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Communication Networks
in the Brain
Neurons, Receptors,
Neurotransmitters, and Alcohol
David M. Lovinger, Ph.D.
DAVID M. LOVINGER, PH.D., is chief of the Laboratory for Integrative Neuroscience at the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
Nerve cells (i.e., neurons) communicate via a combination of electrical and chemical signals. Within the neuron, electrical signals driven by charged particles allow rapid conduction from one end of the cell to the other. Communication between neurons occurs at tiny gaps called synapses, where specialized parts of the two cells (i.e., the presynaptic and postsynaptic neurons) come within nanometers of one another to allow for chemical transmission. The presynaptic neuron releases a chemical (i.e., a neurotransmitter) that is received by the postsynaptic neuron’s specialized proteins called neurotransmitter receptors. The neurotransmitter molecules bind to the receptor proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors exist—ligand-gated ion channels, which permit rapid ion flow directly across the outer cell membrane, and G-protein–coupled receptors, which set into motion chemical signaling events within the cell. Hundreds of molecules are known to act as neurotransmitters in the brain. Neuronal development and function also are affected by peptides known as neurotrophins and by steroid hormones. This article reviews the chemical nature, neuronal actions, receptor subtypes, and therapeutic roles of several transmitters, neurotrophins, and hormones. It focuses on neurotransmitters with important roles in acute and chronic alcohol effects on the brain, such as those that contribute to intoxication, tolerance, dependence, and neurotoxicity, as well as maintained alcohol drinking and addiction. K EY WORDS : Alcohol and other drug effects and consequences; brain; neurons; neuronal signaling; synaptic transmission; neurotransmitter receptors; neurotrophins; steroid hormones; γ -aminobutyric acid (GABA); glutamate; dopamine; adenosine; serotonin; opioids; endocannabinoids
T
he behavioral effects of alcohol are produced through its actions on the central nervous system (CNS) and, in particular, the brain. Synaptic transmission—the process by which neurons in the CNS communi- cate with one another—is a particular target for alcohol actions that alter behavior. Intoxication is thought to result from changes in neuronal com- munication taking place while alcohol is present in the brain. Tolerance to alcohol involves cellular and molecular adaptations that begin during alcohol exposure; the adaptations develop and diversify with repeated episodes of exposure and withdrawal and are
linked to the environment present during exposure. Alcohol dependence develops after several exposure/withdrawal cycles and involves neuroadaptive changes brought about by both the exposure and withdrawal processes. Neurotoxicity produced by alcohol ingestion involves a number of cellular and molecular processes, and neurotransmitters can participate in—and modulate—many of these mechanisms. The actions of alcohol on synaptic transmission also contribute to alcohol-seeking behavior, excessive drinking, and alcoholism. Thus, understanding all of these behav- ioral actions of alcohol requires some knowledge of neuronal signaling in the
brain and, especially, the process of synaptic transmission. This article will focus on the basic processes underlying neuronal communication and review the neuronal actions of several neuro transmitters, neurotrophic factors, and hormones thought to be involved in the neural actions of alcohol. This information, although admittedly incomplete, will provide a foundation for the detailed information on alcohol
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actions provided in subsequent articles in this issue and in Part 2.
Neuron-to-Neuron
Communication
Neurons are the cells within the brain that are responsible for rapid commu nication of information. Although sim ilar to other cells in the body, neurons are specialized in ways that set them apart from other cells and endow them with the properties that allow them to carry out their unique role in the ner vous system. The neuron’s shape is one such unique feature. In addition to the cell body, or soma, which is much like that of other cells, neurons have special ized thin branches know as dendrites and axons. Neurons receive chemical input from other neurons through den drites and communicate information to other cells through axons. Neurons also are “excitable” cells. The neuronal
surface membrane contains an abun dance of proteins known as ion chan nels that allow small charged atoms to pass through from one side of the membrane to the other. Some of these channels are opened when the voltage across the cell membrane changes. One subtype of these “voltage-gated” channels allows the neuron to produce a rapid signal known as the “action potential,” which is the fastest form of intracellular electrical signal conduc tion in biology (see figure 1). Individual neurons usually are completely separated from one anoth er by their outer cell membranes and thus cannot directly share electrical or chemical signals. The exception to this situation is the so-called electrical synapse, in which ion-conducting pores made from proteins called connexins connect the intracellular compart ments of adjacent neurons, allowing direct ion flow from cell to cell
(Kandel et al. 2000). This form of interneuronal communication is much less common in the mammalian CNS than chemical transmission and will not be discussed any further. Rather, the focus will be on chemical inter neuronal communication involving the release of a neurotransmitter from one neuron, which alters the activity of the receiving neuron. This chemical communication usually occurs at a specialized structure called a synapse, where parts of the two cells are brought within 20 to 50 nanometers of one another (see figure 2). The neuron that releases the chemical is called the presynaptic neuron. A spe cialized structure at the tip of the axon of the presynaptic neuron, termed the axon terminal, contains small packets known as vesicles, which are filled with neurotransmitter molecules. When an action potential reaches the axon terminal and stimulates a rise in the concentration of calcium, this ion stimulates the vesicle to fuse with the cell membrane and release the neuro transmitter into the small synaptic gap between cells. The neuron that is acted upon by the chemical is termed the post synaptic neuron. The neurotransmitter molecules released from the presynap tic vesicles traverse the synaptic gap and bind to proteins, termed neuro transmitter receptors, on the surface membrane of the postsynaptic neuron.
