig. 5.9. DAT regulates the availability of dopamine in the brain by translocating
dopamine from the synaptic cleft back into the presynaptic neuron. DAT also transports
serotonin and noradrenalin back to the presynapse. DAT is a solute carrier transporter
and a 2Na + /1Cl − /1 dopamine-symporter (SLC6A3), similar to the noradrenaline transporter NET (see 7 Sect. 5.4). Like NET, it has 12 membrane spanning transmembrane
domains and large regulatory intracellular domains at the N- and C-terminus. The cytoplasmic domains present targets for many post-translational modifications of DAT,
including phosphorylation by protein kinase C and ubiquitination of a specific lysine
residue, which is regulated by the ubiquitin ligase Parkin. Mutations in the parkin gene
have been implicated in familial Parkinson’s disease. The failure of ubiquitine dependent
DAT degradation causes accumulation of the protein and this leads to the death of dopaminergic neurons (Vaughan and Foster 2013).
DAT adapts an inwardly facing or an outwardly facing conformation and this directs
the movement of dopamine into the cell or out. Cocaine directly blocks the inward movement of dopamine. In this way, it prevents the reuptake of dopamine after its release into
the synaptic cleft. This leads to dopamine “overflow”.
Locally applied cocaine works as an anaesthetic. It provided the chemical lead for
development of a number of synthetic local anaesthetics, including lidocaine. In the central nervous system, cocaine induces euphoria, changes feelings for starving and thirst,
abolishes the need for sleep and increases performance and activity. Side effects can be
due to increased sympathetic signalling due to the disturbed noradrenalin uptake and
include anxiousness, increase of breathing and heart frequencies and others. Snuffing and
Dopamine
D1, D5
D2, D3, D4
Gi α
Gi βγ
AC
Gs α
K + –channel
L/N type
Haloperidol
HO
HO
NH 2
AC
Apomorphine
Clozapine
. Fig. 5.8 Schematic representation of intracellular signalling pathways on dopamine receptors D 1 ,
D 5 and D 2 , D 3 , and D 4 . Agonist apomorphine on D 1 , D 5 and D 2 receptors, antagonists haloperidol on D 2 ,
clozapine on D 2 , D 3 , and D 4
5.5 · Dopamine Receptors: Neuroleptics and Cocaine
5
The target for cocaine is the dopamine transporter (DAT) (Vaughan and Foster 2013);
see . Fig. 5.9. DAT regulates the availability of dopamine in the brain by translocating
dopamine from the synaptic cleft back into the presynaptic neuron. DAT also transports
serotonin and noradrenalin back to the presynapse. DAT is a solute carrier transporter
and a 2Na + /1Cl − /1 dopamine-symporter (SLC6A3), similar to the noradrenaline transporter NET (see 7 Sect. 5.4). Like NET, it has 12 membrane spanning transmembrane
domains and large regulatory intracellular domains at the N- and C-terminus. The cytoplasmic domains present targets for many post-translational modifications of DAT,
including phosphorylation by protein kinase C and ubiquitination of a specific lysine
residue, which is regulated by the ubiquitin ligase Parkin. Mutations in the parkin gene
have been implicated in familial Parkinson’s disease. The failure of ubiquitine dependent
DAT degradation causes accumulation of the protein and this leads to the death of dopaminergic neurons (Vaughan and Foster 2013).
DAT adapts an inwardly facing or an outwardly facing conformation and this directs
the movement of dopamine into the cell or out. Cocaine directly blocks the inward movement of dopamine. In this way, it prevents the reuptake of dopamine after its release into
the synaptic cleft. This leads to dopamine “overflow”.
Locally applied cocaine works as an anaesthetic. It provided the chemical lead for
development of a number of synthetic local anaesthetics, including lidocaine. In the central nervous system, cocaine induces euphoria, changes feelings for starving and thirst,
abolishes the need for sleep and increases performance and activity. Side effects can be
due to increased sympathetic signalling due to the disturbed noradrenalin uptake and
include anxiousness, increase of breathing and heart frequencies and others. Snuffing and
Dopamine
D1, D5
D2, D3, D4
Gi α
Gi βγ
AC
Gs α
K + –channel
L/N type
Haloperidol
HO
HO
NH 2
AC
Apomorphine
Clozapine
. Fig. 5.8 Schematic representation of intracellular signalling pathways on dopamine receptors D 1 ,
D 5 and D 2 , D 3 , and D 4 . Agonist apomorphine on D 1 , D 5 and D 2 receptors, antagonists haloperidol on D 2 ,
clozapine on D 2 , D 3 , and D 4
5.5 · Dopamine Receptors: Neuroleptics and Cocaine