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British Medical Bulletin 65:209-222 (2003)
© 2003 Oxford University Press

Addiction

Imaging in clinical neuroscience

A R Lingford-Hughes, S J C Davies, S McIver, T M Williams, M R C Daglish and D J Nutt

Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol, UK


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Alcohol
 Stimulants
 Ecstasy
 Opiates
 Conclusions
 References
 
Alcohol and psycho-active substance misuse has far-reaching social, psychological and physical consequences. Advances in neuroimaging technology have allowed neurobiological theories of addiction to become better characterized. We describe the neurobiology of dependence, withdrawal, abstinence and craving states in alcohol, stimulant and opiate misuse. Structural neuroimaging techniques such as CT and MRI with new analytical approaches such as voxel-based morphometry have shown wide-spread changes in stimulant and opiate abuse and atrophy, particularly in the frontal lobes, in alcoholism. Functional neuroimaging techniques such as PET, SPECT and fMRI reveal altered regional cerebral activity by all drugs of abuse. The neurochemistry of addiction, particularly involving dopamine, serotonin, opiate and GABA, has been studied with PET and SPECT and similarities between all drugs of abuse have been found such as reduced dopaminergic markers. The evidence derived from these advances in neuroimaging is likely to herald the emergence of new biological treatments in this important field.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Alcohol
 Stimulants
 Ecstasy
 Opiates
 Conclusions
 References
 
The profound social, psychological, physical and economic consequences of misuse of alcohol and other pyscho-active substances have been well documented. About a quarter of men and one in seven women in the UK drink more than recommended limits1Go. About 500,000 people in the UK fulfil criteria for opiate addiction, with its associated high morbidity and mortality, and use of cocaine is rising, currently accounting for 10% of reported illicit drug use1Go. While psychological theories appear to predominate in clinical practice and form the basis for most existing treatments, as neurobiological theories become more fully defined and evidence-based, their impact on treatment is likely to increase. This review is not exhaustive, but illustrates how neuroimaging is playing a critical role in this process for some drugs of abuse. With neuroimaging, the neurobiology of addiction through its different stages of intoxication, dependence, withdrawal, and abstinence can now be directly measured in vivo.


   Alcohol
Top
 Footnotes
 Abstract
 Introduction
 Alcohol
Stimulants
 Ecstasy
 Opiates
 Conclusions
 References
 
Structural neuroimaging

Every clinician is aware that alcohol damages the brain, causing atrophy, and early CT studies confirmed this showing increased ventricular and intrasulcal volumes in alcoholics2Go. Magnetic resonance imaging (MRI) has provided better discrimination between grey and white matter and CSF, and more precise quantification of structural changes. Reduced volume in the frontal and temporal cortices, hippocampus, mammillary bodies and cerebellum have been reported, with greater loss seen in older age groups3Go. Reduced white matter in the temporal lobes has been related to a history of seizures, but it is not clear whether it is a cause or a consequence4Go.

MRI has also been valuable in examining changes in gross brain volume over time. For instance, Pfefferbaum et al5Go showed an increase in anterior cortical grey matter volume with reduced CSF volume in the first month of abstinence. These changes were initially attributed to ‘rehydration’ but later to sprouting of new dendrites and axons. MRI and proton MR spectroscopy (MRS) have provided clinicians with evidence that neuronal regeneration (as evidenced by increased N-acetylaspartate/choline) is an important factor underlying the reversal of atrophy6Go. Awareness of this can be useful in enhancing motivation for change in alcohol dependence.

Wernicke's encephalopathy and Korsakoff's syndrome are, respectively, acute and chronic clinical syndromes associated with thiamine deficiency seen in alcohol dependence. MRI studies in alcohol-dependent patients with these clinical features have identified wide-spread reductions in grey-matter volumes especially in the thalamus, diencephalic regions and median and dorsal raphe nuclei. Neuropathologists have long regarded mammillary body shrinkage as a cardinal feature in patients with Korsakoff's syndrome; however, MRI has provided evidence to challenge this theory. Significant shrinkage was detected in some non-amnesic alcoholics, but was universal in patients with Korsakoff's syndrome, suggesting a continuum of mammillary body pathology in chronic alcoholism7Go.

