the neurobiology of opiate motivation - cshl p

The Neurobiology of Opiate Motivation

Ryan Ting-A-Kee1 and Derek van der Kooy1,2

1Institute of Medical Science, University of Toronto, Terrence Donnelly Centre for Cellular and BiomolecularResearch, Toronto, Ontario M5S 3E1, Canada

2Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Terrence DonnellyCentre for Cellular and Biomolecular Research, Toronto, Ontario M5S 3E1, Canada

Correspondence: [email protected]

Opiates are a highly addictive class of drugs that have been reported to possess both do-pamine-dependent and dopamine-independent rewarding properties. The search for how, ifat all, these distinct mechanisms of motivation are related is of great interest in drug addictionresearch. Recent electrophysiological, molecular, and behavioral work has greatly improvedour understanding of this process. In particular, the signaling properties of GABAA receptorslocated on GABA neurons in the ventral tegmental area (VTA) appear to be crucial to under-standing the interplay between dopamine-dependent and dopamine-independent mecha-nisms of opiate motivation.

Opioid drugs play an integral part in humansociety, in part because of their well-doc-

umented analgesic properties (Kanjhan 1995;Rosenblum et al. 2008). However, many of thesecompounds—for example, heroin and otheropiates—are among the most addictive drugsin human history (Kalant 1997; Gruber et al.2007). For these and other reasons, the elucida-tion of their motivational mechanisms of actionhas remained a priority for many researchers.The study of opioids and their addictive prop-erties, and the anatomical and biological mech-anisms that underlie them, has produced a slewof data implicating various receptor subtypesand neurotransmitters. In this article, we focuson research implicating the ventral tegmentalarea (VTA) as a crucial locus in opiate addic-tion. More specifically, we review research sug-gesting that the biology of this brain region

appears crucial for the selection of either do-pamine-dependent or dopamine-independentpathways of opiate motivation.

OPIATE REWARD AND REINFORCEMENTIN THE BRAIN

The concept of motivation is crucial to the sur-vival of all animals. In broad terms, motivationcan be defined as the driving force responsiblefor approach or avoidance behavior. For ourpurposes, the term reward describes those enti-ties that instigate approach behavior (such asbar pressing for sucrose or an attraction to afood-paired environment). The desire to reex-perience this reward can lead to increased rep-etitions of these behaviors, that is, “reinforce-ment.” Although the reinforcement of “good”behaviors such as eating is beneficial, drugs of

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abuse (such as opiates) are problematic in thatthey encourage detrimental drug-seeking anddrug-taking behaviors.

The biological mechanisms underlying opi-ate reward and reinforcement have been studiedin great detail. Opiates mediate their reinforcingactions via a family of G-protein-coupled recep-tors, which are commonly classified into majorsubtypes designated m, d, k, and orphaninFQ/nociceptin (Minami and Satoh 1995; von Zas-trow 2004; Le Merrer et al. 2009). It is theirbinding to these receptors—the m (and to alesser extent d) opioid subtype, in particular—that is thought to be responsible for their pos-itive reinforcing properties (Gruber et al. 2007;Le Merrer et al. 2009). Although these receptorsare found in a large number of brain structures(Mansour et al. 1988; Le Merrer et al. 2009),the direct reinforcing effects of opioids appearto be limited to a select number of brain areas.Chief among these is the midbrain VTA (Wise1989), which houses the dopamine cell bodiesthat project to the nucleus accumbens (NAc)and which are thought to be crucial for bothnatural and drug motivated behaviors (Wiseand Rompre 1989; Wise 1996). Direct injectionof morphine or other opioid drugs into the VTAproduces robust reinforcing effects as measuredby several behavioral paradigms including self-administration and place conditioning (Wise1989; Nader and van der Kooy 1997; Olmsteadand Franklin 1997; Shippenberg and Elmer1998; McBride et al. 1999; van Ree et al. 1999).

THE VTA AND DOPAMINE-DEPENDENTREINFORCEMENT

Owing to its increased activity in response toboth natural and drug reinforcers (Rolls et al.1974; Yokel and Wise 1975; Wise et al. 1978;Spyraki et al. 1982; Bozarth and Wise 1984; DiChiara and Imperato 1985; Zito et al. 1985),dopamine neurotransmission has long beenthe focus of many theories of motivation. It istherefore unsurprising that a predominant rolefor dopamine in opiate motivation has enduredthroughout the years (Bozarth and Wise 1981;Wise 1996; Ford et al. 2006). Indeed, as dis-cussed above, direct infusions of opiates or opi-

oid-like drugs into the VTA result in increaseddopamine activity, supporting the validity ofsuch a model (Gysling and Wang 1983; Johnsonand North 1992).

