BRITISH JOURNAL OF (2003), 182, 97^100 EDITORIAL

partial agonist, this stimulates the D Neurobiology of addiction and implications 33 receptor enough to keep withdrawal at for treatment bay, but not enough to cause a ‘high’ or to be rewarding. It is currently in phase 1 trials. One drug that affects the dopaminergic ANNE LINGFORD-HUGHES and DAVID NUTT system and has proven efficacy in the treat- ment of nicotine addiction is bupropion (Jorenby(Jorenby et aletal, 1999). The exact mechanism underlying this effect still has to be fully characterised; however, it has been shown that bupropion increases dopamine and noradrenaline levels by acting as an uptake Drug and alcohol misuse result in immense withdrawal as well. In an elegant series of inhibitor (Ascher et aletal, 1995).,1995). harm at both individual and societal level. experiments, Schultz (2001) found that in Our understanding of the neuropharma- primates trained to associate a cue with a cology of these disorders is increasing pleasurable experience (food), increased Related systems involved in reward through the use of approaches such as dopaminergic activity was seen in response Our understanding of other neurotrans- neuroimaging and gene targeting and the to the cue and not to the food. If the food mitter systems that are involved in reward availability of specific receptor agonists was not then presented, dopaminergic and that may modulate dopaminergic and antagonists. Our aim here is to describe function dropped. Reduced dopaminergic activity provides further targets for some interesting new findings that are function is thought to be associated with pharmacotherapy. likely to inform advances in treatment. negative affect (e.g. dysphoria). Thus, an individual with an addiction may see a ‘cue’ (e.g. a public house, mirror or needle) OpioidsOpioids THE DOPAMINERGIC and if their drug of choice is not available The opioid system has three receptor PATHWAY may feel dysphoric, which is likely to in- subtypes: mu, kappa and delta. The mu Reward crease the drive to obtain the drug. subtype appears to be key in opiate Over the past 20 years there has been addiction: for mice lacking this receptor, immense interest in the mesolimbic dopami- Withdrawal morphine is no longer rewarding or reinfor- cing (Kieffer, 1999). In addition, a mor- nergic system; most of misuse (except Reduced dopaminergic function has been phine withdrawal syndrome is not seen in benzodiazepines) increase dopamine here. It seen in withdrawal and early abstinence these animals. Neuroimaging studies sug- is widely accepted that increased levels of from many drugs of misuse. Neuroimaging gest that alterations in mu opiate receptor dopamine in the nucleus accumbens are studies in , opiate and alcohol levels may be fundamental to addiction. key in mediating the rewarding effects or addictions have revealed reduced levels of Using [Using[1111C]-carfentanil positron emission positive reinforcement of drugs of misuse dopamine D receptors, which may recover 22 tomography (PET) to label mu opiate (Koob & Le Moal, 2001). Evidence is still to some extent during abstinence, but have receptors in the , Zubieta et aletal accruing to support this. For instance, alco- been shown to persist for months (Volkow (2000) found increased receptor levels in hol and morphine are no longer rewarding et aletal, 1999). Early stages of abstinence are the anterior cingulate in recently abstinent in mice lacking the D22 receptor (D22 knock-knock- associated with elevated levels of craving, humans addicted to cocaine or opiates. This out mice; Maldonado et aletal, 1997; Risinger drug-seeking and risk of relapse, and it is may reflect elevated mu opiate receptor et aletal, 2000). In humans, Volkow et aletal likely that hypodopaminergic function levels or decreased endogenous opioid (1999) showed in a series of neuroimaging plays a mediating role. Presumably the levels. In either case, craving may result. studies using cocaine or methylphenidate release of dopamine produced by the drug Roles for kappa and delta opiate recep- that increased dopamine levels in the brain of choice provides relief from withdrawal, tors in addiction are also evident. Unlike were associated with euphoria and pleasure. although this has not yet been studied. mu receptors, kappa receptor stimulation Interestingly, low levels of dopamine D22 receptors were associated with pleasure reduces dopamine function in the nucleus Pharmacotherapy (Table 1) after methylphenidate in drug-naıdrug-naıve¨ve indivi- accumbens. This may possibly result in dys- duals, whereas high receptor levels were Because of the pre-eminence of the dopa- phoria. In animal models, delta antagonists associated with unpleasant feelings. This minergic reward system in addiction, this can reduce self-administration of alcohol, study gives us an insight into the role of has been a target for pharmacotherapy, suggesting that this receptor also plays a neurobiology in explaining why drug use but with mixed results. One strategy, for key role in reinforcement. for some people is pleasurable and likely instance, has been to block the binding of Naltrexone is a long-acting opiate to be repeated and for others is unpleasant cocaine to the dopamine transporter site antagonist. Its use in opiate addiction is and not repeated. (Nutt, 1993). In cocaine addiction, the de- based on its ability to antagonise any effects velopment of dopaminergic partial agonists of opiates. However, in alcoholism the effi-