Classically, post-mortem work described greater vulnerability of white than grey matter to alcohol. A recent advance, diffusion tensor imaging (DTI), allows quantification of the integrity of cerebral white matter and damage has been reported within all brain regions, particularly in the genu and centrum semiovale, in alcoholics8Go.

Functional neuroimaging

Cerebral blood flow, perfusion and metabolism
 As might be expected, PET and SPECT neuroimaging studies have shown reduced blood flow, perfusion or metabolism in alcohol dependence, with the frontal lobe being particularly susceptible9Go. Improvement in cerebral activity is seen during early abstinence. Volkow et al10Go reported increased metabolism, particularly in frontal regions and more recently frontal lobe rCBF was found to increase progressively with abstinence and return to premorbid levels within 4 years11Go. Notably, George et al12Go showed that multiple detoxifications were associated with greater levels of hypoperfusion. This emphasises the need to optimise the treatment programme to encourage abstinence rather than repeated detoxifications.

Neuropsychological impairments, which in general initially involve the frontal lobe, and ultimately alcoholic dementia are functional consequences of these changes. Although not every study has shown such a relationship, cerebral deficits identified through neuroimaging have been associated with neuropsychological impairment9Go. Clinically, whilst appearing neurologically and psychiatrically healthy, many alcoholics may have subtle deficits detectable only by targeted neuropsychiatric assessment that could impact on treatment. A recent study in a healthy population of alcoholics found reduced medio-frontal lobe metabolism correlated with impairments in verbal fluency13Go.

Neurochemistry
 Neuroimaging has focused on the GABA, dopamine and serotonin systems since they are involved in the neurobiology of alcoholism and its treatment14Go,15Go.

The GABA-benzodiazepine receptor complex (GBzR) has been an intense focus of interest since many of alcohol's central effects are mediated through its agonist action at the GBzR and benzodiazepines alleviate alcohol withdrawal symptoms14Go. It has been proposed that reduced GABA-ergic function is associated with vulnerability to alcoholism. Reduced levels of the GBzRs, particularly in the frontal lobes, have been reported in imaging studies of alcohol dependence using [11C]-flumazenil PET16Go or [123I]-iomazenil SPECT17Go,18Go. One study excluded grey matter atrophy as a significant contributor to this reduction18Go. It is not known whether the reduced levels of GBzR preceded alcohol abuse. These findings may reflect an alteration in the subunit profile of the GBzR that is seen in animal models as a means of reducing sensitivity to alcohol (i.e. tolerance).

Serotonin is implicated in many disorders such as anxiety and depression that co-exist with alcoholism and also in controlling impulsive behaviour14Go. Using [123I]-ß-CIT SPECT, Heinz et al19Go reported that alcohol dependence was associated with reduced levels of the 5-HT transporter in the raphe nucleus in the brainstem (the only region which could be imaged); the reduction correlated with ratings of depression and anxiety. Notably this reduction, but not alcoholism, was associated with a particular allelic variation (ll) of the 5-HT transporter, suggesting that this polymorphism mediates susceptibility to neurotoxicity20Go.

Dopamine is a key neurotransmitter in addiction. All drugs of abuse (except benzodiazepines) increase dopaminergic function in the mesolimbic system, the critical pathway in mediating reward. More recently, a role in associative learning has been recognised and evidence has emerged that a hypodopaminergic state occurs in withdrawal.

Although Volkow21Go reported no differences in striatal dopamine transporter (DAT) levels compared with controls, subsequent studies have reported reductions although only in a subtype of alcoholism. SPECT with another tracer was used to quantify striatal DAT levels in violent (akin to type 2 alcoholism, characterised by early age of onset, antisocial personality traits) and non-violent (akin to type 1, characterised by late age of onset and anxiety) alcoholics. Compared with controls, reduced DAT levels were seen in the non-violent group and slightly higher levels in violent group2Go. This has partly been replicated by Repo et al23Go who described reduced DAT levels in type 1 alcoholism. These studies suggest that subtypes have a particular neurobiology that may have implications for treatment.

