Neuropharmacology 47 (2004) 33–46 www.elsevier.com/locate/neuropharm Structural plasticity associatedwith exposure to drugsof abuse Terry E. Robinson a,Ã, Bryan Kolb b a Department of Psychology (Biopsychology) and Neuroscience Program, The University of Michigan, 525 E. University (East Hall), Ann Arbor, MI 48109, USA b Department of Psychology and Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alta., Canada T1K 3M4 Received19 April 2004; receivedin revisedform 24 May 2004; accepted30 June 2004 Abstract Persistent changes in behavior andpsychological function that occur as a function of experience, such those associatedwith learning andmemory, are thought to be dueto the reorganization of synaptic connections (structural plasticity) in relevant brain circuits. Some of the most compelling examples of experience-dependent changes in behavior and psychological function, changes that can last a lifetime, are those that accrue with the development of addictions. However, until recently, there has been almost no research on whether potentially addictive drugs produce forms of structural plasticity similar to those associated with other forms of experience-dependent plasticity. In this paper we summarize evidence that, indeed, exposure to amphetamine, cocaine, nicotine or morphine produces persistent changes in the structure of dendrites and dendritic spines on cells in brain regions involvedin incentive motivation andreward(such as the nucleus accumbens), andjudgmentandthe inhibitory control of beha- vior (such as the prefrontal cortex). It is suggestedthat structural plasticity associatedwith exposure to drugsof abuse reflects a reorganization of patterns of synaptic connectivity in these neural systems, a reorganization that alters their operation, thus con- tributing to some of the persistent sequela associated with drug use—including addiction. # 2004 Elsevier Ltd. All rights reserved. Keywords: Amphetamine; Cocaine; Morphine; Nicotine; Psychostimulants; Opiates; Dendrites; Dendritic spines; Sensitization; Golgi; Synaptic plasticity 1. Introduction where experience has been shown to alter the physical structure of neurons andsynapses (i.e., producestruc- Persistent changes in behavior andpsychological tural plasticity). For example, changes in behavior that function that occur as a consequence of experience are result from learning (Chang andGreenough, 1982; thought to be mediated by the reorganization or Moser et al., 1994; Stewart andRusakov, 1995; Leuner strengthening of synaptic connections in specific neural et al., 2003), living in an isolatedversus complex circuits. This idea has been a fundamental assumption environment (Greenough et al., 1990; van Praag et al., underlying research on the neurobiology of learning 2000; Kolb et al., 2003a) or recovery of function after andmemory, as well as other forms of experience- brain damage (Kolb andGibb, 1991; Jones et al., 1996; dependent plasticity, since the time of Ramon y Cajal Biernaskie andCorbett, 2001 ) are all associatedwith (1928), andHebb (1949) formalizedthis postulate in structural alterations in relevant neural circuits. Thus, his seminal book, ‘‘The Organization of Behavior’’. a major aim of modern research on the neurobiology Although experimental evidence directly relating of behavioral plasticity, including learning and mem- structural plasticity in the brain to changes in specific ory, is elucidating the molecular mechanisms involved behaviors is very limited, there are numerous examples in the structural reorganization of neuronal circuits (Lamprecht andLeDoux, 2004 ). Ã Corresponding author. Tel.: 1-734-763-4361; fax: +1-734-763- A focus of much research on structural plasticity has 7480. been on the morphology of dendrites and dendritic E-mail address: [email protected] (T.E. Robinson). spines. The vast majority of synaptic inputs onto 0028-3908/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2004.06.025 34 T.E. Robinson, B. Kolb / Neuropharmacology 47 Supplement No. 1 (2004) 33–46 neurons are on dendrites or dendritic spines, and the function. Furthermore, there is growing evidence that amount of synaptic input cells receive varies with the drugs of abuse usurp many of the same cellular and amount of dendritic surface available (Harris and molecular mechanisms involvedin other forms of Kater, 1994). Furthermore, it is estimatedthat over synaptic plasticity (Berke andHyman, 2000; Hyman 90% of excitatory synapses are on dendritic spines, and andMalenka, 2001; Nestler, 2001 ). It is surprising, synaptogenesis associatedwith experiences like learning therefore, that until recently there has been almost no or environmental complexity is reflectedby changes in research on whether any of the long-lasting