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A specific portion of the limbic circuit known as the mesolimbic dopaminergic system is hypothesized to play an important role in translation of motivation to motor behavior- and reward-related learning in particular. It is typically defined as the ventral tegmental area (VTA), the nucleus accumbens, and the bundle of dopamine-containing fibres that connecting them. This system is commonly implicated in the seeking out and consumption of rewarding stimuli or events, such as sweet-tasting foods or sexual interaction. However, ita importance to addiction research goes beyond its role in "natural" motivation: while the specific site or mechanism of action may differ, all known drugs of abuse have the common effect in that they elevate the level of dopamine in the nucleus accumbens. This may happen directly, such as through blockade of the dopamine re-uptake mechanism (see cocaine). It may also happen indirectly, such as through stimulation of the dopamine-containing neurons of the VTA that synapse onto neurons in the accumbens (see opiates). The euphoric effects of drugs of abuse are thought to be a direct result of the acute increase in accumbal dopamine.
The human body has a natural tendency to maintain homeostasis, and the central nervous system is no exception. Chronic elevation of dopamine will result in a decrease in the number of dopamine receptors available in a process known as downregulation. The decreased number of receptors changes the permeability of the cell membrane located post-synaptically, such that the post-synaptic neuron is less excitable- ie, less able to respond to chemical signalling with an electrical impulse, or action potential. It is hypothesized that this dulling of the responsiveness of the brain's reward pathways contributes to the inability to feel pleasure, known as anhedonia, often observed in addicts. The increased requirement for dopamine to maintain the same electrical activity is the basis of both physiological tolerance and withdrawal associated with addiction.
Downregulation can be classically conditioned. If a behavior consistently occurs in the same environment or contigently with a particular cue, the brain will adjust to the presence of the conditioned cues by decreasing the number of available receptors in the absence of the behavior. It is thought that many drug overdoses are not the result of a user taking a higher dose than is typical, but rather that the user is administering the same dose in a new environment.
In cases of physical dependency on depressants of the central nervous system such as opioids, barbiturates, or alcohol, the absence of the substance can lead to symptoms of severe physical discomfort. Withdrawal from alcohol or sedatives such as barbiturates or benzodiazepines (valium-family) can result in seizures and even death. By contrast, withdrawal from opioids, which can be extremely uncomfortable, is rarely if ever life-threatening. In cases of dependence and withdrawal, the body has become so dependent on high concentrations of the particular chemical that it has stopped producing its own natural versions (endogenous ligands) and instead produces opposing chemicals. When the addictive substance is withdrawn, the effects of the opposing chemicals can become overwhelming. For example, chronic use of sedatives (alcohol, barbiturates, or benzodiazepines) results in higher chronic levels of stimulating neurotransmitters such as glutamate. Very high levels of glutamate kill nerve cells (called excitatory neurotoxicity).
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