However, a growing number of publicationshave found evidence for an alternative idea:namely, that dopamine neurotransmission isnot always required for opiate reinforcement(Pettit et al. 1984; Amalric and Koob 1985; Be-chara and van der Kooy 1992; Olmstead et al.1998; Hnasko et al. 2005). Moreover, evidencesuggests that within the VTA itself, opiates arecapable of producing both dopamine-depen-dent and dopamine-independent positive rein-forcement (Nader and van der Kooy 1997; Lav-iolette et al. 2004). What biological mechanismsare responsible for this pattern of results? Amodel capable of organizing these data into apredictive framework would prove very valu-able, indeed.

THE NONDEPRIVED/DEPRIVEDHYPOTHESIS OF OPIATE MOTIVATION

One attempt to explain the interrelationshipbetween dopamine-dependent and dopamine-independent reinforcement highlighted the im-portance of the brainstem tegmental peduncu-lopontine nucleus (TPP). It was found that ex-citotoxic lesions of this area of the brainstem(located near the caudal termination of the me-dial forebrain bundle, a tract of fibers critical forelectrical brain stimulation) (Swanson 1982)could block opiate reinforcement in situationsin which disruptions of dopaminergic neuro-transmission were ineffective (Bechara andvan der Kooy 1992; Olmstead et al. 1998).This model proposed that the split betweenTPP- and dopamine-based reinforcement couldbe traced to differences in drug exposure (Be-chara and van der Kooy 1992; Nader et al. 1994;Dockstader et al. 2001). More specifically, TPPlesions (but not disruptions of dopamine neu-rotransmission) only blocked morphine rein-forcement in previously opiate-naive (nonde-prived) subjects. Conversely, disruptions ofdopamine neurotransmission (but not TPP le-sions) were effective in curtailing morphine re-inforcement only in subjects that had received

R. Ting-A-Kee and D. van der Kooy

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enough drug exposure to render them opiatedeprived and in a state of withdrawal (as ascer-tained by conditioned place aversions and so-matic withdrawal signs) (Fig. 1).

However, this change is not permanent. Overtime, the “active” motivational system shiftsback to the TPP (Nader et al. 1994), indicatingthat it is not the amount of drug exposure that isimportant per se but, rather, the relative motiva-tional state (deprived vs. nondeprived) of theorganism. Additionally, the motivational effectsof food, nicotine, and ethanol also appear tofit this nondeprived/deprived model, althoughfor ethanol the substrates are reversed (dopa-mine is important in the naive state and theTPP, in the dependent and withdrawn state) (Be-chara and van der Kooy 1992; Nader and van derKooy 1994; Laviolette et al. 2002; Laviolette andvan der Kooy 2003; Ting-A-Kee et al. 2009).

Direct infusions of morphine into the VTA,in either nondeprived or opiate-deprived sub-

jects, further suggested that this double dissoci-ation between two motivational states (nonde-prived and deprived) and two output rein-forcement pathways (TPP and dopamine de-pendent) could be localized to the VTA itself(Nader and van der Kooy 1997). Such a resultis partially in accord with previous data positingthe VTA as the likely home of a dopamine-de-pendent motivational signal. However, theobvious question remains: How do opioids pro-duce TPP-dependent and dopamine-depen-dent reinforcement within the VTA? Any poten-tial explanation must take into considerationthe anatomy of the VTA.

VTA ANATOMY

The VTA has long been implicated in the studyof drug addiction (Wise and Rompre 1989; Ka-livas 1993). Dopamine cells make up one of thetwo predominant cell types of the VTA and are

NAcVTA

TPP

TPP

VTA

GABA

DA

NAc

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Figure 1. The nondeprived/deprived hypothesis. (A) A schematic diagram of a rat brain illustrating the basictenets of the nondeprived/deprived hypothesis of opiate motivation. According to the model, in nondeprived(previouslyopiate-naive) subjects, the reinforcing effects of opiates are mediated bya descending projection fromthe midbrain ventral tegmental area (VTA) to the brainstem tegmental pedunculopontine nucleus (TPP).Conversely, in opiate-deprived (dependent and withdrawn) subjects, the reinforcing effects of opiates are me-diated by an ascending dopaminergic projection from the VTA to the nucleus accumbens (NAc). (B) Diagram-matical representation of the basic brain circuitry proposed to be involved in the nondeprived/deprived model.

Opiates and the VTA

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more abundant than their g-amino butyric acid(GABA) counterparts (Swanson 1982; Gyslingand Wang 1983; Johnson and North 1992; Ka-livas 1993; Ford et al. 1995). More recent reportsalso suggest the existence of a smaller subpopu-lation of VTA glutamate cells (Ungless et al.2004; Yamaguchi et al. 2007; Omelchenko andSesack 2009; Dobi et al. 2010).