at the DDatthe 33 receptor, such as BP–897, cacy of naltrexone is thought to be a con- Anticipation currently holds some promise. In rats, BP– sequence of its ability to block the actions The role of dopamine in addiction is now 897 inhibits cocaine-seeking behaviour in of endorphins that are released by alcohol recognised as critical in anticipation and response to cues (Pilla et aletal, 1999). As a and that mediate pleasure (Herz, 1997).

97

Downloaded from https://www.cambridge.org/core. 01 Oct 2021 at 00:34:42, subject to the Cambridge Core terms of use. LINGFORDLINGFORD-HUGHES -HUGHES & NUTT

Glutamate useful, owing to their psychomimetic prop- drug addiction, although their precise erties (cf. ketamine, phencyclidine). Never- remains to be characterised. The Glutamate is the brain’s principal theless, memantine is a non-competitive most potent cannabinoid in excitatory neurotransmitter for which NMDA receptor antagonist, used to treat isis DD99-tetrahydrocannabinol (DD99-THC)-THC) there are three receptors – the ion channels neurological disorders, which has recently (Ashton, 2001). Cannabinoids have been NN-methyl--methyl-DD-aspartate (NMDA), alpha- been shown to attenuate naloxone-precipi- shown to increase opioid synthesis and/or amino-3-hydroxy-5-meamino-3-hydroxy-5-methyl-isoxazole-4-thyl-isoxazole-4- tated withdrawal in humans addicted to release (Manzanares et aletal, 1999). This propionate (AMPA) and kainate – and also opiates (Bisaga et aletal, 2001).,2001). may explain why opiate antagonists block another receptor family which is coupled to There is recent evidence to suggest an some and induce with- G-proteins and the second (metabotropic) important role for other glutamate recep- drawal indrawalin DD99-THC-dependent rats or, messenger system. Glutamatergic neurons tors, such as the metabotropic receptor, conversely, why marijuana may reduce from the prefrontal cortex and amygdala that may be independent of the dopa- opiate withdrawal. project onto the mesolimbic reward minergic system. In mice lacking the mGlu5 There are two cannabinoid receptors:

pathway, from which reciprocal dopa- subtype of the metabotropic glutamatergic CBCB11 in the brain, for which the endogenous

minergic projections arise (Louk et aletal,, receptor, cocaine still increases dopamine compound is anandamide, and CB22 onon

2000). There is evidence that the glutama- in the nucleus accumbens; but the mice do immune cells. CB11 receptors are widely tergic projection from the prefrontal cortex not self-administer cocaine or show distributed throughout the brain, but to the nucleus accumbens plays a role inrolein increased locomotor activity (Chiamulera particularly in the cerebral cortex, hippo- the reinstatement of -seekingseekingstimulant- et aletal, 2001).,2001). campus, cerebellum, thalamus and basal behaviour.behaviour. ganglia (Ameri, 1999). In mice lacking the

The NMDA receptor has been impli- CBCB11 receptor, rewarding and withdrawal cated in nicotine, ethanol, benzodiazepine Cannabinoids responses to morphine and cannabinoids and cannabinoid addiction (Wolf, 1998). Opioids and cannabinoids share some but not to cocaine are reduced (Ledent For example, NMDA antagonists inhibit pharmacological properties producing et aletal, 1999; Martin et aletal, 2000). This sug-

sensitisation (i.e. enhanced responses) to sti- effects such as sedation, hypothermia gests that the CB11 receptor is involved in de- mulants such as cocaine and amphetamine and anti-nociception. In addition, there is pendence on not only cannabinoids but also

and the development of opioid dependence. increasing recognition that opiate– opiates. As a result, CB11 agonists may have Not all NMDA antagonists are clinically cannabinoid interactions are important in clinical utility in treating opiate addiction.

