Synthetic compounds that have shown promise for treating cocaine addiction also may be useful for treating phencyclidine (PCP)-induced psychotic reactions, schizophrenia, and cocaine-induced seizures and death, researchers have found. The compounds are called dopamine D3 receptor agonists, or D3 agonists for short.
Potential Medications Mimic Brain Chemical. Compounds that show promise for treating psychosis and cocaine-induced seizures mimic the action of the messenger chemical dopamine on certain nerve cells in the brain. The compounds-called D3 agonists-stimulate molecules on nerve cells that receive dopamine messages-called dopamine D3 receptors. Scientists have yet to learn how this action reduces psychotic symptoms and seizures.Dopamine is one of several chemicals called neurotransmitters that carry messages between the brain's nerve cells, or neurons. After being released by a transmitting neuron, neurotransmitters interact with molecules called receptors on the surface of a receiving neuron, affecting the neuron's activity. The combined activity of the brain's neurons is responsible for all of the brain's functions-such as feeling, thinking, and controlling movements-just as the combined electrical activity in a computer is responsible for all of the computer's functions. At present, five types of dopamine receptors, designated D1 through D5, have been identified.
Agonists are compounds not normally found in the that stimulate receptors in the same way that neurotransmitters do. Consequently, D3 agonists are compounds that stimulate D3 receptors.
The PCP-Schizophrenia Connection
Dr. Jeffrey Witkin, Dr. Maciej Gasior, and their colleagues at NIDA's Intramural Research Program in Baltimore, Neurogen Corporation in Branford, Connecticut, and the University of Groningen in the Netherlands have found that, in mice, a D3 agonist called (+)-PD 128,907 can block psychotic-like behavior induced by a PCP derivative. Because research suggests that compounds that can reduce this type of psychotic behavior also will reduce symptoms of schizophrenia, Dr. Witkin's team believes the agonist has potential to treat schizophrenia as well.
Developed as a general anesthetic in the late 1950s, PCP became widely abused as a hallucinogen starting in the late 1960s. PCP abusers began appearing at hospital emergency rooms exhibiting symptoms that were nearly indistinguishable from those of schizophrenia, including hallucinations, paranoia, emotional withdrawal, and loss of speech. This commonality of symptoms led researchers to suspect that whatever PCP was doing in the brain might also be happening in the brains of schizophrenics.
The Witkin group's discovery of the potential of D3 agonists for treating PCP psychosis and schizophrenia sprang from their exploration into another property of D3 agonists that previous research had unveiled-their potential for reducing cocaine self-administration in rats, a finding that suggests they may reduce cocaine craving in humans. In the course of the researchers' exploration of that property, they noticed that (+)-PD 128,907 produced an unusual sedative effect on the animals that was similar to that of clozapine, a medication commonly used for treating schizophrenia.
"Clozapine produces a very striking depressant action that can be distinguished from that of other types of depressant drugs," explains Dr. Witkin. "Animals on clozapine are reactive to stimuli in the environment, and yet they are sedate. Also, their movements are normal. In contrast, other sedative-like compounds tend to make animals uncoordinated."
Because the D3 agonist acted like a medication for schizophrenia and because of the similarities between PCP psychosis and schizophrenia, the researchers decided to try the agonist in mice exhibiting psychotic-like symptoms as a result of being given a PCP derivative. Among those symptoms are headweaving, a popcorn-like jumping, and repetitive treading with a forepaw. The forepaw treading is easiest to measure.
Dr. Witkin and his colleagues found that (+)-PD 128,907 reduced this forepaw treading as effectively as clozapine and more effectively than haloperidol, the most commonly used antipsychotic medication. The compound also caused no movement disorders. "This is good news because haloperidol treats only some schizophrenic symptoms and also causes severe movement disorders," says Dr. Witkin. "Clozapine, on the other hand, is effective against all symptoms and generally does not cause movement disorders but can cause a life-threatening blood disorder. Altogether, these findings indicate that (+)-PD 128,907 might be an effective alternative to clozapine and haloperidol for treating schizophrenia," he says.
Blocking Cocaine-Induced Seizures and Deaths
Dr. Witkin and Dr. Gasior next tested the effectiveness of D3 agonists against cocaine-induced seizures and deaths in mice. They pursued their new line of research on the basis of a NIDA-funded study at the University of Miami showing that the brain's D3 receptors might be involved in seizures and deaths among cocaine abusers.
Again, (+)-PD 128,907 proved effective, and so did the other D3 agonists. Whether given before or after a cocaine overdose was administered, the compounds completely blocked the convulsant and lethal effects of the cocaine. "This is a dramatic finding because current medications do not work very well against the seizures and other consequences of cocaine overdoses," says Dr. Witkin.
Why D3 agonists should reduce cocaine self-administration, psychotic-like behavior, and cocaine-induced seizures and death is not yet clear, says Dr. Witkin. "More often than not in medications development, researchers find an interesting effect of a compound through trial and error, and then they try to figure out why the compound has that effect," he says. "That's where we are now with the D3 agonists."
Sources
- Staley, J.K., and Mash, D.C. Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. Journal of Neuroscience 16(19):6100-6106, 1996.
- Witkin, J.M., and Gasior, M. Dopamine D3 receptor involvement in the convulsant and lethal effects of cocaine. Polish Journal of Pharmacology 50(suppl.):44-45, 1998.
- Witkin, J.M., et al. Atypical antipsychotic-like effects of the dopamine D3 receptor agonist, (+)-PD 128,907. European Journal of Pharmacology. 347:R1-R3, 1998.