Regulation of the VTA, and of dopamine andGABA neurons in particular, is complex, involv-ing synaptic connections from multiple areas ofthe brain (Kalivas 1993; Omelchenko et al. 2009;Omelchenko and Sesack 2010). VTA dopaminecells are subject to modulation by a host of localneurotransmitters and various extrinsic effer-ents (for review, see Kalivas 1993) and makeextensive projections to the frontal cortex andvarious limbic areas (Swanson 1982). Most rel-evant for our discussion is the large dopaminer-gic projection to the ventral striatum and thenucleus accumbens (NAc) in particular (Swan-son 1982; Ford et al. 2006). It has been suggestedthat VTA dopamine neurons are not uniform innature, both in terms of their varying input andoutput fields (Kalivas 1993; Kalivas and Alesdat-ter 1993; Blaha et al. 1996; Steffensen et al. 1998;Carr and Sesack 2000; Omelchenko and Sesack2005; Omelchenko and Sesack 2007) and theirstructural and electrophysiological properties(Lammel et al. 2008; Margolis et al. 2008).

Similar to the dopamine cells, separate pop-ulations of VTA GABA cells also exist in terms oftheir varying input and output fields (Thierryet al. 1979, 1980; Sesack and Pickel 1992; Kalivas1993; Van Bockstaele and Pickel 1995; Steffen-sen et al. 1998; Garzon et al. 1999; Carr andSesack 2000; Omelchenko and Sesack 2005;Xia et al. 2011). It has been suggested that theGABA cells of the VTA are electrically connectedvia gap junctions, which may play an importantrole in VTA dopaminergic reward processes(Steffensen et al. 2011). Additionally, some ofthese GABA cells send descending projectionsto the brainstem area, including the TPP (Swan-son 1982; Semba and Fibiger 1992; Steiningeret al. 1992). More recently, it has been proposedthat similar to VTA GABA cells, inhibitoryGABAergic projections from the rostromedialmesopontine tegmental nucleus (also known

as the “posterior tail” of the VTA) also synapsewith both the TPP (Jhou et al. 2009b) and VTAdopamine cells (Jhou et al. 2009a; Balcita-Ped-icino et al. 2011).

Various labeling studies suggest that strongintra-VTA regulation of VTA dopamine, GABA,and glutamate cells also exists (Omelchenkoand Sesack 2009; Dobi et al. 2010). Glutamatecells appear to provide local excitatory input toall three cell types (Dobi et al. 2010). Similarly,GABA cells have been described as “upstream”of the dopamine cells and are thought to pro-vide local inhibitory tone to them (Gysling andWang 1983; Johnson and North 1992; Kalivas1993; Omelchenko and Sesack 2009), in addi-tion to other local glutamate and GABA neu-rons themselves (Dobi et al. 2010).

Because the majority of m-opioid receptorsin the VTA are localized to the GABA cells (Diltsand Kalivas 1989; Garzon and Pickel 2001),it has been proposed that m-opioids producedopamine cell activation via disinhibition. Di-rect opioid binding to VTA GABA cells pro-duces hyperpolarization of these neurons (Gys-ling and Wang 1983; Johnson and North 1992)and, in turn, releases the dopamine cells fromtheir tonic inhibition, allowing for the transmis-sion of a dopamine-dependent reinforcementsignal. This proposal is in accord with variousdopamine theories of motivation (Wise et al.1978; Robinson and Berridge 1993; Wise 1996).

However, m-opioid receptors also are foundpresynaptically in the VTA, on GABAergic ter-minals to both VTA GABA and (to a lesserextent) dopamine cell dendrites (Sesack andPickel 1995; Garzon and Pickel 2001; Svingoset al. 2001; Xia et al. 2011). This raises the pos-sibility that in lieu of (or in addition to) a directinhibitory action on GABA cells, m-opioid re-ceptor agonists may disrupt the release of GABAonto either GABA or dopamine neurons. Be-cause GABA typically produces cellular inhibi-tion (Kaila 1994), such a decrease in GABA re-lease onto VTA GABA receptors will usuallyresult in a net excitatory or depolarizing effecton the GABA neurons themselves—althoughthe actual outcome will depend on the specificsignaling properties of the GABA receptorsthemselves.



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VTA GABA RECEPTORS

GABA receptors are found distributed acrossboth VTA GABA and dopamine cell popula-tions and, consequently, have been proposedto play a crucial role in dopaminergic cell sig-naling and motivational processes in general(McBride et al. 1999; Laviolette and van derKooy 2001; Macey et al. 2001; Walker and Etten-berg 2005; Madhavan et al. 2010). For example,both GABAA receptor agonists and antagonistshave been reported to produce positive reinforc-ing properties when microinjected into the VTA(Ikemoto et al. 1997, 1998; Laviolette and vander Kooy 2001). Although regional specificity—ultimately leading to increased dopamine re-lease—has been proposed to explain this ap-parent paradox (Ikemoto et al. 1997, 1998),there exists an intriguing alternative. Lavioletteand colleagues showed that although both theGABAA receptor agonist muscimol and theGABAA receptor antagonist bicuculline pro-duced rewarding effects, they did so via differ-ent mechanisms (Laviolette and van der Kooy2001; Laviolette et al. 2004). In previously drug-naive rats, muscimol’s rewarding properties weremediated by dopamine neurotransmission andbicuculline’s rewarding properties, by the TPP.Even more surprisingly, these outputs wereswitched in opiate-dependent and withdrawnrats: now, muscimol produced reinforcementvia the TPP and bicuculline, via dopamine.This pattern of results suggested a more complexpicture of VTA GABAA receptor functionalityand, perhaps more importantly, suggested thatVTAGABAA receptors may be close to, oreven at,the site where the switch between naive anddrug-dependent motivation occurs.