behavioral the number of dendritic spines (Greenough et al., 1990; consequences of repeatedexposure to drugsof abuse in Kolb et al., 1998; Woolley, 1999; Rampon et al., 2000). adulthood are accompanied by the kinds of structural Even changes in the shape of existing spines may mod- plasticity normally associatedwith other forms of ify synaptic efficacy by altering the chemical micro- experience-dependent plasticity. (Note that structural environment or the electrotonic properties of the changes in dendrites have been described when drugs synapse (Horner, 1993; Rusakov et al., 1996; Shepherd, are given early in development, but this literature will 1996; Nimchinsky et al., 2002; Tsay andYuste, 2004 ), not be reviewedhere; see StanwoodandLevitt, 2004 or by altering fast synaptic neurotransmission (Kasai for a recent review). et al., 2003). Indeed, dendrites and dendritic spines are We have begun to address this issue in a series of thought to be a locus of experience-dependent structur- experiments in which we askedwhether repeated al plasticity (Harris andKater, 1994; Nimchinsky et al., exposure to cocaine, amphetamine, morphine or nic- 2002; Kasai et al., 2003; Lamprecht andLeDoux, otine, in adult rats, whether administered by an 2004), andtherefore, they providean obvious focus of experimenter (EA) or self-administered (SA), have study in trying to understand how experiences can alter long-lasting effects on the structure of dendrites and brain organization to produce life-long changes in dendritic spines in brain regions thought to mediate behavior andpsychological function. drug-induced changes in incentive motivation and Nearly all research on structural plasticity in the reward(such as the nucleus accumbens; Acb) andin brain has involvedhow learning ( Greenough and cognitive function (such as the prefrontal cortex; PFC). Bailey, 1988; Andersen and Trommald, 1995; Kolb and The purpose of this paper is to summarize what we Whishaw, 1998; Lamprecht andLeDoux, 2004 ), long- have learnedthus far. term potentiation (Andersen and Soleng, 1998; Yuste andBonhoeffer, 2001 ), stress (McEwen, 2000; Vyas et al., 2002), environmental manipulations (Greenough 2. The method et al., 1990; van Praag et al., 2000), recovery of function (Kolb andWhishaw, 1998 ), changes in the A common approach to examine the impact hormonal milieu (Woolley, 1999; Leranth et al., 2003), of experience on synaptic organization is to use pathological states (Fiala et al., 2002), etc., change Golgi-stainedmaterial to quantify the structure of den- synapses or dendritic structure. But one of the most drites and the density of dendritic spines (Greenough, compelling examples of experience-dependent plas- 1984; Greenough et al., 1990; Kolb et al., 1998) and ticity, whereby experience at one point in life changes that is the methodusedin most of the studies summar- behavior andpsychological function for a lifetime, is ized here. In all cases, the structure of dendrites or the addiction. The propensity of addicts to relapse, even density of spines on neurons was quantified using one months to many years after the discontinuation of drug of three measures (Greenough andChang, 1985; Kolb use, andlong after withdrawalsymptoms have sub- andWhishaw, 1998 ). (1) Total dendritic length was sided, provides stark evidence that drug use has long- estimatedby counting the number of ring intersections lasting consequences for behavior andpsychological using an overlay of concentric rings (Sholl, 1981). (2) function. Similarly, very long-lasting changes in The total number of dendritic branches (indicated by behavior produced by repeated exposure to drugs of bifurcations) was countedat each orderaway from the abuse have been described in controlled animal studies, cell body (Coleman andRiesen, 1968 ). (3) Spine den- as exemplified, for example, by phenomena like sity was estimated along a specific segment of dendrite behavioral sensitization (Robinson andBecker, 1986 ). by tracing the dendritic segment, calculating its exact Repeatedintermittent exposure to a variety of drugs of length, andcounting the number of spines along that abuse can produce a hypersensitivity (sensitization) to length (to yieldspines/10 lm). In some experiments, their psychomotor activating andincentive motiva- the frequency of branchedspines (i.e., spines with mul- tional effects that can persist for months to years after tiple heads) was also quantified (Comery et al., 1996). the discontinuation of drug treatment (Paulson et al., There are, of course, limitations in interpreting chan- 1991; Robinson andBerridge, 2003 ). ges in dendritic structure estimated from Golgi material The behavioral evidence leaves no doubt that drugs that need to be kept in mind. This