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Communication Networks in the

Neurons, Receptors, , and

David M. Lovinger, Ph.D.

Nerve cells (i.e., ) communicate via a combination of electrical and chemical signals. Within the , 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 , 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 ) that is received by the postsynaptic neuron’s specialized called neurotransmitter receptors. The neurotransmitter molecules bind to the proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors exist—-gated channels, which permit rapid ion flow directly across the outer , and G-–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 known as and by . 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 . KEY WORDS: Alcohol and other drug effects and consequences; brain; neurons; neuronal signaling; synaptic transmission; neurotransmitter receptors; neurotrophins; steroid hormones; γ-aminobutyric acid (GABA); glutamate; ; ; ; ; endocannabinoids

he behavioral effects of alcohol linked to the environment present brain and, especially, the process of are produced through its actions during exposure. Alcohol dependence synaptic transmission. This article will Ton the central develops after several exposure/withdrawal focus on the basic processes underlying (CNS) and, in particular, the brain. cycles and involves neuroadaptive changes neuronal communication and review Synaptic transmission—the process by brought about by both the exposure the neuronal actions of several neuro­ which neurons in the CNS communi- and withdrawal processes. Neurotoxicity transmitters, , and cate with one another—is a particular produced by alcohol ingestion involves hormones to be involved in target for alcohol actions that alter a number of cellular and molecular the neural actions of alcohol. This behavior. Intoxication is thought to processes, and neurotransmitters can information, although admittedly result from changes in neuronal com- participate in—and modulate—many incomplete, will provide a foundation munication taking place while alcohol of these mechanisms. The actions of for the detailed information on alcohol is present in the brain. Tolerance to alcohol on synaptic transmission also alcohol involves cellular and molecular contribute to alcohol-seeking behavior, DAVID M. LOVINGER, PH.D., is chief adaptations that begin during alcohol excessive drinking, and alcoholism. of the Laboratory for Integrative exposure; the adaptations develop and Thus, understanding all of these behav- at the National Institute diversify with repeated episodes of ioral actions of alcohol requires some on Alcohol Abuse and Alcoholism, exposure and withdrawal and are knowledge of neuronal signaling in the Bethesda, Maryland.

196 Alcohol Research & Health Communication Networks in the Brain actions provided in subsequent articles surface membrane contains an abun­ (Kandel et al. 2000). This form of in this issue and in Part 2. dance of proteins known as ion chan­ interneuronal communication is much nels that allow small charged atoms less common in the mammalian CNS Neuron-to-Neuron to pass through from one side of the than chemical transmission and will Communication membrane to the other. Some of these not be discussed any further. Rather, channels are opened when the voltage the focus will be on chemical inter­ Neurons are the cells within the brain across the cell membrane changes. neuronal communication involving that are responsible for rapid commu­ One subtype of these “voltage-gated” the release of a neurotransmitter from nication of information. Although sim­ channels allows the neuron to produce one neuron, which alters the activity ilar to other cells in the body, neurons a rapid signal known as the “action of the receiving neuron. This chemical are specialized in ways that set them potential,” which is the fastest form communication usually occurs at a apart from other cells and endow them of intracellular electrical signal conduc­ specialized structure called a , with the properties that allow them to tion in (see figure 1). where parts of the two cells are carry out their unique role in the ner­ Individual neurons usually are brought within 20 to 50 nanometers vous system. The neuron’s shape is one completely separated from one anoth­ of one another (see figure 2). The such unique feature. In addition to the er by their outer cell membranes and neuron that releases the chemical is cell body, or , which is much like thus cannot directly share electrical or called the presynaptic neuron. A spe­ that of other cells, neurons have special­ chemical signals. The exception to cialized structure at the tip of the ized thin branches know as this situation is the so-called electrical of the presynaptic neuron, termed the and . Neurons receive , in which ion-conducting pores , contains small packets input from other neurons through den­ made from proteins called connexins known as vesicles, which are filled drites and communicate information connect the intracellular compart­ with neurotransmitter molecules. When to other cells through axons. Neurons ments of adjacent neurons, allowing an reaches the axon also are “excitable” cells. The neuronal direct ion flow from cell to cell terminal and stimulates a rise in the concentration of , 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.

Neurotransmitter Receptors Neurotransmitter receptors are divided into two major classes: ligand-gated (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 Figure 1 Schematic drawing of a neuron showing dendrites, where neurons receive 3A). One part of the protein is special­ chemical input from other neurons; soma (cell body); and axon terminal, ized to bind the neurotransmitter where neurons communicate information to other cells. Voltage-gated sodi­ molecule. This “” is on the um channels in the membrane of the soma, axon, and axon terminal allow extracellular side of the protein. The positively charged sodium to enter the neuron and produce rapid (in part of the protein that is buried within milliseconds) conduction of the excitatory action potential to the terminal. the cell surface membrane forms an ion This signal stimulates neurotransmitter release at the axon terminal. pore, which is basically a fluid-filled hole in the membrane through which the

Vol. 31, No. 3, 2008 197 charged ions can pass (ions cannot pass GTP and GDP. When a neurotransmit­ G-protein–activated inwardly rectify­ through or other solid membrane ter binds to the receptor, the exchange of ing potassium [GIRK] channel). constituents). The between neuro­ GTP for GDP at the intracellular side Activation of this Gβ/γ-GIRK path­ transmitter binding and opening of the of the protein is accelerated, and this way will produce neuronal inhibition, ion pore is on the order of microseconds causes the G-protein to separate into although on a slower timescale than to milliseconds. Thus, at synapses using two parts (the α- and β/γ-subunits), that produced by inhibitory LGICs. ligand-gated channels, the time between which dissociate from the receptor In general, the responses produced by action potential depolarization1 of the protein. The liberated α- and β/γ­ GPCRs are slower in onset and longer axon terminal and the beginning of the subunits then are free to interact with lasting than those produced by LGICs current flowing through the postsynaptic different proteins inside the cell. Both because several molecular steps are LGIC is a matter of 1 to 2 milliseconds. types of subunits can act on “effector” required to get from the receptor pro­ This type of synaptic transmission pro­ proteins to alter cellular biochemistry, tein to the final effector (in contrast duces a rapid and strong influence on , and expression. For to the direct intraprotein signaling postsynaptic neuron function. example, the αS-subunit binds to and within LGICs). The effects of GPCRs Synaptic responses mediated by activates an protein called adenylyl on neuronal physiology also often are LGICs are designated as excitatory cyclase. The function of adenylyl cyclase more subtle than those produced by or inhibitory, depending on whether is to convert the molecule adenosine LGICs because they usually do not their net effect is to make it more or triphosphate (ATP) to cyclic adeno­ directly activate ion current in neu­ less likely that the postsynaptic neuron sine monophosphate (cAMP), and rons. Thus, synaptic transmission will fire an action potential (Kandel et the resultant cAMP can act on mediated by GPCRs often is termed al. 2000). In general, strong excitatory that alter the function of cellular pro­ neuromodulatory. synaptic transmission is mediated by teins through a mechanism called LGICs containing an ion pore that phosphorylation. In another example, allows positively charged ions (i.e., free β/γ-subunits can directly bind to Neurotransmitter Removal cations) to flow across the membrane. and activate a type of ion channel Neurotransmitters are rapidly removed Activation of such a receptor will that selectively allows potassium flux from the synapse after their release. This mainly result in an influx of sodium across the neuronal membrane (the minimizes the time that they interact into the cell, causing the to depolarize, bringing it nearer to the action potential thresh­ old. Fast inhibitory synaptic transmis­ sion usually is mediated by receptors with channels permeable to negatively charged ions (i.e., anions, usually chloride). When activated, these receptors hyperpolarize the membrane potential and/or fix the membrane potential at voltages below the action potential threshold. The types of neuro­ transmitters and receptors that subserve these fast excitatory and inhibitory synaptic roles are reviewed below. GPCRs (shown in figure 3A) are proteins that are specialized for bind­ ing the neurotransmitter molecule and subsequently producing intracel­ lular biochemical reactions that can influence a variety of cellular func­ Figure 2 Schematic drawing of a synapse between two neurons. Synaptic vesicles tions (Brunton et al. 2005; Kandel et contain a neurotransmitter (NT) and release it when their membranes al. 2000). The GPCR proteins bind fuse with the outer cell membrane. Neurotransmitter molecules cross the directly to small intracellular proteins, synaptic cleft and bind to receptors known as ligand-gated ion channels known as G-proteins, as their name (LGICs) and G-protein–coupled receptors (GPCRs) on the postsynaptic implies. The G-proteins are so named neuron. GPCRs on the presynaptic neuron’s axon terminal alter the func­ because they can bind the nucleotides tion of voltage-gated ion channels and modulate neurotransmitter release. Neurotransmitter transporters remove neurotransmitter molecules from the synaptic cleft so that they can be repackaged into vesicles. 1 For a definition of this and other technical terms, see the Glossary, pp. 279–283.