GABAA receptors are part of a family of li-gand-gated ion channels and function primar-ily as chloride ion channels, although they alsopossess a significant permeability for bicarbon-ate ions and other weak acids (Kaila 1994).Each receptor is made up of five subunits (la-beled a, b, g, d, and r), which are, in turn,composed of four transmembrane domains(Kaila 1994; Johnston 1996). The subunitsthemselves come in many distinct varietiesand, in theory, can produce an extremely large

number of subunit combinations, although farfewer appear to exist in nature (Hevers and Lud-dens 1998). The various combinations of sub-units produce differing functional properties(e.g., differences in desensitization) and are of-ten found with a certain degree of regional spe-cificity (Kaila 1994).

In the VTA, GABAA receptors are found pri-marily on GABA neurons as indicated by auto-radiographic localization (Churchill et al. 1992;Kalivas 1993) or by selective inhibition of non-dopamine (presumably GABAergic) cells byGABAA receptor-specific drugs (O’Brien andWhite 1987). On the other hand, GABAB recep-tors—which are metabotropic, G-protein-cou-pled receptors that activate potassium ion chan-nels and/or inhibit calcium channels—mediateslow, prolonged inhibition and are thought tolie primarily on VTA dopamine cells as suggest-ed by antibody staining (Chelib and Johnson1999; Wirtshafter and Sheppard 2001) and thespecific actions of GABAB receptor agonists ondopamine cells (Olpe et al. 1977; Kalivas et al.1990; Laviolette and van der Kooy 2001). Figure2 summarizes the various VTA cell and receptorsubtype interrelationships.

GABAA RECEPTORS POSSESS INHIBITORYAND EXCITATORY SIGNALING PROPERTIES

GABA is the primary inhibitory neurotransmit-ter in the mammalian brain (Kaila 1994). Acti-vation of ionotropic GABAA receptors typicallyresults in an inward influx of chloride ions,thereby hyperpolarizing the cell (Kaila 1994;Johnston 1996). This is termed “classical” or“conventional” GABAergic inhibition. Howev-er, under certain circumstances, GABAA recep-tors are capable of mediating an alternative ex-citatory/depolarizing response—for example,an efflux of chloride ions (Kaila 1994; Steinand Nicoll 2003). A growing literature has fo-cused on this less well-characterized ability ofGABAA receptors.

In studies of the neonatal hippocampus, ac-tivation of GABAA receptors results in cellularexcitation that has been proposed to mediate atrophic signal (Cherubini et al. 1991; Ben-Ari2002). GABA appears to have excitatory actions

Opiates and the VTA


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in many areas of the developing brain; indeed,in vertebrates at least, a developmental shift inGABAA receptor signaling (from excitatory/de-polarizing to inhibitory/hyperpolarizing) ap-pears to be the rule, not the exception (Cheru-bini et al. 1990; Kaila 1994; Ben-Ari 2002;McCarthy et al. 2002). In addition, the excitato-ry actions of GABAA receptors have been pro-posed as a mechanism for mediating neuro-pathic pain in the spinal cord (Coull et al.2003), epileptic seizures in the hippocampus(Rivera et al. 2002), and the ability of the ratsuprachiasmatic nucleus to oscillate betweendaytime excitation and nighttime inhibition(Wagner et al. 1997).

MECHANISMS UNDERLYING THE GABAA

RECEPTOR SIGNALING SWITCH

GABAA receptors mediate inhibitory chlorideion influxes in the adult brain, where the intra-

cellular chloride concentration is lower thanthat found extracellularly (Johnston 1996).However, in cases in which the reverse is true(e.g., in the developing brain where the intracel-lular chloride concentration is higher), GABAactivation of GABAA receptors will result inchloride following its concentration gradientand exiting the cell—an excitatory response(Kaila 1994; Ben-Ari 2002). Consequently, any-thing that disrupts or alters the relative chlorideion concentration gradient of GABAA recep-tor-containing neurons can theoretically pro-vide a mechanism for the excitatory effects ofGABAA receptors.

