School of Medical Science, University of Bristol, UK
Correspondence: Dr Anne Lingford-Hughes, Psychopharmacology Unit, School of Medical Science, University of Bristol, Bristol BS8 1TD, UK. Tel: 0117 925 3066; fax: 0117 927 7057; e-mail: anne.lingford-hughes{at}bristol.ac.uk
A.L.-H. is a member of UK Alcohol Forum, which receives a foundation grant from Merck-Lipha (manufacturers of acamprosate) and has received honoraria from a number of pharmaceutical companies to attend conferences, for lecturing and for consultancy. D.N. has received honoraria from Britannia, GlaxoSmithKline, Merck-Lipha and Reckitt & Coleman for lectures and consultancy.
Drug and alcohol misuse result in immense harm at both individual and societal level. Our understanding of the neuropharmacology of these disorders is increasing through the use of approaches such as neuroimaging and gene targeting and the availability of specific receptor agonists and antagonists. Our aim here is to describe some interesting new findings that are likely to inform advances in treatment.
THE DOPAMINERGIC PATHWAY
Reward
Over the past 20 years there has been immense interest in the mesolimbic
dopaminergic system; most drugs of misuse (except benzodiazepines) increase
dopamine here. It is widely accepted that increased levels of dopamine in the
nucleus accumbens are key in mediating the rewarding effects or positive
reinforcement of drugs of misuse (Koob
& Le Moal, 2001). Evidence is still accruing to support this.
For instance, alcohol and morphine are no longer rewarding in mice lacking the
D2 receptor (D2 knockout mice;
Maldonado et al,
1997; Risinger et al,
2000). In humans, Volkow et al
(1999) showed in a series of
neuroimaging studies using cocaine or methylphenidate that increased dopamine
levels in the brain were associated with euphoria and pleasure. Interestingly,
low levels of dopamine D2 receptors were associated with pleasure
after methylphenidate in drug-naïve individuals, whereas high receptor
levels were associated with unpleasant feelings. This study gives us an
insight into the role of neurobiology in explaining why drug use for some
people is pleasurable and likely to be repeated and for others is unpleasant
and not repeated.
Anticipation
The role of dopamine in addiction is now recognised as critical in
anticipation and withdrawal as well. In an elegant series of experiments,
Schultz (2001) found that in
primates trained to associate a cue with a pleasurable experience (food),
increased dopaminergic activity was seen in response to the cue and not to the
food. If the food was not then presented, dopaminergic function dropped.
Reduced dopaminergic function is thought to be associated with negative affect
(e.g. dysphoria). Thus, an individual with an addiction may see a
cue (e.g. a public house, mirror or needle) and if their drug of
choice is not available may feel dysphoric, which is likely to increase the
drive to obtain the drug.
Withdrawal
Reduced dopaminergic function has been seen in withdrawal and early
abstinence from many drugs of misuse. Neuroimaging studies in cocaine, opiate
and alcohol addictions have revealed reduced levels of dopamine D2
receptors, which may recover to some extent during abstinence, but have been
shown to persist for months (Volkow et
al, 1999). Early stages of abstinence are associated with
elevated levels of craving, drug-seeking and risk of relapse, and it is likely
that hypodopaminergic function plays a mediating role. Presumably the release
of dopamine produced by the drug of choice provides relief from withdrawal,
although this has not yet been studied.
Pharmacotherapy (Table
1)
Because of the pre-eminence of the dopaminergic reward system in addiction,
this has been a target for pharmacotherapy, but with mixed results. One
strategy, for instance, has been to block the binding of cocaine to the
dopamine transporter site (Nutt,
1993). In cocaine addiction, the development of dopaminergic
partial agonists at the D3 receptor, such as BP-897, currently
holds some promise. In rats, BP-897 inhibits cocaine-seeking behaviour in
response to cues (Pilla et al,
1999). As a partial agonist, this drug stimulates the
D3 receptor enough to keep withdrawal at 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 system and has proven efficacy in the treatment of nicotine addiction is bupropion (Jorenby et al, 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 inhibitor (Ascher et al, 1995).
Related systems involved in reward
Our understanding of other neurotransmitter systems that are involved in
reward and that may modulate dopaminergic activity provides further targets
for pharmacotherapy.
Opioids
The opioid system has three receptor subtypes: mu, kappa and delta. The mu
subtype appears to be key in opiate addiction: for mice lacking this receptor,
morphine is no longer rewarding or reinforcing
(Kieffer, 1999). In addition,
a morphine withdrawal syndrome is not seen in these animals. Neuroimaging
studies suggest that alterations in mu opiate receptor levels may be
fundamental to addiction. Using [11C]-carfentanil positron emission
tomography (PET) to label mu opiate receptors in the brain, Zubieta et
al (2000) found increased
receptor levels in the anterior cingulate in recently abstinent humans
addicted to cocaine or opiates. This may reflect elevated mu opiate receptor
levels or decreased endogenous opioid levels. In either case, craving may
result.