198 Alcohol Research & Health Communication Networks in the Brain with receptors so that short, discrete relatively fast time scale, certain small occur at the level of posttranslational synaptic signals are produced. At most chains of amino acids (i.e., peptides) processing. All of these factors synapses in the brain, specific proteins can be secreted by neurons that act as combine to produce a rich variety of known as neurotransmitter transporters so-called growth factors or neurotrophins. neurotrophins in the brain. mediate this removal (Brunton et al. The most widely known neurotrophins Neurotrophins are thought to 2005; Kandel et al. 2000). The transporter are (NGF) and be secreted from different neuronal proteins reside in the cell surface mem­ brain-derived neurotrophic factor structures, including both axon ter­ brane and actively move the neuro­ (BDNF) and related members of this minals and dendrites (see Altar and transmitter molecule from the outside “cysteine knot” dimeric DiStefano 1998 for review). Thus, to the inside of the cell (see figure 2). family that also includes neurotrophin they participate in both “anterograde” In many cases, this uptake occurs at the (NT)-3 and NT-4 (Barde 1994; Barde signaling from the axon terminal presynaptic terminal itself, where the et al. 1982; Levi-Montalcini and of the presynaptic neuron to the post­ neurotransmitter is directly reloaded Cohen 1960; Reichardt 2006). Other synaptic elements of a downstream into vesicles. However, in some cases neurotrophins, such as glial-derived neuron, as well as “retrograde” signal­ nonneuronal support cells (i.e., glial neurotrophic factor (GDNF), which ing, in which release from dendritic cells) also participate in neurotransmitter acts through the transforming growth elements of the postsynaptic neuron uptake. Removal of synaptic neuro­ factor (TGF)β‚ signaling pathway, are activates receptors on the presynaptic transmitters also can occur via enzymes peptides of a different structural class axon terminals. that degrade the neurotransmitter to (Unsicker 1996). The neurotrophins Receptors for neurotrophins couple constituent molecules that do not them­ are peptides, so their primary amino to a wide variety of intracellular sig­ activate receptors. acid sequence is genetically coded and naling cascades. The main receptors is subject to alterations in the synthesis for the cysteine knot family of neu­ of genetic information (i.e., ) Neurotrophins rotrophins are the Trk receptors that can produce different variants of (Kaplan et al. 1991; reviewed by Chao In addition to neurotransmitters that the mature peptide. These peptides also and Hempstead 1995) (see figure 3B). alter neuronal physiology, intracellular are generated from larger propeptides, Each individual neurotrophin binds signaling, and gene expression on a and, thus, variations in sequence can 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. 1993a,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 -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 . Figure 3A Schematic drawing of a ligand-gated ion channel (left) showing the con­ There is evidence that neurotrophin­ fluence of individual subunit proteins that define a pore where the ions bound Trk receptors are internalized flow across the cell membrane. A neurotransmitter binds to part of the and translocated to the nucleus, where protein located outside of the cell. Schematic drawing of a G-protein– they can participate in signaling that coupled receptor (right). Neurotransmitter binds either to sites outside regulates gene expression (reviewed by the cell or in a “pocket” formed by protein domains that span the mem­ Ginty and Segal 2002). Internalization brane. The G-protein that consists of three separate protein subunits of neurotrophin-bound receptors also (α, β, and γ, light blue) is associated with part of the protein inside the cell. is believed to be a major mechanism by which the neurotrophins are

Vol. 31, No. 3, 2008 199 removed from the 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 . 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 of the adrenal 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 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 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 Figure 3B Neurotrophin binding to TRK receptors attracts a variety of intracellular . The second type of steroid hor­ signaling proteins to the intracellular portion of the TrK protein. Activation of mone signaling involves actions on cell these signaling proteins in turn activates proteins that surface receptors. For example, deriva­ act on the nucleus to alter gene expression, as well as other intracellular tives of the sex steroid signaling pathways that promote the growth and differentiation of neurons. interact with the A-type receptors for Activation of neurotrophin–TrK–intracellular signaling pathways also pro­ the neurotransmitter γ-aminobutyric motes long-lasting plasticity of synaptic transmission. acid (GABA) (i.e., GABAA receptors) to BDNF = brain-derived neurotrophic factor. enhance receptor function allosterically