Figure 1 Schematic drawing of a neuron showing dendrites, where neurons receive chemical input from other neurons; soma (cell body); and axon terminal, where neurons communicate information to other cells. Voltage-gated sodi um channels in the membrane of the soma, axon, and axon terminal allow positively charged sodium ions to enter the neuron and produce rapid (in milliseconds) conduction of the excitatory action potential to the terminal. This signal stimulates neurotransmitter release at the axon terminal.
Neurotransmitter Receptors Neurotransmitter receptors are divided into two major classes: ligand-gated ion channel (LGIC) receptors and G-protein–coupled receptors (GPCRs). LGIC receptors are proteins specialized for rapid transduction of the neuro transmitter chemical signal directly into an electrical response (Brunton et al. 2005; Kandel et al. 2000) (see figure 3A). One part of the protein is special ized to bind the neurotransmitter molecule. This “binding site” is on the extracellular side of the protein. The part of the protein that is buried within the cell surface membrane forms an ion pore, which is basically a fluid-filled hole in the membrane through which the
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with receptors so that short, discrete synaptic signals are produced. At most synapses in the brain, specific proteins known as neurotransmitter transporters mediate this removal (Brunton et al. 2005; Kandel et al. 2000). The transporter proteins reside in the cell surface mem brane and actively move the neuro transmitter molecule from the outside to the inside of the cell (see figure 2). In many cases, this uptake occurs at the presynaptic terminal itself, where the neurotransmitter is directly reloaded into vesicles. However, in some cases nonneuronal support cells (i.e., glial cells) also participate in neurotransmitter uptake. Removal of synaptic neuro transmitters also can occur via enzymes that degrade the neurotransmitter to constituent molecules that do not them selves activate receptors.
Figure 3A Schematic drawing of a ligand-gated ion channel (left) showing the con fluence of individual subunit proteins that define a pore where the ions flow across the cell membrane. A neurotransmitter binds to part of the protein located outside of the cell. Schematic drawing of a G-protein– coupled receptor (right). Neurotransmitter binds either to sites outside the cell or in a “pocket” formed by protein domains that span the mem brane. The G-protein that consists of three separate protein subunits (α, β, and γ, light blue) is associated with part of the protein inside the cell.
Neurotrophins
In addition to neurotransmitters that alter neuronal physiology, intracellular signaling, and gene expression on a
relatively fast time scale, certain small chains of amino acids (i.e., peptides) can be secreted by neurons that act as so-called growth factors or neurotrophins. The most widely known neurotrophins are nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and related members of this “cysteine knot” dimeric neurotrophin family that also includes neurotrophin (NT)-3 and NT-4 (Barde 1994; Barde et al. 1982; Levi-Montalcini and Cohen 1960; Reichardt 2006). Other neurotrophins, such as glial-derived neurotrophic factor (GDNF), which acts through the transforming growth factor (TGF)β‚ signaling pathway, are peptides of a different structural class (Unsicker 1996). The neurotrophins are peptides, so their primary amino acid sequence is genetically coded and is subject to alterations in the synthesis of genetic information (i.e., transcription) that can produce different variants of the mature peptide. These peptides also are generated from larger propeptides, and, thus, variations in sequence can
occur at the level of posttranslational peptide processing. All of these factors combine to produce a rich variety of neurotrophins in the brain. Neurotrophins are thought to be secreted from different neuronal structures, including both axon ter minals and dendrites (see Altar and DiStefano 1998 for review). Thus, they participate in both “anterograde” signaling from the axon terminal of the presynaptic neuron to the post synaptic elements of a downstream neuron, as well as “retrograde” signal ing, in which release from dendritic elements of the postsynaptic neuron activates receptors on the presynaptic axon terminals. Receptors for neurotrophins couple to a wide variety of intracellular sig naling cascades. The main receptors for the cysteine knot family of neu rotrophins are the Trk receptors (Kaplan et al. 1991; reviewed by Chao and Hempstead 1995) (see figure 3B). Each individual neurotrophin binds with highest affinity to a particular Trk receptor (e.g., NGF with TrkA, BDNF with TrkB), but there also are lower affinity interactions that are not as specific (Barbacid 1995; Ip et al. 1993 a,b ). Upon neurotrophin binding, the Trk receptors are activated, setting into motion a variety of signaling mechanisms, including the activation of small G-proteins; activation of multifunctional protein kinases, including extracellular signal–regulated kinase (ERK) and the Fyn and Src kinases; activation of lipid-based signaling pathways; and activation of transcription factors that regulate gene expression (Davis 2008). Some of these signaling pathways have effects locally within a particular sub cellular compartment. Other signals (e.g., those involving transcription factors) are transmitted to the nucleus. There is evidence that neurotrophin bound Trk receptors are internalized and translocated to the nucleus, where they can participate in signaling that regulates gene expression (reviewed by Ginty and Segal 2002). Internalization of neurotrophin-bound receptors also is believed to be a major mechanism by which the neurotrophins are
removed from the extracellular space and ultimately degraded by intracel lular peptidases. The diversity of sig naling pathways activated by Trk receptors allows them to participate in a variety of neuronal functions, including not only cell survival and growth but also synaptic plasticity. Neurotrophins are well known for their ability to support the survival and growth of neurons. For example, the pioneering work of Levi-Montalcini and Cohen (1960) showed that the viability of sympathetic peripheral neurons (those outside the CNS) in culture requires NGF and that this neurotrophin stimulates outgrowth of axons and dendrites (Levi-Montalcini 1987). Neurotrophins are widely expressed within the CNS. For exam ple, BDNF is expressed in a number of brain regions, including many that have been implicated in neural mechanisms of addiction (reviewed in Davis 2008).
