Alcohol and the Prefrontal Cortex

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The prefrontal cortex occupies the anterior portion of the frontal lobes and is thought to be one of the most complex anatomical and functional structures of the mammalian brain. Its major role is to integrate and interpret inputs from cortical and sub-cortical structures and use this information to develop purposeful responses that reflect both present and future circumstances. This includes both action-oriented sequences involved in obtaining rewards and inhibition of behaviors that pose undue risk or harm to the individual. Given the central role in initiating and regulating these often complex cognitive and behavioral responses, it is no surprise that alcohol has profound effects on the function of the prefrontal cortex. In this chapter, we review the basic anatomy and physiology of the prefrontal cortex and discuss what is known about the actions of alcohol on the function of this brain region. This includes a review of both the human and animal literature including information on the electrophysiological and behavioral effects that follow acute and chronic exposure to alcohol. The chapter concludes with a discussion of unanswered questions and areas needing further investigation.

Introduction

It is now widely accepted that alcohol and other addictive drugs act within the mesolimbic dopamine (DA) system of the brain. This system originates in the ventral tegmental area (VTA) and projects to various limbic structures, including the nucleus accumbens (NAc), amygdala, and hippocampus. Most notably, it is thought that the positive reinforcing effects of drugs of abuse relate to enhanced DA neurotransmission particularly within the NAc. Therefore, virtually all models of the addiction neurocircuitry feature the mesolimbic DA system as central to the addictive process. However, evidence gained over the past decade or more suggests that drug-induced changes in the prefrontal cortex (PFC) also critically regulate drug and alcohol addiction (Everitt and Robbins, 2005, Kalivas and Volkow, 2005, Kalivas, 2009). This evidence comes from diverse studies that include human and animal behavioral work, brain imaging, electrophysiology, and molecular and cellular observations. Whereas a comprehensive review of the role of the PFC in addiction is beyond the scope of this chapter, our aim is to provide a review of the literature regarding the effects of acute and chronic alcohol exposure on PFC structure and function. Consistent with the accumulating evidence implicating the PFC in addiction to opiates, cocaine, and other psychostimulants, it is our contention that current models of the neurocircuitry of alcohol addiction should prominently include ethanol-induced alterations in PFC structure and function. We further suggest that long-lasting alterations in the executive function of the PFC and its associated networks may play an equal or even greater role in alcohol addiction and relapse to drinking than changes within the mesolimbic DA system.

Section snippets

Anatomy of the Prefrontal Cortex

The cerebral cortex of humans and nonhuman primates is separated into a frontal and posterior region by the Rolandic fissure. The primary motor cortex (area 4) is a relatively narrow cortical area that lies immediately anterior to this fissure, and immediately anterior to the primary motor cortex is the premotor cortex (area 6). The PFC makes up the remaining anterior pole of the frontal cortex (Fig. 1, shaded area) and is divided into three interconnected subregions known as the lateral PFC,

The Executive Function of the Prefrontal Cortex

The perception–action cycle, originally described by Arbib in 1985, is a behavioral construct of circular information flow that describes the interaction of an organism with its environment allowing it to carry out the orderly sequencing of goal-directed actions (Arbib, 1985). As pointed out by Fuster (2008), an important element of this construct is that it includes internal feedback from effectors to sensors to provide representations of current actions to sensory structures to modulate

Pyramidal Neurons

In the neocortex, glutamatergic pyramidal neurons represent approximately 80% of the neuronal population and have been best studied in sensory cortices, especially the visual cortex. Neocortical pyramidal neurons are arranged in layers (I–VI in most parts of cortex, rodent PFC lacks a well-defined layer IV) and make connections with both glutamatergic and γ-amino-butyric acid (GABA) neurons within the cortex and those in subcortical areas. Although less well characterized than interneurons (see

Dopamine

Dopamine modulation of PFC function has long been known to be important for optimizing cognitive performance, especially in tasks requiring working memory. Disruption of this important modulatory input is associated with various neurological and psychiatric illnesses. PFC dopamine arises from terminals provided by dopaminergic neurons whose cell bodies reside in the ventral tegmental area (VTA). These neurons also provide dopaminergic tone to other limbic structures including nucleus accumbens

Effects of Alcohol on PFC Neuron Function—In Vitro Studies

Although the effects of biogenic amines and endogenous cannabinoids on PFC neuron excitability have been examined using in vitro electrophysiological techniques, there is much less known about the actions of alcohol on these neurons. Recent studies from the authors’ laboratories have investigated the effects of acute ethanol exposure on persistent activity patterns in PFC neurons in organotypic cell culture and on synaptic transmission in slices from rat prefrontal cortex. Tu et al. (2007) used

Effects of Alcohol on PFC Neuron Function—In Vivo Animal Studies

Acute administration of ethanol to experimental animals is associated with changes in various neurotransmitter systems in the PFC. Several studies have examined these effects using outbred strains of rats. For example, μ-opioid receptors were upregulated in frontal cortex 2 h after intragastric administration of 2.5 g/kg ethanol (Mendez et al., 2001). In Wistar rats, ethanol (1 g/kg) increased the extracellular levels of 5-HT as measured by in vivo microdialysis (Langen et al., 2002). One day of

Acute Ethanol

Acute ethanol administration in humans has been shown to cause deficits in executive activities that are thought to require the PFC. For example, performance in a spatial recognition task and a planning task was decreased in social drinkers while inebriated (Weissenborn and Duka, 2003) and acute EtOH has been shown to cause poorer decision making using a gambling task to assess PFC function (George et al., 2005). Working memory (WM) tasks are also commonly used to test executive function given

Summary

It is clear from the above discussion that exposure to alcohol, either acutely or chronically, has significant effects on the functional and structural status of the prefrontal cortex. Given the key role that this brain region plays in the integration, manipulation, and evaluation of incoming sensory and cognitive information, it is not surprising that alcoholics display deficits in executive control, decision making, and risk management. Despite these observations, however, there are still

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