The brain works by transmitting information between neurones using the primary neurotransmitters. The primary neurotransmitters are glutamate, which is stimulatory (i.e. it turns cells on), and the closely related amino acid g-aminobutyric acid (GABA) which is inhibitory (i.e. it turns neurones off). The appropriate balance between these neurotransmitters leads to the brain processes underlying action, sensation, learning, and memory. Secondary transmitters are the monoamines and peptides such as dopamine, 5-hydroxytryptamine, noradrenaline (norepinephrine), acetylcholine, and endogenous opiates. These add the tone, valence, and emotion to the primary processes, and some such as noradrenaline are important in memory formation. All 'drugs' (probably even solvents through indirect effects) act by interfering with these neurotransmitters in ways summarized in Jable^.™,3,1 However, it is important to realize that the brain has its own 'addictive' neurotransmitters. The best known are the endogenous opioid peptides such as the endorphins and enkephalins, but there are also endogenous cannabinoids (anandamide) and probably others.(32> It is not yet known whether these endogenous substances are mediators of addiction to cannabis or other drugs, although this would certainly seem possible.
Table 2 Drugs and transmitters
What is certain is that some of the most addictive agents (especially the full agonist opiates such as heroin/morphine) act on the endogenous opioid neurotransmitter pathway, but with a much greater effect than the natural transmitter. The profound ability of opiates such as heroin to produce addiction is because these drugs highjack the natural transmitter system leaving normal levels of stimulation seeming tame by comparison, especially early in withdrawal. Treatment with partial agonist opiates such as buprenorphine offer a compromise in that they are less addicting than heroin yet restore some of the brain's deficiency of opiate tone. They also have the advantage of being much safer than full agonists in overdose and rarely cause death from respiratory depression. Other drugs, in particular alcohol, seem to act in part by indirectly stimulating the endogenous opioid system, which is why opioid antagonists such as naltrexone can be useful treatments. (33)
Other drugs act on the natural stimulant transmitter dopamine. Dopamine deficiency (for instance in Parkinson's disease) has long been known to limit motor behaviour. Stimulant drugs increase energy and stamina by increasing the synaptic levels of dopamine, either by increasing the release or by blocking its reuptake in the basal ganglia. Many drugs of addiction can also increase dopamine availability in other brain regions, the two most important being the nucleus accumbens and the prefrontal cortex.(34) A huge body of evidence points to the nucleus accumbens as being a critical gateway in drug misuse. Almost all abused substances (the only exception being the benzodiazepines) act to increase dopamine release in this area. How they do this varies; cocaine and nicotine act at the level of the dopamine terminals, while heroin and alcohol activate the cell bodies on the brain stem. The net effect is to increase dopamine transmission out of the nucleus accumbens into the basal ganglia and thalamus, frontal cortex, amygdala, and hypothalamus. (26,3°)
This circuit is the one that was shown by Olds in the 1950s to sustain electrical self-stimulation and is the brain's own reward circuit. It is normally activated by positive reinforcers, such as food, water, and sex, that are critical to survival. Because drugs of abuse produce greater effects than the natural reinforcers, the resultant effect is that the brain directs its normal drives away from the natural reinforcers and towards the more pleasurable drugs. In severe addiction, which frequently occurs with the most powerful reinforcers (such as heroin and cocaine), all natural drives may be subsumed to an overwhelming search for and use of the drug. Thus addicts may give up sex, grooming, hygiene, and work, hardly eat or drink, and ignore health problems.
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