One idea concerns changes in the activitiesof various chloride ion cotransporters (Thomp-son et al. 1988; Kaila 1994; Kahle et al. 2008).For example, the NKCC1 transporter is re-sponsible for the movement of chloride ionsinto the cell (Ben-Ari 2002; Kahle et al.2008), and levels of this transporter are reduced

VTA

GABAAreceptor

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GABABreceptor

DA

NAc

GABA

μ

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μ

Figure 2. The anatomy of the ventral tegmental area (VTA). The VTA is composed primarily of dopamine(DA) and GABA neurons, the latter of which are found upstream of the dopamine cells and are thought toprovide tonic inhibition of them. GABAA receptors are localized primarily to GABA cells, and GABAB

receptors to dopamine cells. Both cell types receive projections from areas outside of the VTA, includingGABA synapses containing presynaptic m-opioid receptors. VTA GABA cells also possess m-opioid receptors.Functionally, the dopamine cells project to the nucleus accumbens and comprise the mesolimbic dopami-nergic system, thought to be crucial for the reinforcing properties of opiates in the deprived motivationalstate. Descending GABA projections to the brainstem tegmental pedunculopontine nucleus (TPP) are thoughtto be crucial for the non-dopaminergic reinforcing properties of opioids in the nondeprived motivationalstate.



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throughout development. This coincides withthe developmental change observed in GABAA

receptor signaling, from depolarizing to hyper-polarizing (Liu et al. 2006; Kahle et al. 2008).Conversely, down-regulation (or decreased ac-tivities) of chloride transporters that removeintracellular chloride—such as KCC transport-ers—would have the opposite effect, allowingchloride to accumulate intracellularly (Thomp-son et al. 1988). Research suggests that theseKCC transporters are increased during de-velopment (Rivera et al. 1999; Hubner et al.2001). This increase would improve the clear-ance of chloride and facilitate the loss of GABAA

receptor excitability in developing neurons.Another potential mechanism of GABAA

receptor excitability concerns the ability of oth-er ions to traverse GABAA receptors. Althoughknown primarily as chloride channels, GABAA

receptors also allow the passage of other selectmolecules (Kaila 1994). Chief among these arebicarbonate ions, which possess about one-fifththe permeability of chloride ions and are foundin physiologically relevant concentrations with-in the cell (Kaila 1994). Bicarbonate concentra-tions are usually greater inside of the cell thanoutside, and consequently bicarbonate flowsout of the cell upon opening of the GABAA

receptor channel, an action that produces cellu-lar excitation. Although chloride is generallymore abundant and possesses a higher perme-ability than bicarbonate ions, should the chlo-ride ion concentration gradient break down—perhaps, because of an excessive influx of chlo-ride in response to multiple receptor activa-tions—the bicarbonate ion electrochemicalgradient has been proposed to “take over”and drive the overall response of GABAA recep-tor activation (Kaila et al. 1993; Staley et al.1995). Indeed, high-frequency stimulation ofrat hippocampus pyramidal neurons producesprecisely such an excitatory GABAA receptoreffect (Kaila et al. 1997; Staley and Proctor1999).

In line with this idea, some investigatorshave proposed manipulating the concentrationof bicarbonate ions as a means of controllingthe response properties of GABAA receptors—that is, artificially “switching” them to mediate

excitation as opposed to inhibition. Bicarbon-ate ions are generated by the enzyme carbonicanhydrase, which catalyzes its synthesis fromwater and carbon dioxide (Ridderstrale andWistrand 2000; Kida et al. 2006). By control-ling the activity of this enzyme, it was proposedthat one could control the intracellular concen-tration of bicarbonate and thereby influencethe response properties of GABAA receptors.According to this idea, inhibition of the en-zyme should prevent bicarbonate buildupand, therefore, prevent any bicarbonate-medi-ated depolarizing response. Conversely, activa-tion of the enzyme should have the oppositeeffect, increasing the intracellular bicarbonateconcentration and encouraging GABAA recep-tor-mediated depolarization. To this end, inhi-bition of the carbonic anhydrase enzyme withthe drug acetazolamide was found to reduceneuropathic allodynia caused by GABAA re-ceptor-mediated depolarization (Asiedu et al.2010), and activation of the carbonic anhydraseenzyme was found to facilitate rodent spatialmemory in a Morris water maze test (Sun andAlkon 2001, 2002). Figure 3 shows the proposedGABAA receptor-relevant ion flows.

Changes in GABAA receptor subunits alsohave been proposed as a mechanism to explainchanges in GABAA receptor responses. Researchsuggests that at least some GABAA receptor sub-units are altered during the course of develop-ment, leaving open the possibility that they areinvolved in the switch in GABAA receptor sig-naling (Fritschy et al. 1994). Additionally, theexistence of GABA-gated cation channels hasbeen shown in the nematode Caenorhabditiselegans (Beg and Jorgensen 2003), suggestingthat excitation-specific GABA receptors exist(although whether such receptors are found invertebrates remains unknown).

In summary, it is clear that GABAA recep-tors are capable of producing both inhib-itory and excitatory modes of signaling. Severalmechanisms have been proposed to explain howthis is accomplished. The differing signalingproperties of GABAA receptors underlie a largenumber of biological processes and, as dis-cussed below, also appear to play a central rolein opiate motivation.