Roles for kappa and delta opiate receptors in addiction are also evident. Unlike mu receptors, kappa receptor stimulation reduces dopamine function in the nucleus accumbens. This may possibly result in dysphoria. In animal models, delta antagonists can reduce self-administration of alcohol, suggesting that this receptor also plays a key role in reinforcement.
Naltrexone is a long-acting opiate antagonist. Its use in opiate addiction is based on its ability to antagonise any effects of opiates. However, in alcoholism the efficacy of naltrexone is thought to be a consequence of its ability to block the actions of endorphins that are released by alcohol and that mediate pleasure (Herz, 1997).
Glutamate
Glutamate is the brain's principal excitatory neurotransmitter for which
there are three receptors the ion channels
N-methyl-D-aspartate (NMDA),
alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and kainate
and also another receptor family which is coupled to G-proteins and
the second (metabotropic) messenger system. Glutamatergic neurons from the
prefrontal cortex and amygdala project onto the mesolimbic reward pathway,
from which reciprocal dopaminergic projections arise
(Louk et al, 2000). There is evidence that the glutamatergic projection from the prefrontal cortex
to the nucleus accumbens plays a role in the reinstatement of
stimulant-seeking behaviour.
The NMDA receptor has been implicated in nicotine, ethanol, benzodiazepine and cannabinoid addiction (Wolf, 1998). For example, NMDA antagonists inhibit sensitisation (i.e. enhanced responses) to stimulants such as cocaine and amphetamine and the development of opioid dependence. Not all NMDA antagonists are clinically useful, owing to their psychomimetic properties (cf. ketamine, phencyclidine). Nevertheless, memantine is a non-competitive NMDA receptor antagonist, used to treat neurological disorders, which has recently been shown to attenuate naloxone-precipitated withdrawal in humans addicted to opiates (Bisaga et al, 2001).
There is recent evidence to suggest an important role for other glutamate receptors, such as the metabotropic receptor, that may be independent of the dopaminergic system. In mice lacking the mGlu5 subtype of the metabotropic glutamatergic receptor, cocaine still increases dopamine in the nucleus accumbens; but the mice do not self-administer cocaine or show increased locomotor activity (Chiamulera et al, 2001).
Cannabinoids
Opioids and cannabinoids share some pharmacological properties producing
effects such as sedation, hypothermia and anti-nociception. In addition, there
is increasing recognition that opiatecannabinoid interactions are
important in drug addiction, although their precise nature remains to be
characterised. The most potent cannabinoid in cannabis is
9-tetrahydrocannabinol (
9-THC)
(Ashton, 2001). Cannabinoids
have been shown to increase opioid synthesis and/or release
(Manzanares et al,
1999). This may explain why opiate antagonists block some effects
of cannabis and induce withdrawal in
9-THC-dependent rats
or, conversely, why marijuana may reduce opiate withdrawal.
There are two cannabinoid receptors: CB1 in the brain, for which the endogenous compound is anandamide, and CB2 on immune cells. CB1 receptors are widely distributed throughout the brain, but particularly in the cerebral cortex, hippocampus, cerebellum, thalamus and basal ganglia (Ameri, 1999). In mice lacking the CB1 receptor, rewarding and withdrawal responses to morphine and cannabinoids but not to cocaine are reduced (Ledent et al, 1999; Martin et al, 2000). This suggests that the CB1 receptor is involved in dependence on not only cannabinoids but also opiates. As a result, CB1 agonists may have clinical utility in treating opiate addiction.
The development of a CB1 receptor antagonist, SR141716A (Rinaldi-Carmona et al, 1995), not only accelerated research into cannabinoids but also provided a possible treatment. This antagonist blocks both the physiological and psychological effects of smoked marijuana and therefore could be to cannabis what naltrexone is to heroin.
ALCOHOL WITHDRAWAL: THE ROLE OF GLUTAMATE
The neurobiology of alcoholism involves many different neurotransmitters, but key are the gamma-aminobutyric acid (GABA)-ergic system and the glutamatergic system (Nutt, 1999). In alcohol withdrawal, increased glutamatergic NMDA function is present and is thought to be involved in seizures and cell death, by means of increased Ca2+ influx through its channel and low Mg2+. The hippocampus appears to be a critical site for such glutamatergic hyperactivity. Acamprosate, a taurine derivative, is increasingly used to maintain abstinence from alcohol as it has been shown to double abstinence rates. How acamprosate achieves its therapeutic effect has not yet been fully characterised; it antagonises the NMDA receptor (possibly through the polyamine site). Acamprosate also reduces glutamate levels and may be neuroprotective (Dahchour & De Witte, 2000). If such neuroprotection occurs in humans, this would have important implications for the treatment of alcoholism; currently some workers advocate starting acamprosate with detoxification.