Clinically, withdrawal and early abstinence is a turbulent time and not surprisingly changes in neurochemistry have been found. Laine24Go studied alcoholics in early withdrawal and found that DAT levels were significantly lower than in controls with recovery to normal levels, often in the first 4 days. This supports the hypothesis that hypodopaminergic function occurs in withdrawal as does a study by Guardia et al25Go which found that increased dopamine D2 receptor (DRD2) availability, secondary to low dopamine levels, were associated with greater risk of relapse.

Volkow et al21Go, by contrast, reported reduced striatal DRD2 levels in alcohol dependence. Until the recent development of a very high affinity tracer, [123I]-epidepride, DRD2 could only be imaged in the striatum due to the low levels elsewhere in the brain. D2/D3 receptors can now be measured in the temporal lobe and, using this tracer, Repo et al23Go found no differences in receptor levels here in type 1 alcoholism.

Craving

Craving is a term often used by dependent people to describe their difficulty in controlling their drug use and is implicated in relapse, but it has proved difficult to define this term rigorously in a scientific context. Craving is a multidimensional phenomenon incorporating a desire to gain a positive feeling (e.g. euphoria), to overcome a negative feeling (e.g. withdrawal) or an ‘urge to use’. Cue-exposure paradigms are widely used to study ‘craving’ and have recently been combined with neuroimaging to help characterize the neural networks associated with this experience.

There are only a few neuroimaging studies describing neural activation with craving for alcohol with inconsistent results, likely due to different paradigms. Modell and Mountz26Go described increased activity in the right head of caudate nucleus with [99mTc]-HMPAO SPECT. Two recent functional MRI (fMRI) studies have found craving associated with activation in the left prefrontal cortex and anterior thalamus in non-treatment seeking alcoholics27Go and in the right amygdala and hippocampal area as well as in the cerebellum28Go. These regions are part of the limbic system and, therefore, activation here is not surprising with craving.


   Stimulants
Top
 Footnotes
 Abstract
 Introduction
 Alcohol
 Stimulants
Ecstasy
 Opiates
 Conclusions
 References
 
There have been many functional imaging studies investigating the effects of stimulants on the brain. The continuing rise in the use of stimulants, for example cocaine and methamphetamine, is causing increasing public health concerns. Stimulant use, especially that of crack cocaine, usually follows a relapsing course driven by powerful cravings for further use, emerging almost the instant the extreme euphoria of the drug has worn off.

Structural studies

There are limited studies on the structural changes in stimulant abusers, but generally changes consistent with infarcts and haemorrhages are seen. Recently, striatal hypertrophy has been reported in cocaine addicts that is thought to be secondary to the depletion of dopamine and hypoperfusion29Go. Voxel-based morphometry has been developed to measure the concentration, rather than volume, of white and grey matter from MRI. Using this technique, reduced levels of grey matter in several regions including the orbitofrontal (OFC), cingulate and temporal cortices of cocaine addicts has been reported30Go. Diffusion tensor imaging has recently shown disrupted OFC connectivity31Go.

Functional neuroimaging

Cerebral blood flow, perfusion and metabolism
 Cocaine addiction is associated with wide-spread reductions in metabolism and perfusion that persist in abstinence32GoGo–34Go. This is likely to be due to the vasoconstrictive effects of cocaine which result in cerebral infarcts. A similar pattern is seen with amphetamine abuse35Go,36Go. Methamphetamine abuse is also associated with reduced cerebral activity, particular in the striatum, together with hypermetabolism in parietal cortex, which is thought to reflect gliosis/inflammation37Go,38Go.

As with alcoholism, increased metabolism during the early withdrawal period from cocaine has been reported in the OFC followed by hypometabolism. It was suggested that the increase is associated with craving (see below) which is high during this period. This group postulated that activity in the OFC is indicative of the involvement of neural circuits associated with repetitive or compulsive behaviours rather than merely pleasure and reward33Go. More recently, Volkow et al39Go hypothesised that reduced activity in the OFC was as a result of reduced dopaminergic input since activity here correlated with striatal DRD2 levels. Increasing dopaminergic activity with methylphenidate did not increase metabolism in the OFC of all cocaine addicts, but in those that it was, craving was experienced. This study suggests that increasing dopaminergic function is not sufficient to redress damage from cocaine and that the OFC is critical to craving.

fMRI has been used to examine the effects of drug abuse on cognitive processes thought to be impaired by, or involved in, drug abuse. In an fMRI study, Paulus et al.40Go found that methamphetamine dependence was associated with reduced activation in the prefrontal cortex reflected as impaired decision-making, and that activation in the OFC predicted the duration of methamphetamine abuse.