Steroid Hormones
Steroid hormones––small, complex molecules involved in intercellular communication—are highly lipid soluble and have a variety of actions in the body and brain. For example, corticosteroids are released from the cortex of the adrenal glands located on top of the kidneys in response to external stress and are car ried by the bloodstream to their sites of action throughout the body and brain (Brunton et al. 2005). It now is widely appreciated that steroids have two mechanisms of action. The traditional steroid signaling pathway involves an intracellular steroid receptor that resides in the cytosol when unbound and translocates to the cell nucleus when it is bound with the steroid (Brunton et al. 2005; Hayashi et al. 2004) (see figure 3C). The receptor protein then can bind to DNA and directly influ ence the transcription of a variety of genes. The second type of steroid hor mone signaling involves actions on cell surface receptors. For example, deriva tives of the sex steroid progesterone interact with the A-type receptors for the neurotransmitter γ-aminobutyric acid (GABA) (i.e., GABAA receptors) to enhance receptor function allosterically
Figure 3B Neurotrophin binding to TRK receptors attracts a variety of intracellular signaling proteins to the intracellular portion of the TrK protein. Activation of these signaling proteins in turn activates transcription factor proteins that act on the nucleus to alter gene expression, as well as other intracellular signaling pathways that promote the growth and differentiation of neurons. Activation of neurotrophin–TrK–intracellular signaling pathways also pro motes long-lasting plasticity of synaptic transmission.
BDNF = brain-derived neurotrophic factor.
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Rather, the sections that follow focus on those neurotransmitters whose actions are most strongly implicated in alcohol intoxication, tolerance, depen dence, and addiction. This discussion is organized according to the neuro transmitters’ proposed roles within the chronology of alcohol actions. Those neurotransmitters thought to be most heavily involved in intoxication are dis cussed first, followed by those involved in chronic alcohol effects. The final section addresses those neurotransmit ters that do not appear to be direct tar gets for the neural actions of alcohol but which may be involved in alcohol abuse and addiction and are potential pharmacotherapeutic targets.
GABA
GABA mediates the majority of fast synaptic inhibition in the brain, specifi cally through activation of GABAA receptors. Like glutamate, GABA also is found in all brain regions. The intrinsic ion channel contained in the GABAA receptor protein is permeable to Cl-^ and other anions (Kandel et al. 2000). Activation of the receptor can hyperpolarize neurons through the influx of negative charges at membrane potentials below the threshold for action potential generation. This inhi bition generally counteracts the effect of glutamate and other depolarizing, excitatory synaptic influences. The amino acid glycine produces a similar action in the spinal cord and posterior parts of the brain. Several subtypes of GABAA receptors exist; they are formed by the confluence of individual “subunit” proteins (see figure 4). Each subunit has a slightly different amino acid sequence, and there are 20 subunits in all in the mammalian brain (Sieghart and Sperk 2002). Thus, a variety of different types of GABAA receptors are made in different brain neurons. GABAA receptors are present both at the synapse and on postsynaptic mem branes distant from synapses. These latter “extrasynaptic” GABAA recep tors are sensitive to very low levels of extracellular GABA, and thus they
often produce a continuous inhibitory tone that helps to set the resting poten tial of certain neurons (Stell et al. 2003). The GABAA receptor channel contains numerous sites for allosteric modification. Perhaps the best known among these is the “benzodiazepine” binding site (Sanger 2004; Sigel 2002). This site resides on the extracellularly exposed part of the protein at a site distinct from the agonist binding region. Many compounds, such as Valium, that bind to this site have potent allosteric enhancing effects on the receptor. Other compounds can have an antagonist action at this site and will prevent allosteric enhancement by benzodiazepines without altering the response of the receptor to GABA (Mohler 1983). The diversity of GABAA receptor subtypes has given
rise to different benzodiazepine effects on different receptors and different brain neurons, providing multiple possibilities for pharmaceu tical development. Drugs that target the GABAA receptor have been in widespread use for treatment of disorders ranging from anxiety to epilepsy (Mohler 2006; Sigel 2002). The majority of general anesthetics currently in use produce their actions predominantly through enhancing GABAA receptor function (Hemmings et al. 2005). Almost all of these therapeutic drugs either directly activate the GABAA receptor or activate the benzodiazepine site to produce allosteric enhancement of the receptor, as mentioned above. GABA also can act through a GPCR, the aforementioned GABAB