Ta b l e 1 Molecular targets of drugs of misuse and pharmacological approaches (current and theoretical) directed at these

DrugPrimary targetMain effects/ Other actionsSubstitution therapyPartial agonistsAntagonists/ transmitters blockers

Opiates Mu opiate ? Inc. dopamineKappa and delta opiate MethadoneMethadone BuprenorphineNaltrexone receptorsreceptors receptorsreceptors Buprenorphine NaloxoneNaloxone Nalmefene33 StimulantsStimulants 11 11 11 CocaineDAT Inc. dopamineLocal anaesthetic Bupropion DD33 ligands (BP-897) GR12909 Inc. 5-HT 11 11 11 AmphetaminesDAT Inc. dopamine?NA/5-HT release BupropionBupropion DD33 ligands (BP-897) DD33 receptor drugs NicotineNicotineNicotinic ACH Inc. dopamineNicotine (patches Mecamylamine11 receptorreceptor etc.)etc.) Sedatives AlcoholAlcoholGABA/glutamate Inc. GABA Many other systemsBDZs 22 BDZ partial agonists11 Acamprosate44 Dec. glutamate Naltrexone44 11 BDZs GABAGABA Inc. GABA Long tt1/2 BDZsBDZ partial agonists Flumazenil GHB GABA ?Inc. GABAInc. dopamine BDZs11 BDZ partial agonists11 NoneNone SolventsNot known?Dec. glutamate? membrane changesNone NoneNone NoneNone 11 CannabisCB 11 receptors? dopamineNone None SR141716ASR141716A ?opiates?opiates EcstasyEcstasy 5-HT transporterInc. 5-HTSome DA release alsoSSRIs 11 5-HT drugsdrugs5-HT 11 SSRIs11 11 LSD5-HT 22 receptorsInc. 5-HT None 5-HT drugs 5-HT5-HT22 antagonists

BDZs, benzodiazepines; GHB, gamma-hydroxybutyrate; LSD, lysergic acid diethylamide; DAT, dopamine transporter; ACH, acetylcholine; GABA, gammgamma-aminobutyrica-aminobutyric acid; 5-HT, 5-hydroxytryptamine; Inc., increase in levels or function; Dec., decrease in levels or function; NA, noradrenaline; DA, dopamine; SSRIs, selectiveserotoninreuptakeinhibitors.e serotonin reuptake inhibitors. 1. Theoretically effective but no clinical trial data. 2. Controversial, risk of dependency. 3. Not available in UK. 4. Used to maintain abstinence.

98

Downloaded from https://www.cambridge.org/core. 01 Oct 2021 at 00:34:42, subject to the Cambridge Core terms of use. NEUROBIOLOGY OF ADDICTION AND IMPLICATIONS FOR TREATMENT