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VTA GABAA RECEPTORS FORMA MOTIVATIONAL SWITCHINGMECHANISM FOR OPIATESAccording to the nondeprived/deprived hy-pothesis, the prior drug history of the animal(previously drug naive or drug dependent andin a state of withdrawal) determines the sub-strate mediating opiate reinforcement. The“switch” version of this model proposes thatchanges in VTA GABAA receptors are the crucialintermediary linking (1) motivational state, and(2) output reinforcement pathway.

Both TPP- and dopamine-dependent rein-forcing effects have been observed with intra-VTA opiate infusions (Nader and van der Kooy1997; Laviolette and van der Kooy 2004). There-fore, VTA GABA cells were proposed to act as anatural “switch” capable of shuttling opiate re-inforcement between these two pathways, be-cause these neurons possess anatomical connec-tions with both VTA dopamine cells and the

TPP (although not necessarily by the sameGABA cell) (Swanson 1982; Semba and Fibiger1992; Steininger et al. 1992; Kalivas 1993; La-violette et al. 2004; Omelchenko and Sesack2009). However, the exact mechanics of thisprocess remained problematic. How could asingle GABA cell (or group of cells) shift itssignaling properties to mediate either TPP- ordopamine-dependent reinforcement?

One elegant solution lay in the dual signal-ing properties of the VTA GABAA receptorsthemselves. Recall that GABAA receptors aremainly localized to VTA GABA neurons (Chur-chill et al. 1992; Kalivas 1993) and are capable ofproducing two distinctive modes of signaling(Kaila 1994; Stein and Nicoll 2003). These ex-citatory and inhibitory modes of action havepreviously been proposed to mediate severalbiological processes (Cherubini et al. 1990,1991; Wagner et al. 1997; Rivera et al. 1999; Au-ger et al. 2001; McCarthy et al. 2002; Coull et al.

Acetazolamide

Carbonicanhydrase

VTA GABAAreceptor

KCC

Furosemide

NKCC

HCO3–HCO3

– CO2 + H2O

Cl–Cl–

Cl–

Figure 3. Ion movements in VTA GABAA receptors. Activation of VTA GABAA receptors located on GABAneurons allows for chloride (Cl2) and bicarbonate (HCO3

2) ions to flow down their electrochemical gradients.In the adult, chloride is usually found in greater abundance extracellularly, and, therefore, GABAA receptoractivation produces an influx of chloride, hyperpolarizing the cell. Conversely, bicarbonate is more concentratedintracellularly and therefore flows out of the cell, an excitatory response. Bicarbonate production (from carbondioxide and water) is catalyzed by the carbonic anhydrase enzyme and can be inhibited by the drug acetazolamide,thereby negating any bicarbonate-mediated excitation. The relative intracellular chloride ion concentrations aremaintained by the NKCC and KCC transporters, which move chloride into and out of the cell, respectively. Inadults, levels of the NKCC channel are relatively low. Consequently, blockade of KCC transporter activity (withfurosemide) helps to decrease any inward-directed chloride ion flow, facilitating GABAA receptor excitation.



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2003; Leitch et al. 2005). Similarly, it was pro-posed that the TPP- and dopamine-dependentreinforcement pathways observed by investiga-tors might have their biological bases rooted inthe biphasic actions of VTA GABAA receptors(Laviolette et al. 2004; Vargas-Perez et al. 2009).Such a model would require that opiates exerttheir actions (at least initially in drug-naive sub-jects) on the m-opioid receptors found presyn-aptically in the VTA, which regulate GABA re-lease onto GABAA receptors (Fig. 2) (Sesack andPickel 1995; Garzon and Pickel 2001; Svingoset al. 2001; Xia et al. 2011).

Electrophysiological, molecular, and behav-ioral evidence supports the idea that a switchfrom an inhibitory to an excitatory VTA GABAA

receptor does, in fact, occur in animals that havechanged from a previously drug-naive motiva-tional state, to an opiate-dependent and with-drawn state (Laviolette et al. 2004; Vargas-Perezet al. 2009). In previously drug-naive rats, theGABAA receptor agonist muscimol producedinhibition of GABA neurons via their direct ac-tions on GABAA receptors (Laviolette et al.2004). However, once the rats were opiate de-pendent and in withdrawal, muscimol now pro-duced excitation in a significant subset of thesesame GABA cells, suggesting that at least someof the GABAA receptors had switched to medi-ate excitation (Laviolette et al. 2004; Vargas-Pe-rez et al. 2009). Similarly, CREB phosphoryla-tion (a marker of excitatory GABAA receptoractivity) of VTA GABA cells was increased inopiate-dependent and withdrawn rats as com-pared with their previously drug-naive counter-parts (Laviolette et al. 2004).