Neurochemistry
 As described, the dopaminergic system is critical in addiction, and drugs such as cocaine and amphetamine act directly on this system to increase dopamine resulting in pleasure. There are several studies in vivo in man to support this premise. Volkow41Go reported that blockade of the DAT by cocaine positively correlated with experiencing a ‘high’. At least 50% occupancy of DAT was required for a ‘high’.

More recently, in vivo endogenous dopamine levels can be assessed in man using [11C]-raclopride PET since this dopaminergic D2 receptor marker is sensitive to dopamine. Schlaepfer et al42Go used this protocol to show that cocaine increased dopamine levels in the striatum that were related to its peak physiological and subjective effects. Similarly, Laruelle et al43Go using [123I]-IBZM SPECT reported that amphetamine increased dopamine levels and this correlated with subjective euphoria, alertness and restlessness. Therefore, it is clear that in man dopamine is key in mediating many of the effects of stimulants which supports the fact that the dopaminergic system has been a key target for pharmacotherapy, albeit without much success to date.

Methylphenidate is used clinically to treat attention deficit disorder and concerns have been expressed about giving a drug with abuse potential to children already at higher risk of substance misuse. Compared to other stimulants, methylphenidate abuse is minimal and Volkow et al44Go have shown that its pharmacokinetics contribute to this. The faster the rate of onset of a drug, the higher its addictive potential. The rate of onset of i.v. cocaine and i.v. methylphenidate to the DAT is similar, but that of oral methylphenidate is much slower. Whether methylphenidate is given i.v. or orally, its off-rate from the DAT is much slower than that for cocaine. Both enter the brain equally fast although cocaine is cleared more quickly. DAT is less available with methylphenidate and becomes saturated with repeated use resulting in no further increases in dopamine, thus lowering its abuse potential.

Chronic exposure to cocaine results in decreased DRD2 receptors, which persist for 3–4 months45Go. As described above, this reduction correlates with reduced metabolism in the OFC which receives projections from the nucleus accumbens in the ventral striatum33Go. In addition, dopaminergic function is reduced in cocaine addicts. The amount of dopamine released by methylphenidate in cocaine addicts was 50% less than that in the controls, and the ‘high’ was perceived as less intense. This blunted dopaminergic response in cocaine addicts may lead to increased drug use in an attempt to compensate for the decreased stimulation in this dopaminergic reward pathway.

The activity of the dopamine system has recently been shown to influence experiencing pleasure from drugs. Through a series of experiments in healthy controls with methylphenidate, Volkow et al46Go showed that low DRD2 levels were associated with pleasure and those with high DRD2 levels found methylphenidate unpleasant. Therefore, activity in the dopaminergic system, not surprisingly, appears to be involved in the vulnerability to addiction.

Similarly, reduced levels of striatal dopamine D2 receptor have been reported in methamphetamine addicts which correlated with reduced metabolism in the OFC. Striatal DAT levels are reduced in methamphetamine users and this is associated with motor and memory impairment47Go.48Go. Sekine et al49Go demonstrated striatal DAT levels were inversely correlated with severity of psychiatric symptoms and duration of use of methamphetamine, but not abstinence, suggesting long-lasting damage.

Craving

Identification of brain areas activated during craving for stimulants have generated considerable interest and neuroimaging studies have produced remarkably consistent results. Grant et al56Go using [18GoF]-FDG PET first showed that craving for cocaine correlated with increased activity in the amygdala and dorsolateral prefrontal cortex. Childress et al51Go similarly showed that cocaine craving was associated with increased activity in the amygdala, but also in the anterior cingulate cortex. These regions have all been implicated in addiction with the amygdala involved in associative learning (i.e. between cue and drug), the anterior cingulate cortex with emotional processing and the dorsolateral prefrontal cortex with memory.