200 Alcohol Research & Health Communication Networks in the Brain by producing a conformation, or shape, effect of the neurotransmitter. Other transmitter or cannot overcome change in the receptor (Mitchell et al. small molecules, called competitive antagonist actions, and there is no 2008) (see figure 4). The so-called neuro­ antagonists, can bind to the site normally “competition” for the binding site. steroids that act within the brain can occupied by the neurotransmitter and Other naturally occurring and synthetic be generated locally within CNS prevent receptor activation. These molecules enhance receptor function and thus can have paracrine2 as well as competitive antagonist compounds do by binding to a region of the receptor endocrine actions. not activate the receptor but prevent distinct from the neurotransmitter/ the neurotransmitter from binding. agonist binding site and improving the Antagonists also may change the con­ efficiency of receptor activation. These Receptor formation of the receptor such that compounds generally are known as activation is more difficult. The term Before discussing specific neurotrans­ allosteric enhancers of receptor function. competitive stems from the fact that the Receptor , antagonists, mitter molecules and their cognate neurotransmitter (or agonist) and the receptors, it is important to review ter­ and allosteric modulators are used antagonist “compete” for binding to as pharmaceutical treatments for a minology related to receptor action (see the same part of the receptor, and also Brunton et al. 2005). The term variety of neurological and psychiatric increasing the concentration of one disorders (Brunton et al. 2005). For agonist refers to a molecule that binds molecule can overcome the effects of to and activates the receptor. Of course, example, a called the other. Other types of antagonists can control certain types the neurotransmitter itself is the natu­ bind to parts of the receptor protein ral receptor agonist. However, chemists of movement through its that are distinct from the agonist bind­ agonist action at the B-type receptor have been able to purify or synthesize ing site. For example, noncompetitive other small molecules that mimic the for the neurotransmitter GABA antagonists react with the receptor and (Bowery 2006). Many of the major prevent activation in an allosteric manner 2 antipsychotic drugs used in schizophre­ Paracrine means that the substances are released from even when the neurotransmitter molecule ® a given cell and produce their actions only on nearby nia treatment, such as Haldol , are cells (as opposed to being carried through the blood­ binds to the protein. In this case, competitive antagonists at the type 2 stream to distant targets). increasing the concentration of neuro- receptor for the neurotransmitter dopamine (Kapur et al. 2006). In addition, Valium® (also known as diazepam), Ambien® (also known Glucocorticoid extracellular as ), and related antianxiety and aid drugs are allosteric cytoplasm enhancers of the GABAA receptor (Sanger 2004), which is the other major receptor for this neurotrans­ mitter. Indeed, neurotransmitter receptors are the predominant targets for therapies aimed at treatment of brain disorders.

The Neurotransmitter Molecules Many small organic molecules serve as neurotransmitters in the brain. For example, amino acids such as gluta­ mate and , which are well known as constituents of proteins, also act as neurotransmitters (Kandel et al. 2000). , a molecule that has a prominent role in inflammation and Figure 3C Steroid hormones such as glucocorticoids bind to proteins within the infection in the body, also is a neuro­ cytoplasm of the cell. Upon steroid binding the protein moves to the transmitter (Haas and Panula 2003). A nucleus where it can affect protein synthesis at the transcription step. variety of peptides also have been found to act as neurotransmitters (Kandel et GR = Glucocorticoid receptor; GRE = glucocorticoid response element, a stretch of DNA that binds the GR and activates gene transcription. al. 2000). A review of all neurotrans­ mitters is beyond the scope of this article.

Vol. 31, No. 3, 2008 201 Rather, the sections that follow focus often produce a continuous inhibitory rise to different on those neurotransmitters whose tone that helps to set the resting poten­ effects on different receptors and actions are most strongly implicated in tial of certain neurons (Stell et al. 2003). different brain neurons, providing , tolerance, depen­ The GABAA receptor channel multiple possibilities for pharmaceu­ dence, and addiction. This discussion contains numerous sites for allosteric tical development. is organized according to the neuro­ modification. Perhaps the best known Drugs that target the GABAA transmitters’ proposed roles within the among these is the “benzodiazepine” receptor have been in widespread use chronology of alcohol actions. Those binding site (Sanger 2004; Sigel 2002). for treatment of disorders ranging neurotransmitters thought to be most This site resides on the extracellularly from anxiety to (Mohler heavily involved in intoxication are dis­ exposed part of the protein at a site 2006; Sigel 2002). The majority of cussed first, followed by those involved distinct from the agonist binding region. general anesthetics currently in use in chronic alcohol effects. The final Many compounds, such as Valium, produce their actions predominantly section addresses those neurotransmit­ that bind to this site have potent through enhancing GABAA receptor ters that do not appear to be direct tar­ allosteric enhancing effects on the function (Hemmings et al. 2005). gets for the neural actions of alcohol receptor. Other compounds can have Almost all of these therapeutic drugs but which may be involved in alcohol an antagonist action at this site and either directly activate the GABAA abuse and addiction and are potential will prevent allosteric enhancement receptor or activate the benzodiazepine pharmacotherapeutic targets. by without altering site to produce allosteric enhancement the response of the receptor to GABA of the receptor, as mentioned above. (Mohler 1983). The diversity of GABA also can act through a GABA GABAA receptor subtypes has given GPCR, the aforementioned GABAB 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 glycine produces a similar action in the 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 Figure 4 Schematic drawing of the γ-aminobutyric acid receptor (GABAA) ligand- sequence, and there are 20 subunits in gated ion channel complex. The receptor molecule is formed by the con­ all in the mammalian brain (Sieghart fluence of five subunit proteins. In this case, two of the subunits are of the and Sperk 2002). Thus, a variety of α type, two β, and one γ, although many combinations of the 20 known different types of GABAA receptors subunits are possible. Globular regions of the protein stick out from the are made in different brain neurons. membrane on the extracellular side, and the interfaces between these regions are targets for GABA and for the benzodiazepines and related drugs. GABAA receptors are present both at the synapse and on postsynaptic mem­ The protein domains that span the outer cell membrane are depicted as branes distant from synapses. These cylinders. These regions are thought to be targets for general anesthetics (e.g., propofol) , and alcohol. A hole in the middle of the five latter “extrasynaptic” GABAA recep­ subunits is the ion conduction pathway, or channel pore. tors are sensitive to very low levels of extracellular GABA, and thus they

