BRITISH JOURNAL OF PSYCHIATRY (2003), 182, 97^100 EDITORIAL partial agonist, this drug 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 drugs 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 cocaine, 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 brain, 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- nature remains to be characterised. The Glutamate is the brain’s principal theless, memantine is a non-competitive most potent cannabinoid in cannabis 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 effects of cannabis 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 stimulant-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