Roze 1

Krista Roze

May 10, 2019

Neuronal Correlates of Impulsivity and Alcohol Use Disorders

Alcohol use disorders (AUDs) are composed of a complex set of symptoms stemming

from a combination of genetic, neuronal, and environmental factors. Despite the list of official

diagnostic criteria outlined in the DSM V, the line between “normal” and disordered alcohol use

is blurry nonetheless. This distinction is dependent on both the amount of alcohol consumed in

a sitting as well as the regularity with which it is consumed. Repeated episodes of binge drinking

over a long period of time can result in both acute and chronic detrimental effects within the

brain. The cognitive and behavioral effects of acute alcohol consumption are easily observed;

people under the influence of alcohol exhibit lack of motor coordination, impaired judgment, and

changes in mood, among other symptoms. The presence of an AUD has been shown to be

correlated with impulsivity, although it is not certain if this is a cause or an effect of the disorder.

As outlined below, impulsive behavior can result from three significant terms, among others:

disinhibition, binding specificity of ethanol, and spike-timing dependent plasticity.

Impulsivity is a trait marked by poor planning of actions with little to no regard for the

consequences of those actions. These hasty decisions are a result of impaired function of a

number of neural networks, including the prefrontal cortex, a key player in executive functions

such as planning and decision making. Inhibition is a crucial element of non-impulsive

behaviors, both at the cognitive and cellular levels. Recording event related potentials (ERPs) is

a noninvasive method of visualizing activity in the brain, allowing for use on live human

participants. Chen et al. recorded ERPs from the brains of individuals diagnosed with an AUD to

see how the activity would compare to that of a healthy individual (Chen et al., 2007). The most

notable difference they found was in the amplitude of the P300 wave component (P3) of the
 Roze 2

ERP. The P3 component is a positive voltage amplitude associated with the inhibition of neural

networks consciously perceiving stimuli, which helps to move attention away from irrelevant

information and focus on relevant incoming information (Salti et al., 2012). The larger the

amplitude of the P3 component, the more neurophysiological inhibition in the recorded area.

The researchers found that the P3 amplitude is significantly lower in ERPs recorded from

individuals with an AUD. This suggests that AUDs may stem from disinhibition of relevant neural

networks. Disinhibition is the lack of inhibition of activity, altering normal neuronal and cognitive

functioning. These lowered amplitudes were observed most robustly in the electrodes

corresponding to frontoparietal areas, which are associated with higher executive functioning.

Decreased P3 amplitude is also seen in the ERPs of individuals with conduct disorder, attention

deficit hyperactivity disorder, and antisocial personality disorder, among others. Reduced ability

to regulate behavior is a trait common to many individuals with these disorders, suggesting that

this disinhibition may lead to impulsivity. In addition to collecting ERP data, Chen et al.

administered the Barratt Impulsiveness Scale to those with and without an AUD to measure

three aspects of impulsivity: nonplanning, motor impulsivity, and cognitive impulsivity.

Individuals with an AUD scored higher on average in all three categories, revealing a negative

correlation between P3 amplitude and impulsivity. Neurophysiological disinhibition correlated

with AUDs, especially in the frontoparietal areas, strengthens the claim of an association

between chronic alcohol consumption and impulsivity. However, this reduced P3 amplitude can

be seen already before development of an AUD; previous studies show that adult children of

alcoholics exhibit this same decreased amplitude. Because of this, it is difficult to claim that

chronic alcohol consumption is a cause of this disinhibition and therefore impulsivity. To explore

this connection, we must look at the effects of chronic alcohol consumption at the cellular level.
 Roze 3

Klenowski et al. explored the mechanisms behind alcohol-induced cognitive impairments

through observation of medial prefrontal cortex (mPFC) layer V pyramidal neurons (LVPN)

(Klenowski et al., 2016). A contributing component of AUDs is the voluntary choice of the

individual to consume alcohol, a decision that is mediated in large part by the mPFC. Altered

functioning of the mPFC may lead to impaired judgment when assessing a situation, resulting in

poor decision-making and impulsive actions. If it is found that alcohol is a cause of this

impairment, individuals with an AUD might exhibit a higher level of impulsivity in the situation of

consuming alcohol than individuals without an AUD. Choosing to consume excessive amounts

of alcohol results in a cycle of alcohol consumption and impairment of cognitive functions.

To replicate the voluntary decision-making aspect of an AUD, Klenowski et al. created a

paradigm in which rats were able to choose between drinking either pure water or a mixture of

water and 20% ethanol. Rats in the experimental group were given this choice three times a

week, for 10 weeks, in order to sufficiently simulate chronic alcohol exposure. By the end of the

10 weeks, these rats exhibited a preference for the ethanol solution over the pure water. This

preference was so strong that the average weekly water intake of the experimental group at the

end of the 10 weeks had increased since the first week, a behavior reminiscent of bingeing in

individuals with an AUD. At the neuronal level, the LVPNs of the rats exposed to ethanol

displayed significantly more frequent spontaneous EPSCs (sEPSC) than the control group, due

to increased levels of intrinsic neuronal excitability. This increased activity is a result of NMDA

receptor-mediated glutamatergic neurotransmission upon interacting with ethanol. Heightened

activity in the mPFC of rats that subjected themselves to chronic alcohol exposure seems

counterintuitive to the notion that the mPFC is involved in judgment and executive function. To

address this inconsistency, we must look at the synaptic level of these neurons.
 Roze 4