The development of a CB11 receptorreceptor ) is a full agonist at the mu receptor, the action of GABA, and so result in greater antagonist, SR141716A (Rinaldi-Carmona whereas buprenorphine is a mu partial inhibitory activity in the brain (Nutt & et aletal, 1995), not only accelerated research agonist. Partial agonists give lower levels Malizia, 2001). In contrast to other drugs into cannabinoids but also provided a poss- of response at maximal receptor occu- of misuse, benzodiazepinesbenzodiazepines do not increase ible treatment. This antagonist blocks both pancy. Also, when a partial agonist occu- dopamine releasein the mesolimbic sys- the physiological and psychological effects pies receptors, fewer are available for a tem. Misuse of these drugs is probably dri- of smoked marijuana and therefore could full agonist (e.g. heroin). The partial ago- ven by the development of tolerance be to cannabis what naltrexone is to heroin. nist is therefore acting as an antagonist. leading to withdrawal if these drugs are Consequently, buprenorphine will stimu- not taken. Benzodiazepine dependence in late the mu opioid receptor, but not maxi- the context of drug addiction, where large ALCOHOL WITHDRAWAL: mally (hence, there is less risk of doses of benzodiazepines are taken, is dis- THE ROLE OF GLUTAMATE respiratory depression in overdose), and tinct from dependence in the context of will also prevent the effects of heroin taken long-term use of a prescribed benzodiaze- The neurobiology of alcoholism involves ‘on top’. In addition, its longer half-life al- pine for . many different neurotransmitters, but key lows less than daily dosing, an advantage Gamma-hydroxybutyrate (GHB) is a are the gamma-aminobutyric acid (GABA)- in supervised consumption. short-chain fatty acid which, among other ergic system and the glutamatergic system effects, enhances GABAergic function. (Nutt, 1999). In alcohol withdrawal, GHB inhibits central nervous system activ- increased glutamatergic NMDA function ECSTASY:THE 5-HT SYSTEM ity and is a sedative but is also euphori- is present and is thought to be involved in AND NEUROTOXICITY genic, presumably being linked to an seizures and cell death, by means of increase in dopamine (Nicholson & Balster, increased Ca2+2+ influx through its channel Ecstasy (3,4-methylenedioxymethampheta- 2001). It is increasingly used as a ‘recrea- and low Mg2+2+. The hippocampus appears mine or MDMA) and its derivatives MDA tional club drug’ and there is growing con- to be a critical site for such glutamatergic (Adam) and MDEA (Eve) have both cern about its safety, particularly when hyperactivity. Acamprosate, a taurine deri- stimulant and hallucinogenic properties. combined with alcohol to render women vative, is increasingly used to maintain Acutely, MDMA increases 5-hydroxytryp- vulnerable to sexual assault. abstinence from alcohol as it has been tamine (5-HT or serotonin) levels, and, shown to double abstinence rates. How to a lesser extent, dopamine levels, by acamprosate achieves its therapeutic effect stimulating release and inhibiting uptake. CONCLUSION has not yet been fully characterised; it Animal studies have revealed ecstasy antagonises the NMDA receptor (possibly and its derivatives to be neurotoxic to This is an exciting time in addiction as the through the polyamine site). Acamprosate serotonergic neurons (MDA44MDMAMDMA44 neurobiology of addiction disorders be- also reduces glutamate levels and may be MDEA), but it is controversial whether and comes clearer. Such characterisation not neuroprotective (Dahchour & De Witte, to what extent the same occurs in man (Boot only provides a greater understanding of 2000). If such neuroprotection occurs in et aletal, 2000). Neuroimaging studies using why people become addicted and what humans, this would have important impli- PET and single photon emission tomo- happens to the brain after a period of sub- cations for the treatment of alcoholism; graphy (SPET) to measure 5-HT trans- stance misuse, but also allows better under- currently some workers advocate starting porter levels in persons who are regular standing of current pharmacotherapies and, acamprosate with detoxification. heavy ecstasy users report reduced levels. we hope, the development of new treat- However, methodological questions about ments.ments. the tracer, contribution of blood flow and OPIOID DEPENDENCEDEPENDENCE: : choice of subjects necessarily limit these DECLARATIONOF INTEREST WHAT OTHER conclusions (Semple et aletal, 1999; Reneman NEUROTRANSMITNEUROTRANSMITTER TER et aletal, 2001). There is some evidence for cog- A.L.-H. is a member of UK Alcohol Forum, SYSTEMS ARE INVOLVED? nitive impairments in individuals using which receives a foundation grant from ecstasy which may persist after a period of Merck-Lipha (manufacturers of acampro- As described above, the mu opiate receptor chronic use, and it is not clear how reversible sate) and has received honoraria from a plays a key role in opiate reward, but many these are with time. In animal models, fluox- number of pharmaceutical companies to of the mechanisms underlying opiate toler- etine has been shown to be neuroprotective, attend conferences, for lecturing and for ance, dependence and withdrawal remain apparently by blocking ecstasy uptake into consultancy. D.N. has received honoraria elusive. As the opiate receptor may not 5-HT neurons, but it is unknown whether from Britannia, GlaxoSmithKline, Merck- change with chronic opiate exposure, this protective effect occurs in humans. Lipha and Reckitt & Coleman for lectures changes ‘downstream’ of the receptor may and consultancy. be more critical. For example, noradrener- gic overactivity is seen in opiate withdrawal THE GABAERGIC SYSTEM: REFERENCES and can be treated with aa22 agonists such as TARGET FOR SEDATIVES lofexidine or clonidine (Strang et aletal, 1999).,1999). Ameri, A.(19 (1999) 9 9) The effects of cannabinoids on the In the treatment of opiate addiction, The most widely misused group of drugs brain. Progress in Neurobiology,, 5858,315^348., 315^348. methadone is the most commonly pre- acting on this system are the Ascher, J. A., Cole, J. O., Colin, J. N., et aletal (19 995) 5) scribed drug, although the use of buprenor- benzodiazepines. These modulate the Bupropion: a review of its mechanism of phine is increasing. Methadone (like GABA–benzodiazepine receptor, increasing activity. Journal of Clinical Psychiatry,, 5656, 395^401.,395^401.

