Dopamine/dopaminergic system cocaine

Both amphetamine and cocaine have also been reported to support intracranial self-administration in the mesolimbic/mesocortical dopaminergic system. Rats will self-administer cocaine into the medial prefrontal cortex (Goeders and Smith 1983). while amphetamine is self-administered into the orbitofrontal cortex of rhesus monkeys (Phillips and Rolls 1981) and the nucleus accumbens of rats (Hoebel et al. 1983 Monaco et al. 1981). These data indicate that the mesolimbic/mesocortical dopaminergic system is involved in the initiation of stimulant reinforcement processes, and this work suggests that the region of the nucleus accumbens, more specifically the mesolimbic dopamine system, may be an important substrate for reinforcing properties of several psychomotor stimulant drugs. 

A model for the action of cocaine and amphetamine at a dopaminergic synapse in the central nervous system. Cocaine (right side) blocks the dopamine reuptake transporter (DAT). Amphetamine (left side) has several effects. It enters the nerve ending via reverse transport by the DAT and displaces dopamine (DA) from vesicles by altering their pH. It also inhibits dopamine metabolism by MAO in the nerve ending. The increased intraneuronal dopamine causes reversal of the DAT and dopamine floods into the synapse. 

The reinforcing (i.e. dependence-producing) effects of cocaine are thought to result from its ability to inhibit the reuptake of dopamine and thereby to increase dopaminergic activity, particularly in the ventral tegmental area and the nucleus accumbens, so enhancing the activity of the dopaminergic system in the mesolimbic area (the reward area) of the brain. 

According to Carpenter, Conley, and Buchanan (1998), stimulants such as cocaine and amphetamines activate the dopaminergic system in the brain, which explains why the abuse of stimulants can induce a paranoid psychosis that mimics the positive symptoms representative of schizophrenia. In turn, if a person who is diagnosed with schizophrenia is given stimulants of this type, the psychosis may be exacerbated. It follows, therefore, that the typical antipsychotic medications act by blocking the dopamine receptors. 

The mesolimbic dopaminergic system is the principal reward pathway in the brain. Amphetamine, cocaine, and opiates cause dopamine release in the nucleus accumbens. Food seeking and sexual behavior do so as well. 

The nucleus accumbens is part of the limbic system. It receives dopaminergic input through the mesolimbic system that originates from cell bodies in the ventral segmental area (A 10 cell group). This mesolimbic dopaminergic pathway is part of the reward pathways. Drugs of abuse (cocaine, amphetamine, opiates or nicotine) have been shown to increase the level of dopamine release in these neurons. 

Subchronic oral administration of lithium causes a time-dependent increase in the substance P level in the striatum, which is prevented by coadministration of haloperidol. In PC 12 pheochromocytoma cells, lithium dramatically increases the intracellular levels of the neuropeptide neurotensin and the mRNA encoding it. An extensive overlap between specific and high-affinity neurotensin binding sites and dopamine perikarya and dendrites has been shown to occur in the mesocorticolimbic and nigrostriatal projection systems. Consistent with this observation are the results of observations showing that cocaine, an indirect sympathomimetic agent that enhances the extrapyramidal dopaminergic activity, increases dramatically the striatal content of neurotensin-like immunoreactivity. 

The reinforcing effects of cocaine and cocaine analogues correlate best with their effectiveness in blocking the dopamine transporter, which leads to increased dopaminergic stimulation at critical brain sites. However, cocaine also blocks both norepinephrine (NE) and serotonin (5-HT) reuptake, and chronic use of cocaine produces changes in these neurotransmitter systems as measured by reductions in the neurotransmitter metabolites MHPG (3-methoxy-4 hydroxyphenethyleneglycol) and 5-HIAA (5-hydroxyindoleacetic acid). 

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