Stimulants in the brain

January 29, 2019

Written by: Greer Prettyman

 

For many of us, the day doesn’t really start until the first sip of coffee. That caffeine jolt can help us feel awake or make it easier to stay focused during a long meeting. With a Starbucks on seemingly every corner offering tasty coffee drinks, caffeine is such a ubiquitous part of the culture that it can be easy to forget that caffeine is technically a drug. Caffeine belongs to a class of drugs called stimulants, which also includes amphetamines and cocaine.

A stimulant is any substance that increases activity in the central nervous system—the brain and spinal cord. Stimulants can be used for short perk-ups (like a daily cup of coffee), therapeutics for a variety of conditions, or illicit recreational drugs. Despite all falling within the same drug class, the ways each drug acts on the brain are different, accounting for their diverse uses and differing positive and negative effects. Let’s take a look at how each of these drugs acts to stimulate the brain.

Caffeine

Caffeine’s most classic effect is promoting wakefulness, whether it’s helping you feel awake in the morning or fighting off the urge for an afternoon nap. What’s happening in the brain when caffeine keeps us awake?

After you sip a latte or eat some chocolate, caffeine molecules get into the brain by crossing the blood brain barrier, a gate of sorts that regulates which chemicals can and cannot enter the brain from the bloodstream. Once in the brain, the caffeine molecules block receptors for a neurotransmitter called adenosine. Adenosine is involved in regulating periods of sleep and wake. While you are awake, adenosine builds up and binds to its receptors. As more and more adenosine binds, you become drowsy. In this way, at the end of the day enough adenosine has accumulated that you feel tired and ready to sleep. During sleep, adenosine levels drop, eventually helping you to wake up and start the cycle again.

Caffeine disrupts this process by blocking adenosine, essentially getting in the way so adenosine cannot bind to its receptors. By preventing adenosine from binding and subsequently making you feel drowsy, caffeine helps you feel more awake and alert. How long does caffeine have this effect? Scientists can measure the duration of a drug’s effect via its half-life—the amount of time that half of the drug is still in your system after you first take it. Caffeine has a relatively long half-life that ranges from 3-7 hours, which is why caffeine from an afternoon espresso can still affect adenosine binding hours later, leaving you tossing and turning when you’re trying to fall asleep at night.

Additionally, by changing adenosine activity, caffeine leads to downstream (secondary) changes in other neurotransmitter signaling. Neurotransmitter signaling occurs at the synapse – the point of contact where one neuron sends chemical messages to another. These signals are passed when neurotransmitters are released from the axon of the first cell (called the presynaptic neuron) and bind to receptors on the dendrites of a receiving cell (called the postsynaptic neuron).

Caffeine has been shown to lead to a release of dopamine neurotransmitters into a brain region called the striatum. Both dopamine and the striatum are highly involved in reward and motivation1. Adenosine, the transmitter that is blocked by caffeine, usually acts to inhibit the release of dopamine from presynaptic terminals by binding to a type of receptor called A1 receptors. Caffeine blocks adenosine from binding these receptors, which in turn prevents adenosine from inhibiting dopamine release, and therefore leads to an increase in dopamine released into the synapse (Figure 1).

Caffeine acts on adenosine to increase dopamine in another way as well. Some adenosine receptors and dopamine receptors are coupled together and interact on the receiving neuron, such that binding of adenosine to its receptors reduces the ability of dopamine to bind to its own receptors2 (Figure 1). When caffeine alters adenosine binding, dopamine can bind more easily. These combined effects of caffeine on dopamine, through its blockade on adenosine, lead to increased dopamine signaling in this part of the brain. The extra dopamine signaling leads to increased motivation and as well as psychomotor effects, which is one reason why you might feel jittery or uncoordinated after drinking a lot of coffee.

 

gp_stimulants_a1_dop_fig1
Figure 1: Caffeine’s effects on adenosine and dopamine at the synapse. A) When caffeine isn’t present, adenosine binds to presynaptic A1 receptors to prevent dopamine release from storage. Adenosine also binds to postsynaptic receptors to prevent dopamine from binding to its own receptors. B) When caffeine is present, adenosine cannot bind to presynaptic A1 receptors to prevent dopamine release. Adenosine also can no longer bind to postsynaptic receptors to prevent dopamine from binding to its own receptors.  Together, these effects lead to increased dopamine signaling.