Furthermore, experiments using opposingartificial manipulations of VTA GABAA recep-tors produced opposite effects on opiate moti-vation. Acetazolamide—which inhibits the car-bonic anhydrase enzyme, thereby preventingthe generation of intracellular bicarbonate andtherefore, any bicarbonate-mediated excitation(Fig. 3)—had no effect in previously drug-naive animals (Laviolette et al. 2004; data notshown). However, in opiate-dependent andwithdrawn animals, acetazolamide preventedthe block of both intra-VTA and systemic mor-phine place preferences that is normally ob-

served in subjects also pre-treated with thebroad-spectrum dopamine receptor antago-nist a-flupenthixol. Conversely, furosemide—which blocks the KCC chloride channel thatremoves intracellular chloride, thereby facilitat-ing bicarbonate-mediated excitation (Fig. 3)—had no effect in opiate-dependent and with-drawn animals. However, in previously drug-naive animals that had received lidocaine inac-tivation of the TPP (which normally blocksmorphine place preferences), morphine placepreferences were instead revealed. This furose-mide effect was reversed by coadministrationwith acetazolamide, suggesting that the latter’sactions on the carbonic anhydrase enzyme (and,therefore, on the generation of bicarbonate ions)may be a final common downstream pathwayfor the depolarizing actions of VTA GABAA

receptors.These data argue convincingly in favor of

the idea that during the change to an opiate-deprived animal, VTA GABAA receptors under-go a parallel switch in signaling properties. ThisVTA-based switch is crucial to determiningwhether opiate reinforcement is TPP or dopa-mine dependent.

BRAIN-DERIVED NEUROTROPHIC FACTORIS CRITICAL FOR THE VTA GABAA RECEPTORSWITCHING MECHANISM

Although the above experiments suggest thatopiate reinforcement is, indeed, controlled bya VTA-switching mechanism, it remains to bedetermined what natural mediator(s) is respon-sible for instigating this switch naturally whenanimals undergo a change from a previouslydrug-naive to an opiate-dependent and with-drawn motivational state. One possibility isthe neurotrophic factor brain-derived neuro-trophic factor (BDNF). There is a wealth ofdata suggesting that BDNF plays an importantrole in various aspects of drug addiction (Hallet al. 2003; Lu et al. 2004; Berglind et al. 2007;Lobo et al. 2010). More relevant for this discus-sion are reports suggesting that BDNF is capableof producing a change in the signaling proper-ties of GABAA receptors (Rivera et al. 2002;Coull et al. 2005). Indeed, BDNF has been

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linked to decreases in the activity of neuronalKCC transporters (Rivera et al. 2002; Wake et al.2007). Perhaps not so coincidentally, during thechange from a previously drug-naive to an opi-ate-dependent and withdrawn animal, levels ofVTA BDNF also are increased (Vargas-Perezet al. 2009). A BDNF-induced decrease in theactivity of the KCC transporter on VTA GABAcells should result in the intracellular accumu-lation of chloride ions (similar to the proposedeffect of furosemide), which, in turn, might al-low for another ion flow—such as bicarbonateextrusion—to dominate and produce a depo-larizing response (Staley et al. 1995). Such amechanism might be sufficient to explain theobserved switch in VTA GABAA receptor signal-ing during the change from a previously opiate-naive, to an opiate-dependent and withdrawnmotivational state (Laviolette et al. 2004; Var-gas-Perez et al. 2009). Further support for thisidea comes from the fact that intra-VTA infu-sion of siRNA—targeted to the high-affinityBDNF trkB receptor—prevents the switch toa dopamine-dependent reinforcement systemeven in opiate-dependent and withdrawn ani-mals (data not shown). It is also possible thatother potential actions of BDNF (e.g., onGABAA receptor subunit composition, cell sur-face expression, and cortical excitability) (Ruth-erford et al. 1997; Thompson et al. 1998; Bruniget al. 2001) may play a role in this process. Over-all, the evidence supports the idea that BDNF—released naturally in response to opiate intake—mediates the switch in VTA GABAA receptorsignaling and, therefore, the switch in opiatereinforcement mechanisms.

AN INTEGRATED MODEL OF OPIATEMOTIVATION IN THE VTA

According to the model, opiates exert their func-tional effects by binding to upstream m-opioidreceptors located on presynaptic GABA-releas-ing terminals in the VTA (and not those m-opi-oid receptors located on the GABA cells them-selves) (Garzon et al. 1999; Svingos et al. 2001;Omelchenko and Sesack 2009; Xia et al. 2011).This results in a decrease in tonic GABA releaseonto VTA GABAA receptors, which are located

on GABA perikarya. This decreased activation ofGABAA receptors has different consequencesdepending on the motivational state of the or-ganism.

