BRAINS IN BRIEFS
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Nicotine and Booze: Why smoking as a teen can lead to alcohol abuse as an adult
or technically,
Adolescent nicotine exposure alters GABAA receptor signaling in the ventral tegmental area and increases adult ethanol self-administration
[See Original Abstract on Pubmed]
or technically,
Adolescent nicotine exposure alters GABAA receptor signaling in the ventral tegmental area and increases adult ethanol self-administration
[See Original Abstract on Pubmed]
Authors of the study: Alyse M. Thomas, Alexey Ostroumov, Blake A. Kimmey, Madison B. Taormina, William M. Holden, Kristen Kim, Tiffany Brown-Magnum, and John A. Dani
Take a stroll past any neighborhood bar and you are bound to get a whiff of cigarette smoke from a group huddled outside. It is no secret that smoking and drinking often go hand in hand, but can one actually lead to the other? Scientists say yes. Tobacco use, especially as an adolescent, is a strong predictor for alcohol consumption later in life. But why?
While human data shows a strong correlation between smoking and using drugs/alcohol, scientists have turned to rodent models to determine if nicotine is directly causing the addiction-related behaviors. Indeed, previous rodent studies have directly linked nicotine exposure to enhanced drug use. Interestingly, this association is only seen when the nicotine is administered to adolescent rodents; adult rodents exposed to nicotine do not show an increase in drug consumption later on. Given that adolescent brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are more flexible than fully-grown adult brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. (in both rodents and humans!), researchers have hypothesized that nicotine exposure during adolescence may actually lead to long-term changes in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. However, how these developmental changes lead to excessive drug consumption later in life was still unknown. Enter Alyse Thomas, a University of Pennsylvania researcher in the Dani lab, who was determined to find out.
While previous studies linked adolescent nicotine exposure to increased drug use, Alyse wanted to see if the same phenomenon held true when the rodents were given access to ethanol (the key ingredient in most forms of alcohol). Thinking that it would, Alyse hypothesized that adolescent (but not adult) rats exposed to nicotine would ingest excessive amounts of ethanol. To test this hypothesis, Alyse used a self-administrationa common behavioral task used by researchers to study addiction in animal models, whereby animals push a lever to give themselves a drug behavior paradigm to research the link between nicotine exposure and ethanol ingestion. This paradigm, commonly used by scientists who study drugs and addiction, allows subjects (in this case rats) to consume as much of a substance (in this case ethanol) as they desire. Alyse ran two sets of experiments: one using adolescent rats, and one using adult rats. In both experiments, the rats were injected with either nicotine or salinesalt water; a common control substance intended to have no effect on behavior or physiology for 14 days straight. Four weeks after their last injection, the rats were placed in a self-administrationa common behavioral task used by researchers to study addiction in animal models, whereby animals push a lever to give themselves a drug chamber where they were allowed unlimited access to ethanol. For the next 30 days, Alyse measured the amount of ethanol each of the rats ingested. This allowed her to determine whether short-term nicotine exposure altered ethanol consumption later in the rat’s life. As hypothesized, she found that adolescent (but not adult) rats exposed to nicotine ingested significantly more ethanol than those exposed to salinesalt water; a common control substance intended to have no effect on behavior or physiology. While this finding was expected, Alyse still wanted to know why it was the case. How does two weeks of nicotine exposure alter a rat’s behavior over four months later?
As an expert in her field, Alyse was aware that ethanol consumption is associated with changes in communication between neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. - specifically, the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the ventral tegmental areaa brain region that plays key roles in drug and natural reward response (VTA). This brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region contains two key players: neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that release GABA neurotransmitterschemicals released by neurons; can have an excitatory or inhibitory effect (inhibitory chemicals that “turn off” nearby neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles) and neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that release dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neurotransmitterschemicals released by neurons; can have an excitatory or inhibitory effect (excitatory, “feel good” chemicals). In the VTA, GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles directly communicate with dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Typically, GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles release low levels of their inhibitory chemicals, causing dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to stay silent. However, when dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles sense the presence of drugs or alcohol, they overpower the “off” signals sent from GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and release a flood of “feel good” signals to the rest of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. However, if the communication between these two types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles was impaired (say, by nicotine), the “feel good” response elicited from ethanol consumption might also be impaired. Indeed, Alyse and her labmates discovered that nicotine causes GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to become overactive, leading to underactive dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Therefore, it takes more ethanol to elicit the same “feel good” response that the animal is used to, causing them to consume more.