OPIOID DEPENDENCE: WHAT OTHER NEUROTRANSMITTER SYSTEMS ARE INVOLVED?
As described above, the mu opiate receptor plays a key role in opiate
reward, but many of the mechanisms underlying opiate tolerance, dependence and
withdrawal remain elusive. As the opiate receptor may not change with chronic
opiate exposure, changes downstream of the receptor may be more
critical. For example, noradrenergic overactivity is seen in opiate withdrawal
and can be treated with 2 agonists such as lofexidine or
clonidine (Strang et al,
1999).
In the treatment of opiate addiction, methadone is the most commonly prescribed drug, although the use of buprenorphine is increasing. Methadone (like heroin) is a full agonist at the mu receptor, whereas buprenorphine is a mu partial agonist. Partial agonists give lower levels of response at maximal receptor occupancy. Also, when a partial agonist occupies receptors, fewer are available for a full agonist (e.g. heroin). The partial agonist is therefore acting as an antagonist. Consequently, buprenorphine will stimulate the mu opioid receptor, but not maximally (hence, there is less risk of respiratory depression in overdose), and will also prevent the effects of heroin taken on top. In addition, its longer half-life allows less than daily dosing, an advantage in supervised consumption.
ECSTASY: THE 5-HT SYSTEM AND NEUROTOXICITY
Ecstasy (3,4-methylenedioxymethamphetamine or MDMA) and its derivatives MDA (Adam) and MDEA (Eve) have both stimulant and hallucinogenic properties. Acutely, MDMA increases 5-hydroxytryptamine (5-HT or serotonin) levels, and, to a lesser extent, dopamine levels, by stimulating release and inhibiting uptake.
Animal studies have revealed ecstasy and its derivatives to be neurotoxic to serotonergic neurons (MDA>MDMA>MDEA), but it is controversial whether and to what extent the same occurs in man (Boot et al, 2000). Neuroimaging studies using PET and single photon emission tomography (SPET) to measure 5-HT transporter levels in persons who are regular heavy ecstasy users report reduced levels. However, methodological questions about the tracer, contribution of blood flow and choice of subjects necessarily limit these conclusions (Semple et al, 1999; Reneman et al, 2001). There is some evidence for cognitive impairments in individuals using ecstasy which may persist after a period of chronic use, and it is not clear how reversible these are with time. In animal models, fluoxetine has been shown to be neuroprotective, apparently by blocking ecstasy uptake into 5-HT neurons, but it is unknown whether this protective effect occurs in humans.
THE GABAERGIC SYSTEM: TARGET FOR SEDATIVES
The most widely misused group of drugs acting on this system are the benzodiazepines. These modulate the GABAbenzodiazepine receptor, increasing the action of GABA, and so result in greater inhibitory activity in the brain (Nutt & Malizia, 2001). In contrast to other drugs of misuse, benzodiazepines do not increase dopamine release in the mesolimbic system. Misuse of these drugs is probably driven by the development of tolerance leading to withdrawal if these drugs are not taken. Benzodiazepine dependence in the context of drug addiction, where large doses of benzodiazepines are taken, is distinct from dependence in the context of long-term use of a prescribed benzodiazepine for anxiety.
Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid which, among other effects, enhances GABAergic function. GHB inhibits central nervous system activity and is a sedative but is also euphorigenic, presumably being linked to an increase in dopamine (Nicholson & Balster, 2001). It is increasingly used as a recreational club drug and there is growing concern about its safety, particularly when combined with alcohol to render women vulnerable to sexual assault.
CONCLUSION
This is an exciting time in addiction as the neurobiology of addiction disorders becomes clearer. Such characterisation not only provides a greater understanding of why people become addicted and what happens to the brain after a period of substance misuse, but also allows better understanding of current pharmacotherapies and, we hope, the development of new treatments.
REFERENCES
Ameri, A. (1999) The effects of cannabinoids on the brain. Progress in Neurobiology, 58, 315-348.[CrossRef][Medline]
Ascher, J. A., Cole, J. O., Colin, J. N., et al (1995) Bupropion: a review of its mechanism of antidepressant activity. Journal of Clinical Psychiatry, 56, 395-401.
Ashton, C. H. (2001) Pharmacology and effects
of cannabis: a brief review. British Journal of
Psychiatry, 178,
101-106.
