Cocaine in your brain

What is cocaine?

Cocaine is a psychoactive drug affecting the central nervous system. It is prepared from the leaf of the Erythroxylon coca bush, which grows primarily in Peru and Bolivia. This drug is self administered in several ways. The most common method of cocaine abuse is snorting it (in powder form) into the nasal sinuses, either alone or with heroin (speedball). It is generally sold on the street as a hydrochloride salt - a fine, white crystalline powder known as coke, C, snow, flake, or blow. Another method of administration, which produces its effects more quickly, is smoking it in the form of crack cocaine.

The effects of cocaine

Cocaine produces a wide range of physiological effects in humans, including the stimulation of a plethora of emotional experiences. When people take cocaine, they become euphoric, highly active (locomotion, tremors, and tics), and more talkative than normal. They experience feelings of extreme power and alertness. This initial high is followed by bouts of severe anxiety, paranoia, and depression, which often lead to addiction. Those who become addicted to the drug often turn the habit into an obsession, so that they devote more, and more of their time and money to acquiring and using the drug.

Symptoms of addiction

People who abuse these drugs regularly often exhibit psychotic behavior such as hallucinations, delusions of persecution, mood disturbances, and repetitive behaviors, all of which closely resemble the symptoms of paranoid schizophrenia. Trained mental health professionals have trouble telling a schizophrenic and a cocaine addict apart unless they know the patient's background. Although the psychological and behavioral effects of cocaine use in humans have been well documented, the current knowledge of the neurological basis for the abuse of cocaine in humans is still limited. The majority of knowledge we possess about the mechanisms of the effects of cocaine comes from animal studies performed over the last 20 years. These studies have clearly demonstrated the crucial role of the neurotransmitter dopamine in initiating many of the effects of cocaine use.

Effects on the brain

Cocaine is an indirect dopamine agonist. Once in the brain, it works in large part by occupying, or blocking, dopamine transporter sites in the terminal buttons of neurons in the brain. This prevents the reuptake of dopamine by the neurons that release it, allowing higher concentrations of dopamine to remain in the synapse for an extended period of time. This abnormally long presence, and high concentration, of dopamine in the synapse is believed to cause the high (among other effects) associated with cocaine use. Dopamine has been implicated in several important functions, including movement, attention, learning, and the reinforcing effects of drug use. Therefore, its extended presence in high concentrations will be effective in the particular parts of the brain that control these functions, such as the basal ganglia and the limbic system.

Cocaine and the dopamine transporter

Studies have confirmed that the reinforcing effects of cocaine involve dopamine transporter molecules. In a dopamine study, a group of scientists produced a targeted mutation of the gene responsible for production of the dopamine transporter protein in mice. Their results showed that several compensatory mechanisms in an animals brain help it to adapt to the chronically higher level of dopamine resulting from their mutation induced reuptake inability (Giros et al. 1996). One of these mechanisms is a large decrease in post-synaptic dopamine receptors, rendering dopamine less effective. Another strategy is a corresponding decrease in the concentration of tyrosine hydroxylase (enzyme responsible for the synthesis of dopamine), decreasing the availability of dopamine. So, when cocaine was administered to these animals, it had no effect on the animal's behavior since dopamine reuptake no longer occurred due to lack of functional dopamine transporters (Giros et al. 1996). So, we see that the dopamine transporter is essential for cocaine to be able to produce its effects.

A quick fix

Cocaine has an extremely rapid euphorogenic effect on the user, especially in the case of the smoking method of use, because the drug directly enters the pulmonary blood stream when smoked. Cocaine has a relatively short half-life in the plasma and in the brain. When administered intravenously (IV) to humans, the half-life is in the range of 16 to 87 minutes (18 to 30 minutes in rats). This short half-life accounts for the rapid euphorogenic effects of the drug. Typically, when the drug is administered intravenously, it produces a fast "hit-and-run" effect on the potentiation of the extracellular levels of dopamine. When rats are given a continuous flow of dopamine intravenously, they experience a peak in dopamine levels in 10 minutes, followed by a return to regular levels after 20 to 30 minutes (Hurd and Ungerstedt 1989). Because the initial high experienced by cocaine abusers lasts for only a short time, the initial stimulatory actions of cocaine can be attributed to the elevation of synaptic dopamine levels.