Figure 4 Schematic drawing of the γ-aminobutyric acid receptor (GABA (^) A) ligand- gated ion channel complex. The receptor molecule is formed by the con fluence of five subunit proteins. In this case, two of the subunits are of the α type, two β, and one γ, although many combinations of the 20 known subunits are possible. Globular regions of the protein stick out from the membrane on the extracellular side, and the interfaces between these regions are targets for GABA and for the benzodiazepines and related drugs. The protein domains that span the outer cell membrane are depicted as cylinders. These regions are thought to be targets for general anesthetics (e.g., propofol) neurosteroids, and alcohol. A hole in the middle of the five subunits is the ion conduction pathway, or channel pore.
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receptor. This receptor acts to inhibit neuronal activity in two ways (Bowery et al. 1990). First, activation of GABAB receptors leads to a direct G-protein– mediated activation of the GIRK- type potassium channel. This channel can hyperpolarize neurons and coun teract synaptic excitation. This type of GABAB-mediated modulation is found in many postsynaptic neuronal elements throughout the brain. GABAB receptors also are found on presynap tic terminals of neurons in many brain regions (Bowery et al. 1990). When activated, these receptors inhibit neu rotransmitter release via mechanisms that involve inhibition of voltage- gated calcium channels whose func tion is necessary for proper release. Presynaptic GABAB receptors are found on the axon terminals of both GABAergic and glutamatergic neurons, and thus the net effect of receptor activation can be either disinhibitory or inhibitory depending on which receptors are activated. GABAergic transmission is a sensitive target for both the acute and chronic effects of alcohol (reviewed in Lovinger and Homanics 2007; Siggins et al. 2005). Acute alcohol can produce allosteric enhancement of the function of GABAA receptors, although this effect is not observed at all GABAA receptors, and there is some debate as to which receptor subtypes are most sensitive to alcohol (reviewed in Lovinger and Homanics 2007). Researchers have observed effects at concentrations as low as the low millimolar range (the levels reached with ingestion of a single drink), suggesting that even some aspects of low-dose intoxication might involve enhanced GABAA receptor function. Acute ethanol also enhances the release of GABA at a number of synapses in the brain (Siggins et al. 2005). The mechanisms of this presy naptic enhancement are just beginning to be explored. One interesting set of studies indicates that activation of presynaptic GABAB receptors pre vents alcohol potentiation of GABA release and can bring about a “tolerance” to the alcohol action (Ariwodola and Weiner 2004). Potentiation of
GABAergic synaptic transmission appears to contribute to a number of aspects of acute alcohol intoxication, including motor incoordination, anxiety-reducing effects, sedation, and the internal cues that signal intoxication (Lovinger and Homanics 2007; Siggins et al. 2005; Vengeliene et al. 2008). The brain’s GABAergic system also shows marked changes following chronic alcohol exposure. Some of these changes are likely to be adapta tions to the acute alcohol actions that potentiate GABAergic transmission. The best-characterized changes involve alterations in the subunits that make up the GABAA receptor (Kumar et al. 2004), which alter the efficacy and timing of inhibitory synaptic trans mission. Research also shows that chronic alcohol exposure can produce decreases and increases in GABA release in different brain regions (reviewed in Weiner and Valenzuela 2006). The predominant effect of these chronic alcohol effects is to make the brain hyperexcitable during withdrawal from chronic alcohol exposure. This can produce effects such as heightened anxiety and even overt seizures during withdrawal (Krystal et al. 2006; Kumar et al. 2004). Benzodiazepines commonly are used to treat alcohol withdrawal because of their effectiveness in con trolling these aspects of hyperex citability (Krystal et al. 2006). Drugs that target GABAergic transmission also have been touted as potential pharmacotherapeutic treatments for alcohol abuse and alcoholism (Koob 2004; Krystal et al. 2006), but, as yet, no drugs that explicitly and specifical ly target GABAergic mechanisms are in clinical use for this purpose.
Glutamate
Glutamate is the major excitatory neuro transmitter in the mammalian brain. Fast transmission mediated by this neurotransmitter accounts for synaptic excitation of most, if not all, brain neurons (Kandel et al. 2000), and thus glutamate is found throughout the brain.