202 Alcohol Research & Health Communication Networks in the Brain receptor. This receptor acts to inhibit GABAergic synaptic transmission It is not surprising, therefore, that glu­ neuronal activity in two ways (Bowery appears to contribute to a number of tamate has key roles in a wide variety et al. 1990). First, activation of GABAB aspects of acute alcohol intoxication, of brain functions. The fast synaptic receptors to a direct G-protein– including motor incoordination, excitation produced by glutamate mediated activation of the GIRK- anxiety-reducing effects, sedation, involves the activation of three major type . This channel and the internal cues that signal subtypes of LGICs, termed the AMPA can hyperpolarize neurons and coun­ intoxication (Lovinger and Homanics (α-amino-3-hydroxy-5-methyl­ teract synaptic excitation. This type 2007; Siggins et al. 2005; Vengeliene 4-isoxazolepropionic acid)3-, kainate-, of GABAB-mediated modulation is et al. 2008). and NMDA (N-methyl-D-aspartic found in many postsynaptic neuronal The brain’s GABAergic system acid)4-type receptors based on the syn­ elements throughout the brain. GABAB also shows marked changes following thetic agonists that best activate each receptors also are found on presynap­ chronic alcohol exposure. Some of receptor (Kandel et al. 2000). At most tic terminals of neurons in many brain these changes are likely to be adapta­ excitatory synapses, glutamate released regions (Bowery et al. 1990). When tions to the acute alcohol actions that from presynaptic vesicles crosses the activated, these receptors inhibit neu­ potentiate GABAergic transmission. synapse and binds to AMPA-type rotransmitter release via mechanisms The best-characterized changes involve glutamate receptors. The binding of that involve inhibition of voltage- alterations in the subunits that make glutamate to AMPA receptors directly gated calcium channels whose func­ up the GABAA receptor (Kumar et al. activates the ion pore intrinsic to this tion is necessary for proper release. 2004), which alter the and protein and produces a rapid depolar­ Presynaptic GABAB receptors are timing of inhibitory synaptic trans­ ization of the postsynaptic neuron found on the axon terminals of both mission. Research also shows that that increases the likelihood that this GABAergic and glutamatergic neurons, chronic alcohol exposure can produce neuron will fire an action potential. and thus the net effect of receptor decreases and increases in GABA Thus, timely and accurate communica­ activation can be either disinhibitory release in different brain regions tion within brain circuits depends to a or inhibitory depending on which (reviewed in Weiner and Valenzuela large extent on proper AMPA receptor receptors are activated. 2006). The predominant effect of activation. GABAergic transmission is a these chronic alcohol effects is to The function of NMDA-type sensitive target for both the acute make the brain hyperexcitable during glutamate receptors is more compli­ and chronic effects of alcohol (reviewed withdrawal from chronic alcohol cated. When glutamate binds to the in Lovinger and Homanics 2007; exposure. This can produce effects NMDA receptor, activation of the Siggins et al. 2005). Acute alcohol such as heightened anxiety and even intrinsic ion pore is favored, as is the can produce allosteric enhancement overt during withdrawal case for AMPA receptors and other of the function of GABAA receptors, (Krystal et al. 2006; Kumar et al. LGICs. However, at membrane although this effect is not observed 2004). Benzodiazepines commonly potentials near the resting potential at all GABAA receptors, and there is are used to treat alcohol withdrawal (e.g., –60 to –70 mV), the ion pore some debate as to which receptor because of their effectiveness in con­ of the NMDA receptor is occluded subtypes are most sensitive to alcohol trolling these aspects of hyperex­ by magnesium ions (Kandel et al. (reviewed in Lovinger and Homanics citability (Krystal et al. 2006). Drugs 2000). Magnesium is present at mil­ 2007). Researchers have observed that target GABAergic transmission limolar concentrations in the extra­ effects at concentrations as low as also have been touted as potential cellular solution and binds to a site the low millimolar range (the levels pharmacotherapeutic treatments for within the NMDA receptor ion pore reached with ingestion of a single alcohol abuse and alcoholism (Koob that becomes accessible very shortly drink), suggesting that even some 2004; Krystal et al. 2006), but, as yet, after the ion pore opens. This magne­ aspects of low-dose intoxication might no drugs that explicitly and specifical­ sium pore blocking action is stronger involve enhanced GABAA receptor ly target GABAergic mechanisms are in at more negative membrane potentials function. Acute ethanol also enhances clinical use for this purpose. and is thus reduced as the membrane the release of GABA at a number of potential becomes more depolarized. In synapses in the brain (Siggins et al. practice, at a glutamatergic synapse that 2005). The mechanisms of this presy­ Glutamate contains both AMPA and NMDA recep­ naptic enhancement are just beginning tors, the initial action of glutamate to be explored. One interesting set of Glutamate is the major excitatory neuro­ studies indicates that activation of transmitter in the mammalian brain. 3 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropi­ onic acid) is a specific agonist for the AMPA receptor. presynaptic GABAB receptors pre­ Fast transmission mediated by this 4 vents alcohol potentiation of GABA neurotransmitter accounts for synaptic NMDA (N-methyl-D-) is a specific agonist release and can bring about a “tolerance” excitation of most, if not all, brain at the NMDA receptor and therefore mimics the action of glutamate on that receptor. In contrast to glutamate, to the alcohol action (Ariwodola and neurons (Kandel et al. 2000), and thus NMDA binds to and regulates the above receptor only but Weiner 2004). Potentiation of glutamate is found throughout the brain. not other glutamate receptors.

Vol. 31, No. 3, 2008 203 will be to activate AMPA receptors. including the generation of second drinking and/or in alcoholics This will depolarize the cell because messengers5 from cell membrane lipids. (Krystal et al. 2003). of the influx of cations through the The group II and III mGluRs couple AMPA receptor ion pore. If the depo­ to Gi/o-type G-proteins. Members of larization is sufficiently strong and these latter two mGluR subgroups Dopamine glutamate still is present, the NMDA reside predominantly on presynaptic The neurotransmitter dopamine has receptor pore will become unblocked, axon terminals, where they act to inhib­ been widely implicated in a variety of and ion flux through this receptor- it neurotransmitter release (Coutinho neuronal functions, including brain channel also can participate in acti­ and Knopfel 2002). mechanisms of reward, evaluation of vating the postsynaptic neuron. Therapeutic uses for glutamate environmental stimuli, general behav­ The AMPA and NMDA receptors receptor–targeted drugs are a matter of ioral activity levels, and disorders such have central roles in producing long- intensive research at present. as Parkinson’s disease and lasting changes in synaptic function is an antagonist of NMDA receptor (Brunton et al. 2005; Kandel et al. that are thought to represent molecular function that has been used as a gen­ 2000). Considering that dopamine is mechanisms of and eral anesthetic in animals and, in made by very few cells in the brain and (Kandel et al. 2000). One such change, some cases, humans (Sinner and Graf acts mainly within a subset of brain named long-term potentiation, is a 2008). Recent studies suggest that regions (see figure 5A), this neurotrans­ long-lasting increase in the strength of group II mGluR agonists may be mitter seems to have a disproportion­ signaling at glutamatergic synapses useful in the treatment of ately large impact on brain function. that mediate fast excitatory synaptic (Patil et al. 2007). Dopamine acts exclusively via transmission. When these synapses Acute alcohol exposure generally activation of GPCRs and thus is a are activated repeatedly and persever­ inhibits glutamatergic synaptic trans­ pure neuromodulator. There are five atively (e.g., by high-frequency synap­ mission (Siggins et al. 2005; Woodward identified dopamine receptors that tic input) the repeated activation of 2000). At most synapses in the CNS, fall into two subclasses: those that AMPA receptors will depolarize the NMDA receptor function is the aspect activate G /G -type G-proteins (D1 postsynaptic neuron sufficiently to of glutamatergic synaptic transmis­ s olf and D5) and those that activate Gi/o­ allow for ion current to flow through sion that is most sensitive to alcohol type G-proteins (D2-4) (Lachowicz NMDA receptors. The ion pore of inhibition (Woodward 2000). Alcohol and Sibley 1997). In general, the two the NMDA receptor is especially also inhibits synaptic plasticity that classes of receptors produce separate, permeable to calcium ions that can requires NMDA receptor activation, and often opposing, effects on neu­ activate a variety of intracellular sig­ and this effect may contribute to the ronal physiology. For example, D1­ naling cascades, including protein memory-impairing effects of alcohol. like receptors enhance sodium chan­ kinases. Strong NMDA receptor acti­ Alcohol interactions with NMDA nels in neurons from the brain region vation sets into motion a sequence receptors also may contribute to its known as the , whereas D2 of molecular events that result in the intoxicating effects (Krystal et al. 2003). receptors inhibit these same channels insertion of additional AMPA receptors Chronic alcohol exposure results (Surmeier and Kitai 1993). However, at the synapses, thus strengthening in an increase in NMDA receptor there are situations in which the two synaptic transmission (Kandel et al. number and function that likely is subtypes appear 2000). There now is abundant evidence a compensatory change induced by to work together or even produce that this NMDA receptor–dependent the inhibitory effect of acute alcohol synergistic actions (Lee et al. 2004). long-term potentiation is involved in a (Fadda and Rossetti 1998). This Within the striatum, D1 and D2 variety of types of learning in the brain increased NMDA receptor function receptors mainly are segregated onto (Robbins and Murphy 2006). is thought to contribute to withdrawal two different types of neurons Glutamate also can activate hyperexcitability and perhaps also to (Gerfen 1992). The medium spiny GPCRs known as metabotropic glu­ alcohol-induced neuronal damage. neurons provide the only source of tamate receptors (mGluRs) (Kandel A hyperglutamatergic state also may output from this brain region. Half et al. 2000). Eight mGluRs are known result from chronic alcohol exposure, of these neurons connect to a brain to exist and can be separated into three and there is growing evidence that region called the groups termed I, II, and III (Coutinho decreasing this excessive glutamater­ , forming the so-called and Knopfel 2002). The group I gic transmission might be helpful in “direct” pathway that tends to activate mGluRs couple through the Gq-type reducing relapse to alcohol drinking the cortex. The other half connect to G-protein subtype to activate enzymes (Vengeliene et al. 2008). Indeed, a a brain area called the called phospholipases. These receptors few drugs that target glutamatergic mainly are on postsynaptic structures, transmission, either directly or indi­ 5 A second system is a method of cellular where they serve to activate intracellu­ rectly, have been used for treatment signaling, whereby a diffusible signaling molecule is rapidly generated/released which can then go on to lar signaling that modifies ion channel of alcoholics or currently are being activate effector proteins within the cell to exert a cellular function and biochemical processes tested for their efficacy in reducing response.