 

Amphetamine and Cocaine

Other stimulants also lead to an increase in dopamine signaling, but not through the same adenosine-mediated ways that caffeine does. Amphetamines and cocaine act directly on the dopamine system to produce their stimulant effects.

You’ve probably heard of a drug called Adderall, which is an amphetamine commonly used to treat attention-deficit/hyperactivity disorder (ADHD) and narcolepsy, a disorder that leads to daytime drowsiness and sudden bouts of sleep. Amphetamines are also sometimes used as recreational drugs, since they can boost cognitive and physical performance. These drugs are addictive and can be dangerous if taken incorrectly or abused.

Cocaine is another well-known and potent stimulant. While cocaine is used to provide a numbing effect during some nasal surgeries, its main use is as a recreational drug. Cocaine provides a euphoric high and a burst of energy. It’s also highly addictive and repeated use can lead to reduced ability to feel pleasure without taking increasing doses of the drug.

Like caffeine, amphetamines and cocaine promote wakefulness and focus in part by increasing signaling of dopamine in regions of the brain including the striatum. Unlike dopamine, however, they do not first alter adenosine binding but rather act more directly on dopamine release and transport.

In the synapse, after a neurotransmitter like dopamine is released from the presynaptic neuron, some of the transmitters bind to receptors on the postsynaptic neuron while some of the transmitters remain in the synapse, as you can see in Figure 1. Excess transmitters are moved back into the presynaptic neuron by proteins called transporters. After the transmitters have been transported back to the presynaptic neuron, they can be recycled and released again.

Amphetamines and cocaine both increase dopamine by decreasing the transporter proteins for dopamine that are responsible for reuptake of dopamine back into the presynaptic cell3,4.  By blocking this transport, these drugs leave more dopamine available to bind to receptors on the postsynaptic cell. Cocaine alters this system in a faster and more potent way than amphetamines. In addition, amphetamines also help to release dopamine from its storage in the presynaptic neuron and into the synapse. This produces extra neural activity that is mediated by dopamine in the striatum, including increasing pleasure, focus, and movement.

Dopamine isn’t the whole story, however, as both drugs also exert effects on signaling pathways of other neurotransmitters, including serotonin and norepinephrine, which are involved in regulating mood, sleep, arousal, and appetite. Of course, these effects come at a steep price as both drugs, and especially cocaine, are dangerously addictive and can alter the natural circuitry of the brain.

In contrast to stimulants like cocaine and amphetamines, coffee, though technically a stimulant, has effects, mechanism of action, and safety of use that are markedly different than those of other drugs in this class. If you’re in need of some stimulation, a cup of coffee is a perfectly safe way to go. Many natural activities like a session at the gym or an afternoon nap can also leave you feeling more energized and provide non-chemical ways to stimulate your brain.

 

If you or someone you know needs help dealing with substance abuse, call the Substance Abuse and Mental Health Services Administration National Hotline at 1-800-662-HELP (4357).

 

 

References:

  1. Solinas, M., Ferre, S., You, Z., Karcz-Kubicha, M., Popoli, P., & Goldberg, S.R. (2002). Caffeine Induces Dopamine and Glutamate Release in the Shell of the Nucleus Accumbens. Journal of Neuroscience 22(15): 6321-6324
  2. Ferre, S., Dias-Rios, M., Salamone, J.D., & Prediger, R.D. (2018) New Developments on the Adenosine Mechanisms of the Central Effects of Caffeine and their Implications for Neuropsychiatric Disorders. J Caffeine Adenosine Res 8(4): 121-131.
  3. Calipari, E.S. & Ferris, M.J. (2013) Amphetamine Mechanisms and Actions at the Dopamine Terminal Revisited. Journal of Neuroscience 33(21): 8923-8925.
  4. Hall, F.S., Sora, I., Drgonova, J., Li, X.F., Goeb, M., Uhi, G.R. (2004). Molecular mechanisms underlying the rewarding effects of cocaine. Ann N Y Acad Sci. 1025:47-56.

 

 

Images:

Figure 1: Created using Motifolio Neuroscience Illustration Toolkit

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