It is not surprising, therefore, that glu tamate has key roles in a wide variety of brain functions. The fast synaptic excitation produced by glutamate involves the activation of three major subtypes of LGICs, termed the AMPA (α-amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid)^3 -, kainate-, and NMDA ( N -methyl-D-aspartic acid)^4 -type receptors based on the syn thetic agonists that best activate each receptor (Kandel et al. 2000). At most excitatory synapses, glutamate released from presynaptic vesicles crosses the synapse and binds to AMPA-type glutamate receptors. The binding of glutamate to AMPA receptors directly activates the ion pore intrinsic to this protein and produces a rapid depolar ization of the postsynaptic neuron that increases the likelihood that this neuron will fire an action potential. Thus, timely and accurate communica tion within brain circuits depends to a large extent on proper AMPA receptor activation. The function of NMDA-type glutamate receptors is more compli cated. When glutamate binds to the NMDA receptor, activation of the intrinsic ion pore is favored, as is the case for AMPA receptors and other LGICs. However, at membrane potentials near the resting potential (e.g., –60 to –70 mV), the ion pore of the NMDA receptor is occluded by magnesium ions (Kandel et al. 2000). Magnesium is present at mil limolar concentrations in the extra cellular solution and binds to a site within the NMDA receptor ion pore that becomes accessible very shortly after the ion pore opens. This magne sium pore blocking action is stronger at more negative membrane potentials and is thus reduced as the membrane potential becomes more depolarized. In practice, at a glutamatergic synapse that contains both AMPA and NMDA recep tors, the initial action of glutamate
(^3) AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropi onic acid) is a specific agonist for the AMPA receptor. (^4) NMDA ( N -methyl-D-aspartic acid) is a specific agonist at the NMDA receptor and therefore mimics the action of glutamate on that receptor. In contrast to glutamate, NMDA binds to and regulates the above receptor only but not other glutamate receptors.
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internal segment and thus form the legal prescription medications and ille- 2008), which is taken up by the brain “indirect” pathway that tends to gal drugs of abuse. Perhaps the most and used to make more dopamine. dampen cortical output. The coordi- widely known brain disorder involving Dopamine receptor agonists also are nation of these two pathways deter- the brain dopaminergic system is sometimes used as an adjunct therapy mines one’s ability to initiate actions Parkinson’s disease. This debilitating with L-Dopa (Stacy and Galbreath and control action sequences. Thus, and ultimately lethal neurological disor- 2008). Agonists of the D 2 class of dopamine, working through these der arises from the death of dopamin- dopamine receptors are used in the two receptor subtypes, has key roles ergic neurons and the resultant loss of treatment of the movement disorder in controlling performance of actions, brain dopamine (Kandel et al. 2000). known as restless legs syndrome including those affected by intoxica- The most common therapy for this (Winkelman et al. 2007). Dopamine tion and those involved in addiction. disease involves dopamine replacement receptor- and transporter-targeted Dopaminergic transmission is by treatment with the dopamine pre- drugs also have a large role in the targeted by many drugs, including both cursor L-Dopa (Stacy and Galbreath treatment of other neurological and
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A Human
B
Rat
Figure 5 Neurotransmitters with discrete localization within the brain. A) The chemical structure of the monoamine neurotransmitter dopamine and a schematic drawing of the localization of dopamine-containing neurons in the human and rat brain and the sites where dopamine-containing axons are found. B) The chemical structure of the monoamine neurotransmitter serotonin and similar brain map showing locations of serotonin-containing cells and their axons.
neuropsychiatric disorders. The major ity of antipsychotic drugs have potent actions at the D 2 -like dopamine receptors, although they certainly have effects on other targets that could contribute to their therapeutic efficacy (Kapur et al. 2006). Drugs that block the dopamine transporter, such as methylphenidate (Ritalin®) are used in the treatment of attention deficit hyperactivity disorder (ADHD) (Arnsten 2006) (note the potential abuse liability of this class of drugs, as discussed below) (Faraone and Wilens 2007). Antagonists for D 2 dopamine receptors also are used clinically to reduce vomiting in circumstances such as chemotherapy (Reddymasu et al. 2007). Cocaine, amphetamine, and other “stimulant” drugs block or reverse the action of the dopamine transporter (Amara and Sonders 1998). The net effect of these drugs is to increase levels of dopamine within the synapse. Although these drugs act on other molecular targets, the evidence is fairly convincing that it is the effect on dopaminergic transmission that accounts for the majority of the intoxicating and addictive actions of these drugs. Most other drugs of abuse also influ ence the brain dopaminergic system. Nicotine stimulates the activity of the dopaminergic neurons themselves (Pidoplichko et al. 1997) and also can activate dopamine release from axon terminals (Grady et al. 2007). Morphine and other opiate drugs depress the activity of GABAergic interneurons and, through this effect, indirectly increase the activity of dopaminergic neurons (Johnson and North 1992). Alcohol also increases the activity of these neurons, likely via both direct actions on the neurons and indirect actions through other neurons (Brodie et al. 1999; Ericson et al. 2008; Gessa et al. 1985; Okamoto et al. 2006). Dopaminergic transmission has been implicated in the actions of almost all drugs of abuse, and trans mission mediated by this neurotrans mitter is altered by alcohol exposure in both the acute and chronic phases (reviewed in Vengeliene et al. 2008).