And then...the side effects

When the dopamine levels return to normal, a diversity of psychological and behavioral effects of the cocaine use still exist, especially those associated with unpleasant emotions. Fifteen minutes after an IV injection of cocaine, the subject experiences a craving for more cocaine, even though a high concentration of cocaine should still be present in the brain (Jaffe et al. 1989). It has also been shown that after the self-reported rush of the cocaine high has diminished, continuous IV infusion of cocaine will often induce negative feelings such as dysphoria, anxiety, and paranoia, which are mixed with positive feelings of well being (Kumor et al. 1989). This tells us that even with a steady flow of cocaine to the brain, a cocaine user will still be subject to the negative effects of the drug use, because his dopamine levels will drop back to normal even though the brain is saturated with cocaine. So, the constant abuse of, and addiction to cocaine are characterized by a state in which the negative dysphoric effects are experienced regularly due to the brains compensatory mechanisms for maintaining normal dopamine levels. Since subjects still experience negative effects with normal dopamine levels (Kumor et al. 1989), this leads to the theory that cocaine must also exert its effects (especially the aversive effects) through mechanisms other than the dopamine system. The involvement of opioid neuropeptides in causing the negative effects of cocaine abuse is likely.

Why can't I stop snorting coke?

The nucleus accumbens is a critical site for the reinforcing effects of cocaine. It is located in the basal forebrain, rostral to the preoptic area, and immediately adjacent to the septum. It is part of the neostriatum (ventral striatum), which integrates information related to motor coordination, emotion, and motivation. The nucleus accumbens receives dopamine-secreting terminal buttons from neurons of the ventral tegmental area, and it is thought to be involved in reinforcement and attention. Studies done with microdialysis have shown that natural reinforcers trigger the release of dopamine in the nucleus accumbens. Behaviors such as drinking water when dehydrated, eating salty foods in response to sodium depletion, etc, are reinforced by increasing the dopamine concentration in the nucleus accumbens (Blander et al 1988). Other research has shown that the nucleus accumbens is a critical site for the reinforcing effects of cocaine abuse. Rats will learn to press a lever that causes the injection of a small quantity of amphetamine into the nucleus accumbens (Hoebel et al. 1983). Amphetamine is used instead of cocaine because the injection of cocaine has an anesthetic effect, which would counteract the stimulatory effects. When dopamine receptor blockers are injected into the nucleus accumbens, cocaine no longer has a reinforcing effect (McGregor and Roberts, 1993). This provides further evidence for the reinforcing function of the nucleus accumbens.

Opioid peptides play a physiological role in a wide variety of behaviors, including mood, motivation, and extrapyramidal motor function (Herz 1993). Cocaine abusers often combine heroin (an opiate) and cocaine to make a speedball, which helps them to avoid some of the negative dysphoric and anxious feelings induced by cocaine alone (Kreek 1988). Animal studies have shown a strong involvement of the opioid system in the reinforcing actions of cocaine. A study by Bain and Kornestsky et al. 1987 demonstrated that the opiate antagonist naloxone reduces the rewarding effects of cocaine on self-stimulation behavior. This is reinforced by the fact that, although withdrawal from long-term cocaine abuse does not lead to negative physical symptoms, it does cause unpleasant feelings, including dysphoria and decreased ability to experience pleasure.


It is thought that the basal ganglia is a critical anatomical site of action for cocaine because of the increased motor activation caused by cocaine administration. It is also thought to be connected because of the development of movement disorders in human cocaine users, the characteristics of which are similar to disorders associated with abnormal basal ganglia dopamine function (ie tremors, tics, involuntary movements, and shakes) (Attig et al. 1994). The basal ganglia include the striatum, globus pallidus, subthalamic nuclei, and substantia nigra. Dopamine is primarily synthesized in the cells of the substantia nigra, which projects to the striatum (striatonigral pathway). These dopamine nerve terminals in the striatum typically synapse onto medium spiny cells (which are rich in opioid neuropeptides such as dynorphin and enkephalin) (Freund et al. 1984). So, opioid neuropeptides are involved in the striatonigral pathway. The stimulation of this pathway (by dopamine) has an inhibitory effect on basal ganglia output nuclei (through opioid neuropeptides release), which serve to inhibit motor control, and the result is increased behavioral activation (Alexander and Crutcher 1990). So, cocaine causes hyperactivity by modulating the striatal pathways.