More recently, fMRI studies have shown activation in similar areas including the anterior cingulate, prefrontal and orbitofrontal cortices in response to salient cues52Go,53Go. The increased temporal resolution of fMRI was exploited by Wexler et al who showed that the anterior cingulate cortex was activated in cocaine addicts even if they did not go on to experience craving for cocaine (see opiate craving below). The temporal and spatial resolution of fMRI has also been used by Breiter et al54Go to map the distinct regional effects of i.v. cocaine in the brain and relate these to subjective effects. ‘Rush’ was associated with activation in areas including the basal forebrain, caudate, cingulate and prefrontal cortices, whereas activation associated with craving occurred in the nucleus accumbens, right parahippocampal gyrus and prefrontal cortex.


   Ecstasy
Top
 Footnotes
 Abstract
 Introduction
 Alcohol
 Stimulants
 Ecstasy
Opiates
 Conclusions
 References
 
In the UK, 3,4-methylenedioxymethamphetamine (MDMA) or ‘Ecstasy’ receives much attention. It is increasingly popular amongst young people despite evidence of toxicity to serotonergic neurons in animals and fears of ensuing psychiatric morbidity in man.

Reduced 5-HT transporters (5-HTT) have been reported in a number of studies suggesting serotonergic damage from Ecstasy use. Two early studies with [11C]-McN-5652 PET and [123I]-ß-CIT SPECT showed reduced 5-HTT throughout the brain in Ecstasy users55Go,56Go, but methodological concerns have been expressed. More recently, Reneman et al57Go using [123I]-ß-CIT SPECT showed reduced 5-HTT levels in cortical regions in Ecstasy users but not in ex-Ecstasy users. Although verbal memory was impaired, no correlation was seen between performance and 5-HTT levels. Further studies are required to characterize serotonergic changes with Ecstasy use in man and to take into account confounders such as other drug use and psychiatric morbidity.


   Opiates
Top
 Footnotes
 Abstract
 Introduction
 Alcohol
 Stimulants
 Ecstasy
 Opiates
Conclusions
 References
 
In the UK, opiate dependence is associated with higher rates of morbidity than all other illicit drugs and accounts for the largest proportion of people in treatment services. There are only a few neuroimaging studies investigating the consequences of opiate misuse and addiction on the brain.

Structural imaging

There is little evidence from CT or MRI of consistent structural changes associated with long-term opiate use58Go.

Functional neuroimaging

Imaging the acute effects of opiates
 Two studies have examined the effect on the brain of an acute dose of opiates. Firestone et al59Go used [15GoO]–H2O PET to measure rCBF in response to an acute dose of the short-acting opiate agonist, fentanyl. There was significantly increased activity in cingulate, orbitofrontal and medial prefrontal cortices, as well as the caudate nuclei. These areas are involved in learning, reward, and addiction. Schlaepfer et al60Go similarly used [99mTc]-HMPAO SPECT to compare the effects of hydromorphone, an agonist at the mu receptor, which is responsible for the pleasurable effects of opiates, to those of butorphanol, an agonist at the kappa receptor, which mediates dysphoria. Hydromorphone, but not butorphanol, induced more euphoric effects and produced significant increases in activity in the anterior cingulate cortex, amygdalae, and thalamus. These regions are part of the limbic system, which is key in addiction.

Effects of substitution pharmacotherapy and chronic opioid use in opiate addicts
 Clinically, methadone, a mu agonist, is the most widely used substitution therapy for opiate addicts and greater efficacy is seen at higher doses (60 mg) of methadone. It is presumed that higher doses of methadone occupy more opiate receptors, thus preventing access to the receptor of any opiate used ‘on top’, but this has not been shown in man. Kling et al61Go imaged opiate receptors of patients maintained on methadone with [18F]-cyclofoxy, an antagonist at the mu and kappa opioid receptors. They found that methadone resulted in fewer available opioid receptors, particularly in thalamus, amygdala, caudate, anterior cingulate cortex, and putamen, compared with normal controls. A correlation between opiate receptor availability and plasma methadone levels was only seen in the caudate and putamen.

Buprenorphine is increasingly used in substitute therapy and is a partial agonist at the mu receptor and antagonist at the kappa receptor; it has several advantages over methadone including reduced risk of respiratory depression and dysphoria. Zubieta et al62Go used the mu selective PET radioligand [11C]-carfentanyl to measure opiate receptor availability in three patients maintained on differing doses. There was dose-dependent inverse relationship between buprenorphine dose and opiate receptor availability with 36–50% occupancy at 2 mg and 79–95% at 16 mg.