204 Alcohol Research & Health Communication Networks in the Brain 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 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 D2 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 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

A B Human

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 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.

Vol. 31, No. 3, 2008 205 neuropsychiatric disorders. The major­ The acute alcohol-induced increase in Activation of A1 adenosine ity of antipsychotic drugs have potent firing of dopaminergic neurons appears receptors in turn activates Gi/o class actions at the D2-like dopamine to drive increases in extracellular G-proteins. In general, these G-proteins receptors, although they certainly have dopamine levels in the brain regions activate GIRK potassium channels, effects on other targets that could to which these neurons project inhibit voltage-gated calcium chan­ contribute to their therapeutic efficacy (reviewed in Gonzales et al. 2004). nels, inhibit adenylyl cyclase, or activate (Kapur et al. 2006). Drugs that block Imaging of dopamine receptors in phosphorylation of certain intracellu­ the , such as the also suggests that lar protein kinase enzymes (Fredholm (Ritalin®) are used in acute alcohol exposure alters dopamine et al. 2005). Adenosine A2a receptors the treatment of deficit levels in key brain structures (reviewed activate Gs or Golf–type G-proteins hyperactivity disorder (ADHD) in Wong et al. 2003). These effects (Fredholm et al. 2007). These G- (Arnsten 2006) (note the potential may contribute to the process by proteins stimulate adenylyl cyclase abuse liability of this class of drugs, as which animals encode the reinforcing to enhance production of the second discussed below) (Faraone and Wilens value of alcohol. messenger cyclic AMP (Fredholm et 2007). Antagonists for D2 dopamine As animals learn to consume al. 2007). receptors also are used clinically to alcohol in the laboratory, increases in After producing its actions on reduce vomiting in circumstances brain dopamine levels become associ­ synaptic adenosine receptors, the such as (Reddymasu neurotransmitter is transported back ated with stimuli that predict access et al. 2007). into cells via a cell membrane neuro­ to alcohol (Gonzales et al. 2004). , , and other transmitter transporter protein known “” drugs block or reverse the Thus, dopamine also plays a role in as the adenosine transporter (Fredholm action of the dopamine transporter learning about environmental contexts et al. 2005). Adenosine also can be (Amara and Sonders 1998). The net that encourage drinking. Chronic metabolized by enzyme proteins effect of these drugs is to increase levels alcohol consumption can to a known as adenosine deaminase and of dopamine within the synapse. hypodopaminergic state that motivates adenosine kinase (Fredholm et al. Although these drugs act on other the drinker to seek alcohol in order 2005). The transporter and enzymes molecular targets, the evidence is fairly to restore the desired levels of the regulate the duration of adenosine convincing that it is the effect on neurotransmitter (Volkow et al. 2007). signals within the synaptic cleft. dopaminergic transmission that accounts However, despite these findings, Inhibition of either process can prolong for the majority of the intoxicating pharmacotherapies aimed at the the time that the neurotransmitter and addictive actions of these drugs. dopaminergic system have not shown is present in the synapse and, conse­ Most other drugs of abuse also influ­ particular efficacy in reducing alcohol quently, the duration of activation of ence the brain dopaminergic system. drinking either in animal models or in the adenosine receptors. stimulates the activity of humans with alcohol abuse disorders. The behavioral effects of modifying the dopaminergic neurons themselves Perhaps the development of drugs with brain adenosinergic communication (Pidoplichko et al. 1997) and also greater specificity for certain subtypes are very familiar to many of us. can activate dopamine release from of dopamine receptors will prove acts as an antago­ axon terminals (Grady et al. 2007). more efficacious in this context. nist (Dunwiddie and Masino 2001). and other drugs The major behavioral effects of caf­ depress the activity of GABAergic feine, including enhanced activity and and, through this effect, Adenosine focused attention, appear to involve indirectly increase the activity of inhibition of the function of both dopaminergic neurons (Johnson and Adenosine is a nucleoside (a A1- and A2a-type adenosine receptors, North 1992). Alcohol also increases compound with a -containing although locomotor stimulation by the activity of these neurons, likely base linked to a sugar molecule) that is caffeine is predominantly because of via both direct actions on the neurons produced during nucleic acid . A2a antagonism. and indirect actions through other This compound also participates in a Acute alcohol exposure increases neurons (Brodie et al. 1999; Ericson number of types of cell–cell communi­ adenosine signaling in cell lines of et al. 2008; Gessa et al. 1985; Okamoto cation, including synaptic transmission neural origin (Nagy et al. 1990). This et al. 2006). in all regions of the nervous system. effect appears to involve inhibition of Dopaminergic transmission has Adenosine primarily is a neuromodula­ a nucleoside transporter that normally been implicated in the actions of tory transmitter and produces its actions produces rapid uptake of adenosine almost all drugs of abuse, and trans­ via the activation of two main types of into cells. This inhibitory action mission mediated by this neurotrans­ GPCRS, the A1 and A2a adenosine increases extracellular adenosine levels mitter is altered by alcohol exposure receptors (Fredholm et al. 2005). Other and prolongs the duration of adeno­ in both the acute and chronic phases adenosine receptors exist but are present sine signaling to the cell. The role of (reviewed in Vengeliene et al. 2008). only in small quantities within the CNS. these changes in adenosinergic trans-

