Cocaine acts as a potent central nervous system (CNS) stimulant with significant behavioural effects on the locomotor, memory and cognitive functions. It exerts its effects by binding to both alpha and beta subunits of nicotinic acetylcholine receptor (nAChR) present in brain cells of limbic and cortical areas. Cocaine-induced release of glutamate and subsequent activation of NMDA receptors enhances and enhances synaptic transmission. These alterations cause changes in dopamine transmission and have been widely implicated in the pathophysiology of drug abuse.
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Cocaine action on nAChR leads to an enhanced recruitment of the apical inhibitory receptor, GABA-A, to the binding site of receptor. This effect leads to both partial inhibition of the receptor and its opening up to extracellular neurotransmitter levels. This allows the activation of both nAChR and GABA-A receptors, thus increasing synaptic release of glutamate, which results in stimulation of dopaminergic, glutamatergic and GABAergic neurons. This leads to the release of neurotransmitters such as dopamine, histamine, serotonin, acetylcholine and acetylcholinesterase. The increase in neurotransmitters increases the amount of extracellular dopamine, which is responsible for the action of cocaine.
Cocaine dose-dependently stimulates release of dopamine by trans-synaptic release and by direct neurotransmission of dopamine through dopamine neurons, while it also increases the levels of extracellular GABA and neuromodulators. Some endogenous ligands and antagonists of cholinergic receptors such as alcohol and certain opioids also influence the action of cocaine. The action of cocaine also depends on the release of acetylcholine by glutamatergic neurons, which exerts a cholinergic effect on the brain.
Effects of cocaine on the CNS
The cerebral cortex and hippocampus contain the major number of nAChR and play a critical role in the development and/or maintenance of drug-seeking behavior. Cocaine produces strong or chronic neurochemical alterations of the brain in these areas with increased excitability and decrease in threshold for cortical and hippocampus activation. The response of neuronal cells to cocaine is regulated by phosphorylation of ephrin-B and kinase B (ERK) pathways and acetylcholinesterase. Following injury, cholinergic receptors and neuronal signaling in the medial septum (MR) area of the brain are decreased, while dopamine release is increased. The nucleus (NAc) is the main site of the effect of cocaine in the brain and contains two principal populations of dopamine-producing neurons: the Type 2 (immediate) neurogenic dopamine neurons, which have the highest density in the central nervous system, and the Type 1 (long-term) neurons. The activation of these neurons is not sufficient to cause cocaine abuse and is responsible for tolerance to repeated cocaine use, because these dopamine neurons may show long-term changes in the neurotransmitter metabolism and cell-surface receptor binding. For the initial period after exposure, the only significant effect is an increased release of dopamine.
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Evidence shows that the mechanism for the action of cocaine on nAChR involves a complex series of events. First, cocaine binds to receptors with high affinity to activate intracellular signaling pathways. These signaling pathways involve a series of enzymes, including phosphodiesterases (PDE), monoamine oxidase (MAO) and acetylcholinesterase, which degrade dopamine and norepinephrine (NE). There is a time-course of involvement in the effect of cocaine on receptor substrates: first, cocaine binds to the receptors with high affinity; then, it activates PDE1, leading to inactivation of the enzyme and subsequent release of the neurotransmitter; the neurotransmitters remain available and increase receptor levels. The downstream effect of the decrease in receptor function is an increase in the uptake of the neurotransmitter by the membrane. This is mediated by the receptor-mediated neurotransmitter-intracellular binding and by the inwardly rectifying K+ current, which causes changes in the location of the receptor. During this process, receptor-mediated signaling pathways are initiated.
Changes in the extracellular concentration of dopamine, serotonin, and histamine are triggered by receptor-mediated signaling pathways in the brain. These effect-based pathways include monoamine oxidase, acetylcholinesterase and their inhibitors, as well as the serotonin transporter (SERT) and their inhibitors. In addition, there is evidence that some mechanisms are involved in the release of neurotransmitters in the central nervous system: different signaling pathways also stimulate the expression of PDE enzymes, PDE1 and PDE2, which stimulate the release of serotonin from acetylcholine receptors. These responses are mediated by the classical glutamate receptor-mediated signaling pathway. The action of these drugs also involves activation of the NMDA receptor, which is a glutamate-gated channel, and that of the NMDA receptor antagonist, MK-801 (Methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which is an N-methyl-D-aspartate antagonist, causing an immediate reversal of the action of the neurotransmitter.
Cocaine acts mainly on the DA receptor, since DA is its main metabolite. The effect on the DAT is also important and it prevents further release of dopamine in the synapse. Furthermore, in the nucleus , dopamine release is decreased, whereas cocaine inhibits the release of NE. In these areas, cocaine causes a neuronal system shift, where the primary or “release” zone of DA and the “saturation” zone of NE are opposite to each other. These changes lead to the increase in the amplitude of theta rhythms, and consequently, addiction. In addition, the cytosolic half-life of cocaine is about two hours, and an increase in the availability of cocaine at sites of presynaptic activation is required for behavioral effects of cocaine on the animal, e.g., to maintain addiction. The benzodiazepine receptor in the nucleus mediates many of the behavioral effects of cocaine, and this inhibits the uptake of dopamine, which is necessary for the maintenance of the addiction. The benzodiazepine receptor also inhibits release of dopamine, so that there is a decrease in the amplitude of theta rhythms and the dose required for a change in the amplitude is increased. The blockade of the benzodiazepine receptor is essential for the action of cocaine on DA-receptor receptors, for maintaining the addiction.
The activation of nicotinic receptors and the subsequent release of acetylcholine and serotonin causes the putative stimulation of the central nervous system. These effects are mediated by the neurotransmitter-extracellular-bundling (TET) theory. The binding of dopamine to the DA receptors leads to the recruitment of the adenylyl cyclase enzyme to the synapse, which leads to the release of DA. The TET theory is supported by studies in which dopamine levels in the blood are decreased during the daytime, and are increased during the evening and night. During the daytime, the levels of dopamine are higher than during the night, but the acetylcholine levels are lower during the night than during the day. It is thought that during the night, the DA signals stimulate the release of acetylcholine and that during the day, this release leads to the inhibition of the acetylcholine neurotransmitter, causing a decrease in the concentrations of acetylcholine. The TET theory has been criticized because it is not a biological cause of the variations in drug effects. Also, as suggested by the amphetamine research, the TET theory does not explain the dramatic variations in behavior caused by the different amphetamines. The interaction of the brain dopamine system with DA receptor agonists is similar to that between morphine and the endogenous opioid system. In the thalamus, this system is also responsible for the enhancement of analgesia in the absence of naloxone.
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