Abnormal functioning of the mPFC due to alcohol consumption lies in the dysregulation

of neurotransmission between LVPNs. Weitlauf & Woodward examined the effects of ethanol on

glutamatergic and GABAergic systems, and found that ethanol significantly impacted NMDA

receptor-mediated events (Weitlauf & Woodward, 2008). At an acute level, a sufficiently high

concentration of ethanol significantly inhibited NMDA eEPSCs, while AMPA receptor-mediated

eEPSCs were unaffected. This suggests that ethanol has a selective inhibitory effect on the

excitatory glutamatergic responses in LVPNs. The binding specificity of a ligand is the extent to

which it does or does not bind to certain receptors; here, ethanol interacts with NMDA receptors

but not AMPA receptors. These are the main output neurons connecting the mPFC to the rest of

the brain, meaning that inhibition of this neurotransmission results in impaired higher cognitive

functioning in a number of areas. From this we can reason that acute exposure to alcohol can

lead to impaired judgment and impulsivity through its binding specificity to NMDA receptors.

If acute alcohol exposure results in inhibition of mPFC LVPNs in charge of executive

functioning, why does chronic alcohol exposure result in the excitation of these same neurons?

These differences can be explained by the plasticity of these neurons and their NMDA

receptors. Kroener et al. conducted an experiment that would assess the effects of chronic

alcohol exposure on LVPNs (Kroener et al., 2012). Mice were exposed to ethanol vapor for 16

hours a day over a three week period to replicate effects of chronic alcohol consumption. Upon

completion of this treatment period, the experimenters measured the contributions of NMDA and

AMPA currents to overall excitatory synaptic current of LVPNs. NMDA contributed a significant

amount more than AMPA after chronic alcohol exposure. Looking at the mPFC, the researchers

found increased levels of the NR1 and NR2B NMDA receptor subunits, which have been shown

to play an important role in spike-timing-dependent plasticity (STDP). STDP strengthens neural

connections dependent on the precise timing of presynaptic and postsynaptic action potentials.
 Roze 5

These receptor subunits likely contribute to NMDA receptor trafficking to the synapse as part of

a homeostatic response to the inhibition of NMDA receptors caused by chronic alcohol

consumption. Kroener et al. found that these increased levels of available NMDA receptors

came with increased EPSCs, showing that spike-timing-dependent plasticity occurs to counter

the deleterious effects of chronic alcohol consumption on NMDA receptors.

To assess effects on cognitive functioning, the mice were taught a strategy to obtain a

food reward. This test was conducted before and after chronic alcohol exposure. After the

exposure period, the mice were prompted again to respond correctly to obtain food; here, there

was no difference in performance between the control and experimental groups. However, when

the mice were taught a new strategy to obtain food and again subjected to chronic alcohol

exposure and retested, the mice exposed to alcohol performed significantly worse than the

control group. The mice affected by chronic alcohol exposure exhibited reduced cognitive

flexibility, meaning they were less likely to change their behavior in response to changing

situations. This behavior is evidence that the mice lacked the ability to inhibit an irrelevant

response, the same property that a normal amplitude P3 ERP component represents. It is

unknown why these detrimental cognitive effects persist despite the homeostatic plasticity of

mPFC neurons. Functioning behavioral flexibility may regulate cognitive control over alcohol

intake, explaining why individuals with an AUD may not exhibit as much behavioral control.

It’s evident that a wide variety of neural correlates, and thus cognitive functions, both

cause and result from chronic alcohol consumption. Persistent exposure especially results in

altered functioning of NMDA receptors within layer V pyramidal neurons in the medial prefrontal

cortex through disinhibition, selective binding by ethanol, and spike-timing-dependent plasticity.

These processes further affect cognitive functioning in individuals with an AUD, which can lead

to lessened behavioral inhibition and thus increased impulsivity.

 Roze 6

Works Cited

Chen, A. C., Porjesz, B. , Rangaswamy, M. , Kamarajan, C. , Tang, Y. , Jones, K. A., Chorlian,

D. B., Stimus, A. T. and Begleiter, H. (2007), Reduced Frontal Lobe Activity in Subjects
With High Impulsivity and Alcoholism. Alcoholism: Clinical and Experimental Research,
31: 156-165. doi:10.1111/j.1530-0277.2006.00277.x

Klenowski, P. M., Fogarty, M. J., Shariff, M., Belmer, A., Bellingham, M. C., & Bartlett, S. E.
(2016). Increased Synaptic Excitation and Abnormal Dendritic Structure of Prefrontal
Cortex Layer V Pyramidal Neurons following Prolonged Binge-Like Consumption of
Ethanol. eNeuro, 3(6), ENEURO.0248-16.2016. doi:10.1523/ENEURO.0248-16.2016

Kroener, S., Mulholland, P. J., New, N. N., Gass, J. T., Becker, H. C., & Chandler, L. J. (2012).
Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal
cortex. PloS one, 7(5), e37541. doi:10.1371/journal.pone.0037541

M. Salti, Y. Bar-Haim, D. LamyThe P3 component of the ERP reflects conscious perception, not
confidence. ​Consciousness and Cognition,​ 21 (2012), pp. 961-968,
10.1016/j.concog.2012.01.012

Weitlauf, C. and Woodward, J. J. (2008), Ethanol Selectively Attenuates NMDAR-Mediated

Synaptic Transmission in the Prefrontal Cortex. Alcoholism: Clinical and Experimental
Research, 32: 690-698. doi:10.1111/j.1530-0277.2008.00625.x