The acute alcohol-induced increase in firing of dopaminergic neurons appears to drive increases in extracellular dopamine levels in the brain regions to which these neurons project (reviewed in Gonzales et al. 2004). Imaging of dopamine receptors in the human brain also suggests that acute alcohol exposure alters dopamine levels in key brain structures (reviewed in Wong et al. 2003). These effects may contribute to the process by which animals encode the reinforcing value of alcohol. As animals learn to consume alcohol in the laboratory, increases in brain dopamine levels become associ ated with stimuli that predict access to alcohol (Gonzales et al. 2004). Thus, dopamine also plays a role in learning about environmental contexts that encourage drinking. Chronic alcohol consumption can lead to a hypodopaminergic state that motivates the drinker to seek alcohol in order to restore the desired levels of the neurotransmitter (Volkow et al. 2007). However, despite these findings, pharmacotherapies aimed at the dopaminergic system have not shown particular efficacy in reducing alcohol drinking either in animal models or in humans with alcohol abuse disorders. Perhaps the development of drugs with greater specificity for certain subtypes of dopamine receptors will prove more efficacious in this context.
Adenosine
Adenosine is a purine nucleoside (a compound with a nitrogen-containing base linked to a sugar molecule) that is produced during nucleic acid metabolism. This compound also participates in a number of types of cell–cell communi cation, including synaptic transmission in all regions of the nervous system. Adenosine primarily is a neuromodula tory transmitter and produces its actions via the activation of two main types of GPCRS, the A1 and A2a adenosine receptors (Fredholm et al. 2005). Other adenosine receptors exist but are present only in small quantities within the CNS.
Activation of A1 adenosine receptors in turn activates Gi/o class G-proteins. In general, these G-proteins activate GIRK potassium channels, inhibit voltage-gated calcium chan nels, inhibit adenylyl cyclase, or activate phosphorylation of certain intracellu lar protein kinase enzymes (Fredholm et al. 2005). Adenosine A2a receptors activate Gs or Golf–type G-proteins (Fredholm et al. 2007). These G- proteins stimulate adenylyl cyclase to enhance production of the second messenger cyclic AMP (Fredholm et al. 2007). After producing its actions on synaptic adenosine receptors, the neurotransmitter is transported back into cells via a cell membrane neuro transmitter transporter protein known as the adenosine transporter (Fredholm et al. 2005). Adenosine also can be metabolized by enzyme proteins known as adenosine deaminase and adenosine kinase (Fredholm et al. 2005). The transporter and enzymes regulate the duration of adenosine signals within the synaptic cleft. Inhibition of either process can prolong the time that the neurotransmitter is present in the synapse and, conse quently, the duration of activation of the adenosine receptors. The behavioral effects of modifying brain adenosinergic communication are very familiar to many of us. Caffeine acts as an adenosine receptor antago nist (Dunwiddie and Masino 2001). The major behavioral effects of caf feine, including enhanced activity and focused attention, appear to involve inhibition of the function of both A1- and A2a-type adenosine receptors, although locomotor stimulation by caffeine is predominantly because of A2a antagonism. Acute alcohol exposure increases adenosine signaling in cell lines of neural origin (Nagy et al. 1990). This effect appears to involve inhibition of a nucleoside transporter that normally produces rapid uptake of adenosine into cells. This inhibitory action increases extracellular adenosine levels and prolongs the duration of adeno sine signaling to the cell. The role of these changes in adenosinergic trans-
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on a few neuropeptides that have been implicated in alcohol actions on the brain. Most of the neurotransmitter molecules discussed above are synthe sized within the axon terminal itself and are then delivered into the vesi cles waiting near the presynaptic release sites. Peptide neurotransmitters, however, normally are synthesized in the neuronal cell body, some distance from the site of release (Kandel et al. 2000). The neuropeptides then are packaged into vesicles and transported inside the vesicle to the axon terminal. Thus, it is somewhat easier to deplete the store of neuropeptide transmitters in a given axon terminal, and it can only be refilled after transport from the cell body. The opioid peptides are some of the most widely known neuropeptides. These include β-endorphin (which consists of 31 amino acids), dynorphin (13 amino acids), and the enkephalins (5-amino-acid