Bisaga, A., Comer, S. D., Ward, A. S., et al (2001) The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology (Berl), 157, 1-10.[CrossRef][Medline]
Boot, B. P., McGregor, I. S. & Hall, W. (2000) MDMA (Ecstasy) neurotoxicity: assessing and communicating the risks. Lancet, 355, 1818-1821.[CrossRef][Medline]
Chiamulera, C., Epping-Jordan, M. P., Zocchi, A., et al (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nature Neuroscience, 4, 873-874.[CrossRef][Medline]
Dahchour, A. & De Witte, P. (2000) Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Progress in Neurobiology, 60, 343-362.[CrossRef][Medline]
Herz, A. (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology, 129, 99-111.[CrossRef][Medline]
Jorenby, D. E., Leischow, S. J., Nides, M. A., et al
(1999) A controlled trial of sustained-release bupropion, a
nicotine patch, or both for smoking cessation. New England Journal
of Medicine, 340,
685-691.
Kieffer, B. L. (1999) Opioids: first lessons from knockout mice. Trends in Pharmacological Sciences, 20, 19-26.[CrossRef][Medline]
Koob, G. F. & Le Moal, M. (2001) Drug addiction, dysregulation of reward, and allostastis. Neuropsychopharmacology, 24, 97-129.[CrossRef][Medline]
Ledent, C., Valverde, O., Cossu, G., et al
(1999) Unresponsiveness to cannabinoids and reduced addictive
effects of opiates in CBI receptor knockout mice.
Science, 283,
401-404.
Louk, J. M. J., Vanderschuren, L. J. & Kalivas, P. W. (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology (Berl), 151, 99-120.[CrossRef][Medline]
Maldonado, R., Saiardi, A., Valverde, O., et al (1997) Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature, 388, 586-589.[CrossRef][Medline]
Manzanares, J., Corchero, J., Romero, J., et al (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends in Pharmacological Sciences, 20, 287-294.[CrossRef][Medline]
Martin, M., Ledent, C., Parmentier, M., et al (2000) Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CBI knockout mice. European Journal of Neuroscience, 12, 4038-4046.[CrossRef][Medline]
Nicholson, K. L. & Balster, R. L. (2001) GHB: a new and novel drug of abuse. Drug and Alcohol Dependence, 63, 1-22.[CrossRef][Medline]
Nutt, D. (1993) Neurochemistry of drugs other than alcohol. Current Opinion in Psychiatry, 6, 395-402.
Nutt, D. (1999) Alcohol and the brain. Pharmacological insights for psychiatrists. British Journal of Psychiatry, 175, 114-119.[Abstract]
Nutt, D. & Malizia, A. L. (2001) New
insights into the role of the GABAAbenzodiazepine receptor
in psychiatric disorder. British Journal of
Psychiatry, 179,
390-396.
Pilla, M., Perachon, S., Sautel, F., et al (1999) Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature, 400, 371-375.[CrossRef][Medline]
Reneman, L., Lavalaye, J., Schmand, B., et al
(2001) Cortical serotonin transporter density and verbal
memory in individuals who stopped using 3,4-methylenedioxymethamphetamine
(MDMA or "ecstasy"): preliminary findings. Archives of
General Psychiatry, 58,
901-906.
Rinaldi-Carmona, M., Barth, F., Heaulme, M., et al (1995) Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist. Life Sciences, 56, 1941-1947.[CrossRef][Medline]
Risinger, F. O., Freeman, P. A., Rubinstein, M., et al (2000) Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice. Psychopharmacology (Berl), 152, 343-350.[Medline]
Schultz, W. (2001) Reward signaling by dopamine
neurons. Neuroscientist,
7, 293-302.
Semple, D. M., Ebmeier, K. P., Glabus, M. F., et al (1999) Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (ecstasy) users. British Journal of Psychiatry, 175, 63-69.[Abstract]
Strang, J., Bearn, J. & Gossop, M. (1999) Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. American Journal on Addictions, 8, 337-348.[CrossRef][Medline]
Volkow, N. D., Fowler, J. S. & Wang, G. J. (1999) Imaging studies on the role of dopamine in cocaine reinforcement and addiction in humans. Journal of Psychopharmacology, 13, 337-345.[Medline]
Wolf, M. E. (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Progress in Neurobiology, 54, 679-720.[CrossRef][Medline]
Zubieta, J., Greenwald, M. K., Lombardi, U., et al (2000) Buprenorphine-induced changes in mu-opioid receptor availability in male heroin-dependent volunteers: a preliminary study. Neuropsychopharmacology, 23, 326-334.[CrossRef][Medline]
Received for publication January 22, 2002. Revision received May 22, 2002. Accepted for publication May 29, 2002.