9999

Downloaded from https://www.cambridge.org/core. 01 Oct 2021 at 00:34:42, subject to the Cambridge Core terms of use. LINGFORDLINGFORD-HUGHES -HUGHES & NUTT

Ashton, C. H.(2001) Pharmacology and effects of cannabis: a brief review. British Journal of Psychiatry,, 178178,, ANNE LINGFORD-HUGHES, MRCPsych, DAVID NUTT,FRCPsych, School of Medical Science,University of 101^106. Bristol, UK

Bisaga, A.,Comer,A., Comer, S. D.,Ward, A. S., et aletal (2001)(2001) The CorrespCorrespondence:ondence: Dr Anne Lingford-Hughes,PsychopharmacologyLingford-Hughes,Psychopharmacology Unit, School of Medical Science, NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. ,Bristol BS8 1TD,UK.Tel: 0117 925 3066; fax: 0117 927 7057; e-mail: anne.lingford- Psychopharmacology (Berl),, 157157,1^10. hugheshughes@@bristol.ac.uk

Boot, B. P., McGregor, I. S. & Hall,W.(2000) MDMAMDMA (First received 22 January 2002, final revision 22 May 2002, accepted 29 May 2002) (Ecstasy) neurotoxicity: assessing and communicating the risks. Lancet,, 355,1818^1821.

Chiamulera, C., Epping-Jordan, M. P., Zocchi, A., etet al (2001)(2001) Reinforcing and locomotor stimulant effects of Manzanares, J., Corchero, J., Romero, J., et aletal (1999)(19 9 9) Rinaldi-Carmona, M., Barth, F., Heaulme, M., et aletal cocaine are absent in mGluR5 null mutant mice. Nature Pharmacological and biochemical interactions between (19 95) Biochemical and pharmacological Neuroscience,, 44,873^874. opioids and cannabinoids. Trends in Pharmacological characterisation of SR141716A, the first potent and Dahchour, A. & De Witte, P.(2000) Ethanol andandEthanol Sciences,, 20, 287^294. selective brain cannabinoid receptor antagonist. Life amino acids in the central nervous system: assessment of Sciences,, 5656,1941^1947. the pharmacological actions of acamprosate. Progress in Martin, M., Ledent, C., Parmentier, M., et aletal (2000) Risinger, F.O.,F. O., Freeman, P. A., Rubinstein, M., et al Neurobiology,, 60, 343^362. Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in (2000)(2000) Lack of operant ethanol self-administration in Herz, A.(19 997) 7) Endogenous opioid systems and CB1 knockout mice. European Journal of Neuroscience,, 12,, dopamine D2 receptor knockout mice. alcohol addiction. Psychopharmacology,, 129, 99^111.9 9 ^ 111. 4038^4046. Psychopharmacology (Berl),, 152, 343^350.