peptides that end in either methionine [met-enkephalin] or leucine [leu-enkephalin]) (Kandel et al. 2000). The notoriety of these peptides stems from the fact that they serve as agonists for the receptors that also are activated by morphine, heroin, and the other opiate drugs. These receptors are known as opiate receptors, and there are three different subtypes designated the μ, δ, and κ receptors (Connor and Christie 1999). In addi tion, a peptide known as nociceptin or orphanin FQ has actions at a separate opiate-like receptor called the ORL- receptor (Connor and Christie 1999). All of these receptors preferentially couple to Gi/o-type G-proteins and thus generally are known to inhibit neurotransmitter release and reduce the activity of neurons (Williams et al. 2001). Opioid peptides are found in many regions of the nervous system. Like other neuropeptides, the opioids usually are stored in and released from large vesicles different from those that contain the small molecules (e.g., glutamate or GABA). These opioid peptide–containing vesicles often are found in the same axon terminals with the smaller diameter, small molecule– containing vesicles, and thus many
neurons have the capacity to release both small molecule and opioid pep tide neurotransmitters (Kandel et al. 2000). Opiate receptors are found on both presynaptic and postsynaptic structures (Williams et al. 2001). The termination of transmission mediated by opioid peptides involves peptidases, which are specific enzymes that catalyze the degradation of the peptide into its constituent amino acids (Schwartz et al. 1981). These amino acids are then taken back into cells via amino acid transporters, where they can be used for future peptide or protein synthesis. Opiate receptors have been targeted for a number of therapeutic uses. Morphine, heroin, fentanyl, and other powerful opiate receptor agonists have long been used for pain reduction (Brunton et al. 2005). The opiate receptor partial agonist methoadone is a well-known and effective treatment for addiction to opiate drugs (Brunton et al. 2005), basically substituting for morphine or heroin to prevent with drawal symptoms without having the same debilitating effects. Of course, opiate agonists are among the drugs with the strongest abuse/addiction liability (Brunton et al. 2005). Injectable heroin is perhaps the best-known addictive opiate and continues to be a problem for people worldwide. However, abuse of power ful synthetic opiates taken in pill form, such as Oxycontin®^ (also known as Oxycodone), has been on the rise in recent years (Compton and Volkow 2006). Another psychoactive drug, the plant derivative known as salvanorin A, acts as an agonist at κ-opioid receptors (Roth et al. 2002). When ingested, it produces a relatively short- lasting disorientation, such that the user becomes unaware of his/her loca tion in space and time. Acute alcohol alters endogenous opioid peptides and opiate receptors (Charness 1989; Gianoulakis 1989). However, the contribution of these actions to intoxication remains unclear. Chronic alcohol exposure also alters brain opiatergic systems (Charness 1989; Gianoulakis 1989). Interestingly, opiate receptors have emerged as use ful targets for pharmacotherapeutic
treatment of alcohol use disorders (reviewed in O’Brien 2005; O’Malley and Froehlich 2003). Use of the gen eral opiate receptor antagonist nal trexone is approved for the treatment of alcoholics. This compound also reduces alcohol drinking in rodents, apparently via blockade of the μ-type opiate receptor (Altshuler et al. 1980; Gonzales and Weiss 1998; Krishnan- Sarin et al. 1998). The mechanism of action may involve a reduction of endogenous opioid peptide actions that normally promote increases in dopamine release (Gonzales and Weiss 1998). Many other neuropeptides origi nally found to act as hormones also have been found to act as neurotrans mitters. Corticotrophin-releasing hor mone (CRH) was originally known for its role in the pituitary gland, where it stimulates a cascade of molecular processes that ultimately leads to the release of the cortisone-like steroid hormones (e.g., corticosteroids) (Brunton et al. 2005). Within the brain, CRH can communicate signals related to stress, mood, and changes in other bodily functions (Reul and Holsboer 2002). The cellular release of this neuropeptide is stimulated by alcohol (Nie et al. 2004) as well as by exposure to stressful stimuli. Mounting evidence suggests that CRH and its receptors participate in the interactions between stress and alcohol, including increased drinking or relapse to drinking following stressful events (Heilig and Koob 2007). A variety of other neuropeptides have been implicated in brain responses to alcohol and alcohol drinking behav ior (see Thorsell 2007 and Wurst et al. 2007 for more information).