Chronic opiate agonist treatment in animal models has been shown to increase opiate receptor levels, albeit inconsistently63Go. Preliminary data from our group and the study of Zubieta et al62Go also suggest an increase in man. A trend towards a small increase in opiate receptor levels was found in opiate addicts immediately after detoxification from methadone64Go and in subjects maintained on buprenorphine, opiate receptor availability was increased compared to controls.

Opiate withdrawal
 The opiate antagonist, naloxone, has been used to precipitate withdrawal by Wang et al65Go. [11C]-Raclopride PET was used to characterise dopaminergic function in withdrawal, which was hypothesized from animal models to be reduced. Whilst a significant decrease in dopamine DRD2 receptor levels was found in opiate-dependent subjects compared with controls, there was no significant change in striatal dopamine concentration during withdrawal. It is, therefore, not clear whether altered dopaminergic levels do play a role in opiate withdrawal.

Craving

There have only been a few studies on opiate craving, but there are similarities in the regions activated to those seen for cocaine, supporting the hypothesis that there is a common pathway involved in addiction for drugs of abuse. Daglish et al66Go used a [15O]-H2O PET individualised cue-exposure paradigm and reported increased rCBF in the anterior cingulate cortex was seen in response to the salient drug cue, whereas craving itself was associated with activation in the left orbitofrontal cortex. This is similar to the findings of Wexler et al53Go on cocaine. Sell et al67Go used similar techniques to show ‘urge to use’ correlated strongly with increase rCBF in the inferior frontal and orbitofrontal cortices. Therefore, the orbitofrontal cortex appears to be associated with craving and further studies are required to explore the contributions of other regions to the experience of craving.


   Conclusions
Top
 Footnotes
 Abstract
 Introduction
 Alcohol
 Stimulants
 Ecstasy
 Opiates
 Conclusions
References
 
Neuroimaging is playing a central role in determining the neurobiology of addiction. Reductions in dopamine D2 receptors have been reported for all drugs of abuse studied including cocaine, methamphetamine, alcohol and opiates suggesting that these reductions are not specific to any type of addiction, but reflect a common abnormality in addiction. In addition neural networks involved in craving for different drugs of abuse appear similar. With greater sophistication of imaging techniques, there will be further exploration of these craving circuits and better understanding of the neurobiology of addiction.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Alcohol
 Stimulants
 Ecstasy
 Opiates
 Conclusions
 References
 
Correspondence to: Prof. DJ Nutt, Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK


   References
Top
 Footnotes
 Abstract
 Introduction
 Alcohol
 Stimulants
 Ecstasy
 Opiates
 Conclusions
 References
 