With another piece of the puzzle in place, Alyse next wanted to know why nicotine causes these GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to become overactive. Perhaps if she could figure out the cause of the overactivation, she could figure out how to stop it. Alyse therefore took the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from her adolescent nicotine- and salinesalt water; a common control substance intended to have no effect on behavior or physiology-exposed rats and looked directly into their VTA GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Fascinatingly, she found that the nicotine-exposed neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had a significant buildup of chloride ions within them, which could either be caused by too much chloride coming in, or not enough chloride flowing out. Alyse figured out that it was the latter scenario - nicotine-exposed GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles were unable to properly expel chloride ions, causing them to build up and over activate the cell. With this last piece of the puzzle, Alyse was finally able to link adolescent nicotine exposure to increased alcohol consumption in adulthood (Figure 1).
Armed with a full understanding of the pathway, Alyse performed her final (and most important) experiment yet. Knowing that nicotine causes GABA neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles chloride channelsChannels are specialized proteins found on the surface of the cell. They allow molecules (i.e. neurotransmitters, salts, water) to go from outside to inside the cell and vice versa. to stop working, Alyse hypothesized that repairing these channelsChannels are specialized proteins found on the surface of the cell. They allow molecules (i.e. neurotransmitters, salts, water) to go from outside to inside the cell and vice versa. would restore the pathway and lead to a normal level of ethanol ingestion, even when adolescent rats are exposed to nicotine. Sure enough, when Alyse injected a drug that restored the chloride ion expulsion, the rats no longer ingested excessive amounts of ethanol. This finding means that not only did Alyse determine why nicotine exposure leads to excessive alcohol consumption, but she also discovered a potential treatment strategy for those suffering from alcohol addiction. As excessive alcohol consumption is responsible for more than 95,000 deaths per year in the United States alone, Alyse’s work could help reduce many tragic and preventable deaths in the future.
While human data shows a strong correlation between smoking and using drugs/alcohol, scientists have turned to rodent models to determine if nicotine is directly causing the addiction-related behaviors. Indeed, previous rodent studies have directly linked nicotine exposure to enhanced drug use. Interestingly, this association is only seen when the nicotine is administered to adolescent rodents; adult rodents exposed to nicotine do not show an increase in drug consumption later on. Given that adolescent brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are more flexible than fully-grown adult brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. (in both rodents and humans!), researchers have hypothesized that nicotine exposure during adolescence may actually lead to long-term changes in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. However, how these developmental changes lead to excessive drug consumption later in life was still unknown. Enter Alyse Thomas, a University of Pennsylvania researcher in the Dani lab, who was determined to find out.
While previous studies linked adolescent nicotine exposure to increased drug use, Alyse wanted to see if the same phenomenon held true when the rodents were given access to ethanol (the key ingredient in most forms of alcohol). Thinking that it would, Alyse hypothesized that adolescent (but not adult) rats exposed to nicotine would ingest excessive amounts of ethanol. To test this hypothesis, Alyse used a self-administrationa common behavioral task used by researchers to study addiction in animal models, whereby animals push a lever to give themselves a drug behavior paradigm to research the link between nicotine exposure and ethanol ingestion. This paradigm, commonly used by scientists who study drugs and addiction, allows subjects (in this case rats) to consume as much of a substance (in this case ethanol) as they desire. Alyse ran two sets of experiments: one using adolescent rats, and one using adult rats. In both experiments, the rats were injected with either nicotine or salinesalt water; a common control substance intended to have no effect on behavior or physiology for 14 days straight. Four weeks after their last injection, the rats were placed in a self-administrationa common behavioral task used by researchers to study addiction in animal models, whereby animals push a lever to give themselves a drug chamber where they were allowed unlimited access to ethanol. For the next 30 days, Alyse measured the amount of ethanol each of the rats ingested. This allowed her to determine whether short-term nicotine exposure altered ethanol consumption later in the rat’s life. As hypothesized, she found that adolescent (but not adult) rats exposed to nicotine ingested significantly more ethanol than those exposed to salinesalt water; a common control substance intended to have no effect on behavior or physiology. While this finding was expected, Alyse still wanted to know why it was the case. How does two weeks of nicotine exposure alter a rat’s behavior over four months later?