206 Alcohol Research & Health Communication Networks in the Brain mission in acute intoxication is not of these GPCRs are found on presy­ derivatives, such as 3,4-methylene­ clear, although removing the alcohol- naptic and postsynaptic neuronal dioxymethamphetamine (MDMA, sensitive nucleoside transporter in structures in different brain regions. also known as ecstasy), alter serotonin mice alters intoxication and alcohol By activating these receptors, molecules and increase intake (Choi et al. 2004). Chronic can enhance or inhibit neurotrans­ synaptic serotonin levels (McKenna alcohol exposure causes a compensatory mitter release at certain synapses and and Peroutka 1990). This may account downregulation of A2a adenosine can produce slow hyperpolarizing for their sensory-enhancing effects. receptors and decreases in the adenylyl or depolarizing synaptic responses Acute alcohol has mixed effects cyclase signaling by these receptors at others. Intracellular signaling via on transmission (reviewed (Diamond et al. 1991). These receptors serotonin-activated GPCRs also can in Lovinger 1997). A slowing of sero­ predominantly are found in brain influence the function of intracellular tonergic is observed (Daws regions involved in neural processes enzymes as well as alter gene expression. et al. 2006), but this does not appear important for reward, habit formation, Serotonin also can activate a single to be because of impairment of the and addiction (Jarvis and Williams type of LGIC-type neurotransmitter serotonin transporter targeted by 1989). Thus, alterations in adenosine receptor, the so-called 5-HT3 receptor SSRIs. Alcohol also potentiates the signaling in these brain regions could (Thompson and Lummis 2007). This function of the 5-HT3 receptor contribute to alcohol addiction (Choi receptor contains a channel that is (Lovinger 1999). permeable to positively charged cations et al. 2004; Naassila et al. 2002). Chronic alcohol exposure has and thus produces fast activation of been demonstrated to interact with neurons when bound to serotonin. Serotonin One interesting facet of the action various aspects of serotonergic trans­ of this receptor is that often it resides mission that could alter anxiety and The neurotransmitter serotonin (also on axon terminals that contain and affect (reviewed in Lovinger 1997). known as 5-hydroxytryptamine or 5­ release GABA. Thus, activation of these Based on the well-known role of HT) is a close molecular relative of serotonin in neural mechanisms presynaptic 5-HT3 receptors leads dopamine that belongs to the family of to a rapid release of GABA that will underlying mood and stress responses, neurotransmitters known as monoamines then inhibit downstream neurons. pharmacotherapies aimed at the (Kandel et al. 2000). Like dopamine, In addition to the use of SSRIs serotonergic system have long been serotonin is made by small discrete for neuropsychiatric therapy, as men­ touted as potential treatments for clusters of neurons located at the base tioned above, a variety of other thera­ alcoholism (reviewed in Ait-Daoud et of the brain (see figure 5B). These peutic uses exist for serotonergic drugs. al. 2006). Treatments with SSRIs are serotonergic neurons connect to other The SSRIs produce their actions via efficacious in reducing alcohol intake neurons located throughout the CNS, inhibition of the serotonin transporter in laboratory animals (LeMarquand including neurons in the protein, as their name implies. et al. 1994; Pettinati et al. 1996) but and other structures. Thus, is an anxiety-reducing drug have had mixed success in humans serotonin has the capacity to influence that acts on the 5-HT-1A receptor (Ait-Daoud et al. 2006; Naranjo and a variety of brain functions including (Barrett and Vanover 1993), and use Kadlec 1991). It is possible that these sensations related to environmental of this drug has been suggested for drugs might work best in patients stimuli, pain , learning and other disorders. The 5-HT3 antago­ with comorbid depression. The 5­ memory, and sleep and mood (Kandel nists routinely are used to reduce HT3 antagonist reduces et al. 2000). The role of serotonin in nausea and vomiting resulting from relapse in alcoholics, particularly in mood control has received considerable chemotherapy and can be used for those with early onset (reviewed in attention in both the laboratory and similar purposes following surgical Ait-Daoud et al. 2006). the clinic, as selective serotonin reup­ anesthesia, and these drugs also have take inhibitors (SSRIs) such as Prozac® been used for treatment of irritable are the most widely prescribed drugs for bowel syndrome (Thompson and Opioids and Other Peptides depression and other mood disorders Lummis 2007). (Brunton et al. 2005; Kandel et al. 2000). The brain serotonergic system Peptides have long been known to The majority of serotonin actions also is the target of psychoactive drugs, function as hormones within the body in the brain occur via activation of including many that are illegal. The and to participate in synaptic commu­ GPCRs. The human brain has 15 largest class of hallucinogenic drugs, nication in the brain (Brunton et al. serotonin-activated GPCRs that activate including LSD, , and psilo­ 2005; Kandel et al. 2000). All of the a wide variety of G-protein subtypes cybin, are all partial agonists of the known peptide actions in the brain are (Kitson 2007). Thus, serotonin can 5-HT2 receptor subtypes, and the neuromodulatory, and thus these agents produce neuromodulatory effects that 5-HT2A receptor is implicated in the act through GPCRs. Many peptides tend to either increase or decrease effects of these drugs (Fantegrossi et act as neurotransmitters (i.e., the so-called neuronal output. Different subtypes al. 2008). Several amphetamine ); this section will focus