Withdrawal from cocaine can cause a drastic fall in the level of extracellular dopamine in the nucleus accumbens (Rosetti 1992). This decrease is thought to be caused by an increased secretion of dynorphin, one of the endogenous opioids. Dynorphin stimulates kappa receptors, which inhibit the effects of dopamine. This system operates on somewhat of a feedback mechanism. Stimulation of the dopamine D1 receptors increases the extracellular concentration of dynorphins. The kappa receptors presynaptically inhibit the release of dopamine from the terminal buttons, acting as heteroreceptors (Engber et al. 1992). So, the negative effects of withdrawal from cocaine abuse are caused by the residual effects of the kappa receptor stimulation, which causes the decrease in the extracellular levels of dopamine in the nucleus accumbens.


In summary, the dopaminergic systems stimulated by cocaine administration have been shown to initiate reinforcement neural circuits, primarily exerting an effect on the nucleus accumbens. The mechanism by which cocaine effects this system is by blocking the reuptake of dopamine into the terminal buttons. There is also some evidence for the opioid neuropeptides, such as dynorphin and enkephalin, being involved in the aversive effects of cocaine abuse. Much, however, is left to be studied about the mechanisms that underlie the wide range of behavioral and physiological effects of cocaine.

by Ben Goodman

Works Cited:

Alexander, G., and Crutcher, M. Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends in Neuroscience 13:266- 271, 1990.

Attig, E., Amyot, R., and Botez, T. Cocaine induced chronic tics. Journal of Neurological Neurosurgical Psychiatry 9: 1143-1144, 1994.

Bain, G.T., and Kornestsky, C. Naloxone attenuation of the effect of cocaine on rewarding brain stimulation. Life Science 40: 1119-1125, 1987.

Blander, D.S., Mark, G.P., hernandez, L., and Hoebel, B.G. Angiotensin and drinking induce dopamine release in the nucleus accumbens. Neuroscience Abstracts, 14: 527, 1988.

Engber, T.M., Boldry, R.C., Kuo, S., and Chase, T.N. Dopaminergic modulation of striatal neuropeptides: Differential effects of D1 and D2 receptor stimulation on somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin. Brain Research. 581: 261-268, 1992.

Freund, T.F., Powell, J.F., and Smith, A.D. Tyrosine hydroxylase immunoreactive boutons in synaptic contacts with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience. 13: 1189-1216, 1984.

Giros, B., jaber, M., Jones, S.R., Wightman, R.M., and Caron, M.G. hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 379: 606-612, 1996.

Herz, A. Opioids. New York: Springer-Verlag, 1993.

Hoebel, B.G., Monaco, A.P., hernandez, L., Aulisi, E.F., Stanley, B.G., and Lenard, L. Self-injection of amphetamine directly into the brain. Psychopharmacology. 81: 158-163, 1983.

Hurd, Y. L., and Ungerstedt, U. Cocaine: An in vivo microdialysis evaluation of its acute action on dopamine transmission in rat striatum. Synapse 3: 48-54, 1989.

Jaffe, J.H., Cascella, N.G., Kumor, N.M., and Sherer, M.A. Cocaine induced cocaine craving. Psychopharmacology 97: 59-64, 1989.

Kreek, M.J. multiple drug abuse patterns and medical consequences. Psychopharmacology: The third generation of Progress. New York: Raven Press, 1988. Pp. 1597-1604.

Kumor, K., Sherer, M., Gomez, J., Cone, E., and Jaffe, J.H. Subjective response during continuous infusion of cocaine. Pharmacological Biochemistry and Behavior 33: 443-452, 1989.

McGregor, A., and Roberts, D.C.S. Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement. Brain Research. 624: 245-252, 1993.

Rosetti, A.L., Hmaidan, Y., and Gessa, G.L. marked inhibition of mesolimbic dopamine release: A common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. European Journal of Pharmacology. 49: 301-310, 1992.

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