In nondeprived, previously drug-naive ani-mals, activation of GABAA receptors inhibitsVTA GABA cells (including those GABA cellsthat provide local inhibition to VTA dopaminecells). Opiate binding to presynaptic m-opioidreceptors decreases this inhibitory response(functionally similar to the direct antagonistactions of bicuculline on VTA GABAA recep-tors) and, consequently, depolarizes the GABAcells. This results in (1) continued inhibition ofthe dopamine cells, and (2) the initiation of areinforcement signal from VTA GABA cells tothe TPP. Thus, opiate reinforcement in drug-naive animals is TPP dependent (Fig. 4).

Conversely, in opiate-deprived subjectswhere activation of VTA GABAA receptors ex-cites GABA cells, opiate administration wouldhave the exact opposite effect. Opiate bindingto presynaptic m-receptors again reduces GABArelease onto GABAA receptors. This loss of anexcitatory input causes VTA GABA cells to hy-perpolarize (this same effect would be observedif opiates now bound to m-opioid receptorslocated directly on the VTA GABA cells them-selves). Consequently, (1) no reinforcementsignal is sent to the TPP, and (2) the inhibitionof VTA GABA cells disinhibits the dopaminecells, leading to the production of a dopa-mine-dependent reinforcement signal (Fig. 4).The simplest version of this model assumes thatthe VTA GABA cells important for the switch-ing mechanism project to both the TPP andlocal dopamine cells, although it is possiblethat separate GABA cell populations exist in-stead.

SUMMARY

The nondeprived/deprived “switch” hypothesissuggests that GABAA receptors on VTA GABAneurons form a switching mechanism that con-trols the substrates underlying opiate motiva-tion. In lieu of opiates acting upon separate sitesof action (to produce TPP- and dopamine-dependent reinforcement), the opioid site of



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action is proposed to remain constant, and acommon downstream effector—VTA GABAA

receptors—instead change their functional pro-perties. Manipulation of this functionality—bycontrolling whether VTA GABAA receptor acti-vation produces inhibition or excitation—con-trols the active opiate reinforcement outputsystem (TPP or dopamine dependent), irre-spective of the animal’s previous drug history.This change is temporary and may be naturallymediated by the actions of BDNF in the VTA.The nondeprived/deprived “switch” modelthus provides an experimentally tested, predic-tive framework for organizing reports of bothdopamine-dependent and dopamine-indepen-dent opioid reinforcement. This result is an im-portant step in our continued attempt to ex-plore the mechanisms underlying motivation

and suggests that an emphasis on research indrug-deprived subjects may be a worthwhileendeavor.

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Opiates and the VTA


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2012; doi: 10.1101/cshperspect.a012096Cold Spring Harb Perspect Med Ryan Ting-A-Kee and Derek van der Kooy The Neurobiology of Opiate Motivation

Subject Collection Addiction

PharmacotherapiesThe Persistent Challenge of Developing Addiction

Paul J. Kenny, et al.Sarah E. Swinford-Jackson, Charles P. O'Brien, Next Generations

Neurophysiology, Behavior, and Health in the Consequences of Parental Opioid Exposure on

Fair M. Vassoler and Mathieu E. Wimmer

Opioid-Associated ComorbiditiesBrain Axis in−Opioid Modulation of the Gut

Li Zhang and Sabita RoySubstance Use DisordersAnimal Models of the Behavioral Symptoms of

Louk J.M.J. Vanderschuren and Serge H. AhmedEpigenetics of Drug Addiction

Andrew F. Stewart, Sasha L. Fulton and Ian MazeTranslational Research in Nicotine Addiction

et al.Miranda L. Fisher, James R. Pauly, Brett Froeliger,

Genetic Vulnerability to Opioid AddictionBrian Reed and Mary Jeanne Kreek Transgenerational Echo of the Opioid Crisis

Neonatal Opioid Withdrawal Syndrome (NOWS): A

Reiner, et al.Andrew E. Weller, Richard C. Crist, Benjamin C.

Underlying Opioid AddictionGlutamatergic Systems and Memory Mechanisms

PetersJasper A. Heinsbroek, Taco J. De Vries and Jamie

-THC, and Synthetic Cannabinoids9∆Impairment of Synaptic Plasticity by Cannabis,

R. LupicaAlexander F. Hoffman, Eun-Kyung Hwang and Carl

Mechanisms of Nicotine AddictionMarina R. Picciotto and Paul J. Kenny Transmission in the Ventral Tegmental Area

Drug-Evoked Synaptic Plasticity of Excitatory

LüscherCamilla Bellone, Michael Loureiro and Christian

Neural Substrates and Circuits of Drug Addiction

FuchsMatthew W. Feltenstein, Ronald E. See and Rita A. of Ventral Tegmental Area Dopamine Neurons

Opioid-Induced Molecular and Cellular Plasticity

Marie A. Doyle and Michelle S. Mazei-Robison

DependenceThe Role of the Central Amygdala in Alcohol

Marisa Roberto, Dean Kirson and Sophia KhomRelease in Reward Seeking and AddictionA Brain on Cannabinoids: The Role of Dopamine

Kate Z. Peters, Erik B. Oleson and Joseph F. Cheer

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