Endocannabinoids and
Other Lipid-Derived
Neuromodulators
Molecules derived from the chemical modification of the lipids found in neuronal membranes are another class of neuromodulatory substances. Throughout the body, lipid-derived molecules are known to have paracrine
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actions. The lipid metabolites known as prostaglandins are perhaps the best- known examples of such paracrine agents (Brunton et al. 2005). It is worth not ing that lipid-derived compounds do not have to be released from synaptic vesicles. Unlike other neurotransmitters, they usually escape from neurons directly through the cell surface membrane. Many of these lipid-derived agents are involved in synaptic communica tion. Endocannabinoids (a contrac tion of endogenous cannabinoids) are an example (Chevaleyre et al. 2006). Arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) are two compounds that can be pro duced upon breakdown of membrane lipids that contain the fatty acid known as arachidonic acid. These compounds are produced throughout the brain and body and have been implicated in a number of physiological functions. Endocannabinoids have an intriguing retrograde signaling action at synapses (Alger 2002). In other words, synaptic communication by these compounds generally occurs in a direction opposite to that of traditional neurotransmitters. The endocannabinoids often are produced by postsynaptic neuronal elements and act on their cognate receptors, cannabinoid 1 (CB1) receptors, which are found almost exclusively on presynaptic axon ter minals in the brain. This signaling requires that the compound traverse the synapse in a backward, or retro grade, direction. This action of endo cannabinoids has now been found throughout the nervous system. The CB1 receptor is a GPCR that links to Gi/o-type G-proteins. The most common effect of activating this receptor is inhibition of neuro transmitter release (Lovinger 2008). Thus, retrograde endocannabinoid signaling results in decreased release of several types of neurotransmitters, including both GABA and glutamate. Endocannabinoid effects are therefore disinhibitory (relief from GABAergic inhibition) or inhibitory (decreased glutamatergic excitation) depending on the brain region and synapses in which they act. The presence of endo cannabinoids in the synapse often
leads to inhibition of neurotransmitter release that persists for as long as the endocannabinoid is present (Chevaleyre et al. 2006; Lovinger 2008). Endo cannabinoids also can trigger a long- lasting depression of neurotransmitter release called long-term synaptic depression (LTD) (Chevaleyre et al. 2006; Lovinger 2008). This depression is set into motion by endocannabinoid activation of CB1 receptors but does not require sustained CB1 activation for its long-term maintenance. Accum ulated evidence suggests that the synap tic depression produced by retrograde endocannabinoid signaling has key roles in brain mechanisms of learning and memory as well as addiction (Lovinger 2008). The term “cannabinoid” within the name of these compounds reflects that fact that the endocannabinoids have something in common with drugs derived from the Cannabis sativa plant, such as marijuana. Indeed, the CB receptor is itself the major target for Δ-9tetrahydrocannabinol (Δ-9THC), the primary psychoactive ingredient in cannabis-derived drugs (Brunton et al. 2005). The endocannabinoids produce much milder and shorter-last ing versions of the effects produced by cannabinoids in the brain, includ ing relief from anxiety, relief from pain, actions that affect movement initia tion, balance and coordination, and effects on cognition (Lovinger 2008; Piomelli et al. 2000). Knowledge of the neuronal effects of Δ-9THC pro vides a great deal of information on the effects of specific CB1 agonists. Indeed, a number of synthetic agonists have been developed for this receptor, and they produce strong intoxication, movement impairment, decreased learning and short-term memory, pain relief, and, at high doses, a loss of movement known as catalepsy (Howlett 1995). At low-to-moderate doses, these compounds also stimulate appetite, a well-known effect of mari juana and other illegal cannabis-derived drugs (Di Marzo et al. 2001). Antagonists for the CB1 receptor also have neural actions, and there is increasing evidence of the therapeutic usefulness of these compounds. Studies
in laboratory animals indicate that CB1 antagonists reduce feeding and the metabolic changes that often accompany obesity (Di Marzo et al. 2001; Ravinet Trillou et al. 2003). The CB1 antagonist known as Acomplia®, Rimonabant, or SR already is in use in Europe for treatment of obesity and the associated metabolic disorder. Antagonists for this receptor also reduce self-administration of a number of drugs of abuse, most notably nicotine and alcohol (Maldonado et al. 2006; Wang et al. 2003). Indeed, researchers have observed a variety of interactions between alcohol and the brain endocannabinoid system, sug gesting involvement of this system in alcohol dependence (Colombo et al. 2007). Research on alcohol interac tions with the brain endocannabinoid signaling system still is in the early stages. Chronic alcohol has been shown to increase AEA and 2-AG levels in cells and tissue (Basavarajappa and Hungund 1999; Basavarajappa et al. 2000, 2003). There also is evidence that chronic alcohol exposure down- regulates CB1 receptors (Basavarajappa et al. 1998). Clearly, further studies are needed to explore the mechanisms through which endocannabinoids par ticipate in the neural actions of alcohol. Agonists for the CB1 receptor already are in use, mainly for treating chemotherapy side effects. These agonists reduce nausea induced by chemotherapy and also stimulate appetite in both chemotherapy patients and people with AIDS (Pertwee 2005). Formulations of cannabis plant extracts containing THC and other cannabinoids also have been touted for treatment of multiple sclerosis and other neurological disorders (Wade et al. 2003). Targeting enzymes involved in endocannabinoid synthesis and degradation also is a promising avenue for future applied pharmaco logical research (Pertwee 2005). For example, inhibiting the fatty acid amide hydrolase (FAAH) enzyme that metabolizes AEA prolongs the pain-reducing function of the endocannabinoid system in certain paradigms (Hohmann et al. 2005),
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