BELLADONNA ALKALOIDS

BELLADONNA ALKALOIDS

The belladonna alkaloids work by a completely different mechanism, which explains the different state that they cause. They act by prevent­ing the actions of the neurotransmitter acetylcholine at one of its recep­tors. Acetylcholine is the neurotransmitter that nerves use to stimulate muscle and allow movement, and it is also the neurotransmitter mim­icked by nicotine. It has two types of receptors: one is stimulated by nic­otine, and the other (called the muscarinic receptor, because researchers discovered that it was stimulated by the compound muscarine from the Amanita muscaria mushroom) slows the heart and probably helps to

form memories. We'll describe this in more detail in the chapter on PCP, KETAMINE, AND DEXTROMETHORPHAN

All three drugs block the actions of the neurotransmitter glutamate at one of its receptors, although PCP and ketamine are much better at it than dextromethorphan. This blockade can, on its own, produce most of the effects of these drugs, including feeling disconnected from your body or environment after either recreational use or medical use in anesthesia. This feeling has made it impossible to use these drugs to treat stroke, a medical use for which there was great hope when the ability of these drugs to limit stroke-induced brain damage was discovered. However, in clinical trials of these drugs, patients hallucinated. As you can imagine, it was terrifying for patients to wake up in the hospital, seriously ill, afraid that the stroke rather than the treatment was causing hallucinations.

PCP and to a lesser extent ketamine act like amphetamine to release the neurotransmitter dopamine. This accounts for the locomotor activation that PCP-intoxicated people can experience. Scientists once thought that these drugs directly affected dopamine neurons, but now they think PCP effects are the result of glutamate receptor blockade. In any case, this causes sonic good feelings and is why both drugs are somewhat addicting.

These drugs also decrease sensations of pain to a varying extent. NMDA receptor blockade likely plays a major role in the effect, but it also may reflect some activity on a group of receptors called "sigma" receptors that when activated cause a spectrum of effects including hallucinations and a loss of pain sensations. These receptors were once classified as opi­ate receptors, but they are not anymore. We do not know what they do in regulating normal brain function. Interest in this system has risen in recent years because researchers found that drugs that specifically stimu­lated this receptor system produced hallucinations without affecting the other opiate systems. Dextromethorphan is also a very weak stimulant of this receptor, which might contribute to its effects.

The most useful drugs are those that are most selective. PCP, ketamine, and dextromethorphan suffer from being the opposite—they block the action of the major neurotransmitter in the brain that excites other neu­rons, and so they affect many important brain functions.