As an expert in her field, Alyse was aware that ethanol consumption is associated with changes in communication between neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. - specifically, the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the ventral tegmental areaa brain region that plays key roles in drug and natural reward response (VTA). This brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region contains two key players: neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that release GABA neurotransmitterschemicals released by neurons; can have an excitatory or inhibitory effect (inhibitory chemicals that “turn off” nearby neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles) and neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that release dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neurotransmitterschemicals released by neurons; can have an excitatory or inhibitory effect (excitatory, “feel good” chemicals). In the VTA, GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles directly communicate with dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Typically, GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles release low levels of their inhibitory chemicals, causing dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to stay silent. However, when dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles sense the presence of drugs or alcohol, they overpower the “off” signals sent from GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and release a flood of “feel good” signals to the rest of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. However, if the communication between these two types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles was impaired (say, by nicotine), the “feel good” response elicited from ethanol consumption might also be impaired. Indeed, Alyse and her labmates discovered that nicotine causes GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to become overactive, leading to underactive dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Therefore, it takes more ethanol to elicit the same “feel good” response that the animal is used to, causing them to consume more.
With another piece of the puzzle in place, Alyse next wanted to know why nicotine causes these GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to become overactive. Perhaps if she could figure out the cause of the overactivation, she could figure out how to stop it. Alyse therefore took the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from her adolescent nicotine- and salinesalt water; a common control substance intended to have no effect on behavior or physiology-exposed rats and looked directly into their VTA GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Fascinatingly, she found that the nicotine-exposed neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had a significant buildup of chloride ions within them, which could either be caused by too much chloride coming in, or not enough chloride flowing out. Alyse figured out that it was the latter scenario - nicotine-exposed GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles were unable to properly expel chloride ions, causing them to build up and over activate the cell. With this last piece of the puzzle, Alyse was finally able to link adolescent nicotine exposure to increased alcohol consumption in adulthood (Figure 1).
Armed with a full understanding of the pathway, Alyse performed her final (and most important) experiment yet. Knowing that nicotine causes GABA neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles chloride channelsChannels are specialized proteins found on the surface of the cell. They allow molecules (i.e. neurotransmitters, salts, water) to go from outside to inside the cell and vice versa. to stop working, Alyse hypothesized that repairing these channelsChannels are specialized proteins found on the surface of the cell. They allow molecules (i.e. neurotransmitters, salts, water) to go from outside to inside the cell and vice versa. would restore the pathway and lead to a normal level of ethanol ingestion, even when adolescent rats are exposed to nicotine. Sure enough, when Alyse injected a drug that restored the chloride ion expulsion, the rats no longer ingested excessive amounts of ethanol. This finding means that not only did Alyse determine why nicotine exposure leads to excessive alcohol consumption, but she also discovered a potential treatment strategy for those suffering from alcohol addiction. As excessive alcohol consumption is responsible for more than 95,000 deaths per year in the United States alone, Alyse’s work could help reduce many tragic and preventable deaths in the future.
Figure 1. The Neurological Link Between Nicotine and Alcohol Abuse. Adolescent nicotine exposure decreases the ability of GABA neurons to get rid of chloride ions (1), causing a buildup of chloride in the cell (2). The buildup of negative charge causes the GABA neuron to release more neurotransmitter (3). As these neurotransmitters are inhibitory, they decrease the activity of the dopamine neuron that the GABA neuron is communicating with (4). Now in adulthood, the dopamine neuron requires more alcohol (5) in order to feel as “good” as the normal brain does, leading to excessive alcohol consumption.
About the brief writer: Kelsey Nemec
Kelsey is a PhD Candidate in Chris Bennett’s lab. She is interested in understanding how peripheral immune cells infiltrate the brain, with the hopes of harnessing them to treat brain diseases.