Vol. 31, No. 3, 2008 207 on a few neuropeptides that have been neurons have the capacity to release treatment of alcohol use disorders implicated in alcohol actions on the brain. both small molecule and pep­ (reviewed in O’Brien 2005; O’Malley Most of the neurotransmitter tide neurotransmitters (Kandel et al. and Froehlich 2003). Use of the gen­ molecules discussed above are synthe­ 2000). Opiate receptors are found eral opiate nal­ sized within the axon terminal itself on both presynaptic and postsynaptic trexone is approved for the treatment and are then delivered into the vesi­ structures (Williams et al. 2001). The of alcoholics. This compound also cles waiting near the presynaptic termination of transmission mediated reduces alcohol drinking in rodents, release sites. Peptide neurotransmitters, by opioid peptides involves peptidases, apparently via blockade of the µ-type however, normally are synthesized in which are specific enzymes that catalyze opiate receptor (Altshuler et al. 1980; the neuronal cell body, some distance the degradation of the peptide into Gonzales and Weiss 1998; Krishnan- from the site of release (Kandel et al. its constituent amino acids (Schwartz et al. 1998). The mechanism 2000). The neuropeptides then are et al. 1981). These amino acids are then of action may involve a reduction packaged into vesicles and transported taken back into cells via amino acid of endogenous actions inside the vesicle to the axon terminal. transporters, where they can be used for that normally promote increases in Thus, it is somewhat easier to deplete future peptide or protein synthesis. dopamine release (Gonzales and the store of transmitters Opiate receptors have been targeted Weiss 1998). in a given axon terminal, and it can for a number of therapeutic uses. Many other neuropeptides origi­ only be refilled after transport from Morphine, , fentanyl, and other nally found to act as hormones also the cell body. powerful opiate receptor agonists have have been found to act as neurotrans­ The opioid peptides are some of long been used for pain reduction mitters. Corticotrophin-releasing hor­ the most widely known neuropeptides. (Brunton et al. 2005). The opiate mone (CRH) was originally known These include β-endorphin (which receptor methoadone is for its role in the pituitary , where consists of 31 amino acids), a well-known and effective treatment it stimulates a cascade of molecular (13 amino acids), and the for addiction to opiate drugs (Brunton processes that ultimately leads to the (5-amino-acid peptides that end in et al. 2005), basically substituting for release of the cortisone-like steroid either methionine [met-] morphine or heroin to prevent with­ hormones (e.g., corticosteroids) or leucine [leu-enkephalin]) (Kandel drawal symptoms without having the (Brunton et al. 2005). Within the et al. 2000). The notoriety of these same debilitating effects. brain, CRH can communicate signals peptides stems from the fact that they Of course, opiate agonists are related to stress, mood, and changes serve as agonists for the receptors that among the drugs with the strongest in other bodily functions (Reul and also are activated by morphine, heroin, abuse/addiction liability (Brunton et Holsboer 2002). The cellular release and the other opiate drugs. These al. 2005). Injectable heroin is perhaps of this neuropeptide is stimulated by receptors are known as opiate receptors, the best-known addictive opiate and alcohol (Nie et al. 2004) as well as by and there are three different subtypes continues to be a problem for people exposure to stressful stimuli. Mounting designated the µ, δ, and κ receptors worldwide. However, abuse of power­ evidence suggests that CRH and its (Connor and Christie 1999). In addi­ ful synthetic taken in pill form, ® receptors participate in the interactions tion, a peptide known as or such as Oxycontin (also known as between stress and alcohol, including orphanin FQ has actions at a separate ), has been on the rise in increased drinking or relapse to opiate-like receptor called the ORL-1 recent years (Compton and Volkow drinking following stressful events receptor (Connor and Christie 1999). 2006). Another , the (Heilig and Koob 2007). All of these receptors preferentially plant derivative known as salvanorin A variety of other neuropeptides couple to Gi/o-type G-proteins and A, acts as an agonist at κ-opioid have been implicated in brain responses thus generally are known to inhibit receptors (Roth et al. 2002). When to alcohol and alcohol drinking behav­ neurotransmitter release and reduce ingested, it produces a relatively short- ior (see Thorsell 2007 and Wurst et the activity of neurons (Williams et lasting disorientation, such that the al. 2007 for more information). al. 2001). user becomes unaware of his/her loca­ Opioid peptides are found in tion in space and time. many regions of the nervous system. Acute alcohol alters endogenous Endocannabinoids and Like other neuropeptides, the opioids opioid peptides and opiate receptors Other Lipid-Derived usually are stored in and released from (Charness 1989; Gianoulakis 1989). Neuromodulators large vesicles different from those that However, the contribution of these contain the small molecules (e.g., actions to intoxication remains unclear. Molecules derived from the chemical glutamate or GABA). These opioid Chronic alcohol exposure also alters modification of the lipids found in peptide–containing vesicles often are brain opiatergic systems (Charness neuronal membranes are another found in the same axon terminals with 1989; Gianoulakis 1989). Interestingly, class of neuromodulatory substances. the smaller diameter, small molecule– opiate receptors have emerged as use­ Throughout the body, lipid-derived containing vesicles, and thus many ful targets for pharmacotherapeutic molecules are known to have paracrine

208 Alcohol Research & Health Communication Networks in the Brain actions. The lipid metabolites known leads to inhibition of neurotransmitter in laboratory animals indicate that as are perhaps the best- release that persists for as long as the CB1 antagonists reduce feeding and known examples of such paracrine agents endocannabinoid is present (Chevaleyre the metabolic changes that often (Brunton et al. 2005). It is worth not­ et al. 2006; Lovinger 2008). Endo­ accompany obesity (Di Marzo et al. ing that lipid-derived compounds do also can trigger a long- 2001; Ravinet Trillou et al. 2003). not have to be released from synaptic lasting depression of neurotransmitter The CB1 antagonist known as vesicles. Unlike other neurotransmitters, release called long-term synaptic Acomplia®, Rimonabant, or SR141716 they usually escape from neurons directly depression (LTD) (Chevaleyre et al. already is in use in for treatment through the cell surface membrane. 2006; Lovinger 2008). This depression of obesity and the associated metabolic Many of these lipid-derived agents is set into motion by endocannabinoid disorder. Antagonists for this receptor are involved in synaptic communica­ activation of CB1 receptors but does also reduce -administration of a tion. Endocannabinoids (a contrac­ not require sustained CB1 activation number of drugs of abuse, most notably tion of endogenous cannabinoids) are for its long-term maintenance. Accum­ nicotine and alcohol (Maldonado et an example (Chevaleyre et al. 2006). ulated evidence suggests that the synap­ al. 2006; Wang et al. 2003). Indeed, Arachidonoyl ethanolamide (AEA) tic depression produced by retrograde researchers have observed a variety of and 2-arachidonoyl glycerol (2-AG) endocannabinoid signaling has key interactions between alcohol and the are two compounds that can be pro­ roles in brain mechanisms of learning brain , sug­ duced upon breakdown of membrane and memory as well as addiction gesting involvement of this system in lipids that contain the known (Lovinger 2008). alcohol dependence (Colombo et al. as . These compounds The term “” within 2007). Research on alcohol interac­ are produced throughout the brain the name of these compounds reflects tions with the brain endocannabinoid and body and have been implicated that fact that the endocannabinoids signaling system still is in the early in a number of physiological functions. have something in common with drugs stages. Chronic alcohol has been shown Endocannabinoids have an intriguing derived from the sativa plant, to increase AEA and 2-AG levels in action at synapses such as marijuana. Indeed, the CB1 cells and tissue (Basavarajappa and (Alger 2002). In other words, synaptic receptor is itself the major target for Hungund 1999; Basavarajappa et al. communication by these compounds Δ-9tetrahydrocannabinol (Δ-9THC), 2000, 2003). There also is evidence generally occurs in a direction opposite the primary psychoactive ingredient that chronic alcohol exposure down- to that of traditional neurotransmitters. in cannabis-derived drugs (Brunton regulates CB1 receptors (Basavarajappa The endocannabinoids often are et al. 2005). The endocannabinoids et al. 1998). Clearly, further studies produced by postsynaptic neuronal produce much milder and shorter-last­ are needed to explore the mechanisms elements and act on their cognate ing versions of the effects produced through which endocannabinoids par­ receptors, cannabinoid 1 (CB1) by cannabinoids in the brain, includ­ ticipate in the neural actions of alcohol. receptors, which are found almost ing relief from anxiety, relief from pain, Agonists for the CB1 receptor exclusively on presynaptic axon ter­ actions that affect movement initia­ already are in use, mainly for treating minals in the brain. This signaling tion, balance and coordination, and chemotherapy side effects. These requires that the compound traverse effects on (Lovinger 2008; agonists reduce nausea induced by the synapse in a backward, or retro­ Piomelli et al. 2000). Knowledge of chemotherapy and also stimulate grade, direction. This action of endo­ the neuronal effects of Δ-9THC pro­ in both chemotherapy patients cannabinoids has now been found vides a great deal of information on and people with AIDS (Pertwee 2005). throughout the nervous system. the effects of specific CB1 agonists. Formulations of cannabis plant The CB1 receptor is a GPCR Indeed, a number of synthetic agonists extracts containing THC and other that links to Gi/o-type G-proteins. have been developed for this receptor, cannabinoids also have been touted The most common effect of activating and they produce strong intoxication, for treatment of this receptor is inhibition of neuro­ movement impairment, decreased and other neurological disorders transmitter release (Lovinger 2008). learning and short-term memory, (Wade et al. 2003). Thus, retrograde endocannabinoid pain relief, and, at high doses, a loss Targeting enzymes involved signaling results in decreased release of movement known as catalepsy in endocannabinoid synthesis and of several types of neurotransmitters, (Howlett 1995). At low-to-moderate degradation also is a promising including both GABA and glutamate. doses, these compounds also stimulate avenue for future applied pharmaco­ Endocannabinoid effects are therefore appetite, a well-known effect of mari­ logical research (Pertwee 2005). For disinhibitory (relief from GABAergic juana and other illegal cannabis-derived example, inhibiting the fatty acid inhibition) or inhibitory (decreased drugs (Di Marzo et al. 2001). amide hydrolase (FAAH) enzyme glutamatergic excitation) depending Antagonists for the CB1 receptor that metabolizes AEA prolongs on the brain region and synapses in also have neural actions, and there is the pain-reducing function of the which they act. The presence of endo­ increasing evidence of the therapeutic endocannabinoid system in certain cannabinoids in the synapse often usefulness of these compounds. Studies paradigms (Hohmann et al. 2005),