Jorenby, D. E., Leischow, S. J., Nides, M. A., et aletal Nicholson, K. L. & Balster, R. L. (2001)(2001) GHB: a new Schultz,W.(2001) Reward signaling by dopamine (19(1999) 9 9) A controlled trial of sustained-release bupropion, and novel drug of abuse. Drug and Alcohol Dependence,, neurons.neurons. Neuroscientist,, 77,,293^302. 293^302. a nicotine patch, or both for smoking cessation. New 6363,1^22. Semple, D. M., Ebmeier, K. P., Glabus, M. F., et al England Journal of Medicine,, 340340, 685^691.,685^691. (1999)(1999) Reduced in vivoinvivo binding to the serotonin Nutt,Nutt , D.(19 93) Neurochemistry of drugs other than transporter in the cerebral cortex of MDMA (‘ecstasy’) Kieffer, B. L.(1999) Opioids: first lessons from alcohol.alcohol. Current Opinion in Psychiatry,, 66, 395^402.,395^402. knockout mice. Trends in Pharmacological Sciences,, 2020,, users.users. British Journal of Psychiatry,, 175175,,63^69. 63^69.

19^26. __ (1999)(19 9 9) Alcohol and the brain. Pharmacological Strang, J., Bearn, J. & Gossop, M.(1999) LofexidineLofexidine insights for psychiatrists. British Journal of Psychiatry,, 175175,, Koob, G. F. & Le Moal, M.(2001) Drug addiction, for opiate detoxification: review of recent randomised 114114^119. ^ 119. dysregulation of reward, and allostastis. and open controlled trials. American Journal on ,, 24,97^129. Addictions,, 88, 337^348.,337^348. __ &Malizia,A.L.(2001)New insights into the role Ledent, C.,Valverde,C.,Valverde,O.,Cossu, O., Cossu, G., et aletal (19(1999) 9 9) of the GABAAA^^benzodiazepine benzodiazepine receptor in psychiatric Volkow, N. D., Fowler, J. S. & Wang, G. J.(19 (1999) 9 9) Unresponsiveness to cannabinoids and reduced disorder.disorder. British Journal of Psychiatry,, 179179, 390^396.,390^396. Imaging studies on the role of dopamine in cocaine addictive effects of opiates in CB1receptor knockout reinforcement and addiction in humans. Journal of Pilla, M., Perachon, S., Sautel, F., et aletal (1999)(19 9 9) mice. Science,, 283, 401^404.,401^404. Psychopharmacology,, 1313, 337^345. Selective inhibition of cocaine-seeking behaviour by a Louk, J. M. J.,Vanderschuren, L. J. & Kalivas, P.W. partial dopamine D3 receptor agonist. Nature,, 400400,, Wolf,Wolf,M.E. M. E.(19 (1998) 9 8) The role of excitatory amino acids in (2000)(2000) Alterations in dopaminergic and glutamatergic 371^375. behavioral sensitization to psychomotor . transmission in the induction and expression of Progress in Neurobiology,, 5454, 679^720. behavioral sensitization: a critical review of preclinical Reneman, L., Lavalaye, J., Schmand, B., et aletal (2001)(2001) studies.studies. Psychopharmacology (Berl),, 151151, 99^120.,99^120. Cortical serotonin transporter density and verbal Zubieta, J., Greenwald, M. K., Lombardi,U., et aletal memory in individuals who stopped using 3,4 - (2000)(2000) Buprenorphine-induced changes in mu-opioid Maldonado, R., Saiardi, A.,Valverde, O., et aletal (19 9 7) methylenedioxymethamphetamine (MDMA or receptor availability in male heroin-dependent Absence of opiate rewarding effects in mice lacking ‘‘ecstasy’’): preliminary findings. Archives of General volunteers: a preliminary study. Neuropsycho- dopamine D2 receptors. Nature,, 388388, 586^589. PsychiatryPsychiatry,, 5858, 901^906. pharmacology,, 2323, 326^334.,326^334.

100

Downloaded from https://www.cambridge.org/core. 01 Oct 2021 at 00:34:42, subject to the Cambridge Core terms of use.