Vol. 31, No. 3, 2008 209 and strategies like this may be useful be part of a stress-like effect of with­ actions on the nervous system. Neuro­ in treating certain neuropathic pain drawal (Adinoff et al. 1998). Within transmitters and synaptic communica­ disorders. the brain, alcohol also appears to inter­ tion, as well as neurotrophins and act with the so-called neurosteroids, steroid hormones, figure prominently including the progesterone metabo­ in these neural effects of alcohol. ■ Alcohol Interactions lites that can potentiate GABAA recep­ With Neurotrophins and tor function. Acute alcohol exposure Steroid Hormones enhances levels of progesterone in the Financial Disclosure blood plasma and also increases brain Alcohol has been shown to alter intra­ The author declares that he has no levels of and other cellular signaling induced by different competing financial interests. neurosteroids (VanDoren et al. 2000), neurotrophins. The most consistent and there is evidence that this mecha­ finding is that acute exposure to alcohol nism may contribute to some neuro­ inhibits the signaling and cellular effects References physiological and behavioral effects produced by BDNF (Davis et al. 1999; of the drug (Biggio et al. 2007; Morrow ADINOFF, B.; IRANMANESH, A.; VELDHUIS, J.; AND Fattori et al. 2008; Li et al. 2004; et al. 2001). All of these steroid com­ FISHER, L. Disturbances of the stress response: The Ohrtman et al. 2006). This inhibition pounds are released in response to role of the hypothalamic-pituitary-adrenal axis during may contribute to the damaging effects alcohol withdrawal and abstinence. Alcohol Research stressful stimuli, and thus these sub­ of fetal alcohol exposure on brain & Health 22(1):67–72, 1998. stances may contribute to interactions development but also appears to affect between stressful environmental stim­ AIT-DAOUD, N.; MALCOLM, R.J. JR.; AND JOHNSON, neurotrophin actions in the adult animal. uli and the neural actions of alcohol. B.A. An overview of medications for the treatment of Studies of chronic alcohol effects on alcohol withdrawal and alcohol dependence with an the expression and actions of this neu­ emphasis on the use of older and newer anticonvul­ rotrophin are more mixed (reviewed in Summary sants. Addictive Behaviors 31(9):1628–1649, 2006. Davis 2008). Chronic alcohol exposure PMID: 16472931 in adult animals reportedly increases Communication within the brain ALGER, B.E. Retrograde signaling in the regulation levels of BDNF mRNA in several brain involves electrical activation of neurons of synaptic transmission: Focus on endocannabi­ regions (Baek et al. 1996; McGough et and chemical transmission between noids. Progress in Neurobiology 68:247–286, 2002. al. 2004; Tapia-Arancibia et al. 2001); neurons at structures called synapses. PMID: 12498988 in a few cases, levels of the protein itself Transmission can be broken down into ALTSHULER, H.L.; PHILLIPS, P.A.; AND FEINHANDLER, were increased (Bruns and Miller 2007; fast synaptic transmission mediated by D.E. Alteration of ethanol self-administration by Miller 2004; Miller and Mooney 2004). LGICs and slower-developing neuro­ naltrexone. Life Sciences 26:679–688, 1980. PMID: However, a number of other studies modulation mediated by GPCRs. 6767889 have reported decreases in BDNF mRNA Neurotrophins and steroid hormones or no effect (Bowers et al. 2006; also influence neuronal function by ALTAR, .A., AND DISTEFANO, P.S. Neurotrophin trafficking by anterograde transport. Trends in MacLennan et al. 1995; Miller et al. altering intracellular signaling pathways Neuroscience 21(10):433–437, 1998. PMID: 9786341 2002; Pandey et al. 1999; Zhang et al. and gene expression. Extensive research 2000). Some intracellular signaling targets has shown that many aspects of synap­ AMARA, S.G., AND SONDERS, M.S. Neurotransmitter downstream from the Trk receptors, tic transmission are altered by alcohol transporters as molecular targets for addictive drugs. most notably the Fyn and Src protein at doses and brain concentrations Drug and Alcohol Dependence 51(1–2):87–96, 1998. kinases, also may be targets of acute encountered during drug ingestion. PMID: 9716932 and chronic alcohol actions (Miyakawa Alcohol can affect numerous neuro­ ARNSTEN, A.F. : Therapeutic actions in et al. 1997; Wang et al. 2007). transmitter, neurotrophin, and steroid ADHD. 31(11):2376– Alcohol exposure has well-known systems in the brain to pro­ 2383, 2006. PMID: 16855530 effects on the levels of the corticosteroid duce acute intoxication, as well as neuro­ ARIWODOLA, O.J., AND WEINER, J.L. Ethanol poten­ hormones released from the adrenal adaptations that contribute to tolerance tiation of GABAergic synaptic transmission may be glands. Acute and chronic alcohol and dependence. The neurotoxic self-limiting: Role of presynaptic GABA(B) recep­ exposure enhances levels of cortisol effects produced by alcohol ingestion tors. Journal of Neuroscience 24(47):10679–10686, (the major adrenocorticoid hormone also involve neurotransmitters. Many 2004. PMID: 15564584 in humans), at least in part by increas­ of the neurotransmitter systems that BAEK, J.K.; HEATON, M.B.; AND WALKER, D.W. ing secretion of adrenocorticotropic are implicated in alcohol actions are Up-regulation of high-affinity neurotrophin receptor, hormone from the currently considered as potential targets trk B-like protein on western blots of rat cortex after (Gianoulakis 1998; Rivier 1996). The for pharmacotherapeutic approaches chronic ethanol treatment. Brain Research: Molecular hypothalamic–pituitary–adrenal (HPA) to combating alcohol abuse and alco­ Brain Research 40:161–164, 1996. PMID: 8840027 axis responsible for brain stimulation holism. Articles in this two-part series BARBACID, M. Neurotrophic factors and their recep­ of cortisol secretion also is activated will describe the specific neural effects tors. Current Opinion in 7:148–155, during alcohol withdrawal and may that contribute to different alcohol 1995. PMID: 7612265

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