  1. Office for National Statistics. Living in Britain: results from the 1998 general household survey: an inter-departmental survey carried out by the Office for National Statistics between April 1998 and March 1999. London: The Stationery Office, 2000
  2. Pfefferbaum A, Rosenbloom M, Crusan K, Jernigan TL. Brain CT changes in alcoholics: effects of age and alcohol consumption. Alcohol Clin Exp Res 1988; 12: 81–7[CrossRef][ISI][Medline]
  3. Pfefferbaum A, Sullivan EV, Rosenbloom MJ, Mathalon DH, Lim KO. A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Arch Gen Psychiatry 1998; 55: 905–12[Abstract/Free Full Text]
  4. Sullivan, EV, Marsh L, Mathalon DH, Lim KO, Pfefferbaum A. Relationship between alcohol withdrawal seizures and temporal lobe white matter volume deficits. Alcohol Clin Exp Res 1996; 20: 348–54[CrossRef][ISI][Medline]
  5. Pfefferbaum A, Sullivan EV, Mathalon DH, Shear PK, Rosenbloom MJ, Lim KO. Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapsed alcoholics. Alcohol Clin Exp Res 1995; 19: 1177–91[CrossRef][ISI][Medline]
  6. Bendszus M, Weijers HG, Wiesbeck G et al. Sequential MR imaging and proton MR spectroscopy in patients who underwent recent detoxification for chronic alcoholism: correlation with clinical and neuropsychological data. Am J Neuroradiol 2001; 22: 1926–32[Abstract/Free Full Text]
  7. Sullivan EV, Lane B, Deshmukh A et al. In vivo mammillary body volume deficits in amnesic and nonamnesic alcoholics. Alcohol Clin Exp Res 1999; 23: 1629–36[CrossRef][ISI][Medline]
  8. Pfefferbaum A, Sullivan EV. Microstructural but not macrostructural disruption of white matter in women with chronic alcoholism. Neuroimage 2002; 15: 708–18[CrossRef][ISI][Medline]
  9. Moselhy HF, Georgiou G, Kahn A. Frontal lobe changes in alcoholism: a review of the literature. Alcohol Alcohol 2001; 36: 357–68[Abstract/Free Full Text]
  10. Volkow ND, Wang GJ, Hitzemann R et al. Recovery of brain glucose metabolism in detoxified alcoholics. Am J Psychiatry 1994; 151: 178–83[Abstract/Free Full Text]
  11. Gansler DA, Harris GJ, Oscar-Berman M et al. Hypoperfusion of inferior frontal brain regions in abstinent alcoholics: a pilot SPECT study. J Stud Alcohol 2000; 61: 32–7[ISI][Medline]
  12. George MS, Teneback CC, Malcolm RJ et al. Multiple previous alcohol detoxifications are associated with decreased medial temporal and paralimbic function in the postwithdrawal period. Alcohol Clin Exp Res 1999; 23: 1077–84[CrossRef][ISI][Medline]
  13. Dao-Castellana MH, Samson Y, Legault F et al. Frontal dysfunction in neurologically normal chronic alcoholic subjects: metabolic and neuropsychological findings. Psychol Med 1998; 28: 1039–48[CrossRef][ISI][Medline]
  14. Nutt DJ. Alcohol and the brain. Br J Psychiatry 1999; 175: 114–9[Abstract/Free Full Text]
  15. Lingford-Hughes A, Hume SP, Feeney A et al. Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]-Ro15 4513 positron emission tomography. J Cereb Blood Flow Metab 2002; 22: 878–89[CrossRef][ISI][Medline]
  16. Gilman S, Koeppe RA, Adams K et al. Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics. Ann Neurol 1996; 40: 163–71[CrossRef][ISI][Medline]
  17. Abi-Dargham A, Krystal JH, Anjilvel S et al. Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]-iomazenil. Am J Psychiatry 1998; 155: 1550–5[Abstract/Free Full Text]
  18. Lingford-Hughes AR, Acton PD, Gacinovic S et al. Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy. Br J Psychiatry 1998; 173: 116–22[Abstract/Free Full Text]
  19. Heinz A, Higley JD, Gorey JG et al. In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates. Am J Psychiatry 1998; 155: 1023–8[Abstract/Free Full Text]
  20. Heinz A, Jones DW, Mazzanti C et al. A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 2000; 47: 643–9[CrossRef][ISI][Medline]
  21. Volkow ND, Wang GJ, Fowler JS et al. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res 1996; 20: 1594–8.[ISI][Medline]
  22. Tiihonen J, Kuikka J, Bergstrom K et al. Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics. Nat Med 1995; 1: 654–7[CrossRef][ISI][Medline]
  23. Repo E, Kuikka JT, Bergstrom KA, Karhu J, Hiltunen J, Tiihonen J. Dopamine transporter and D2-receptor density in late-onset alcoholism. Psychopharmacology (Berl) 1999; 147: 314–8[CrossRef][Medline]
  24. Laine TP, Ahonen A, Torniainen P et al. Dopamine transporters increase in human brain after alcohol withdrawal. Mol Psychiatry 1999; 4: 189–91, 104–5[CrossRef][ISI][Medline]
  25. Guardia J, Catafau AM, Batlle F et al. Striatal dopaminergic D(2) receptor density measured by [123I]-iodobenzamide SPECT in the prediction of treatment outcome of alcohol-dependent patients. Am J Psychiatry 2000; 157: 127–9[Abstract/Free Full Text]
  26. Modell JG, Mountz JM. Focal cerebral blood flow change during craving for alcohol measured by SPECT. J Neuropsychiatry Clin Neurosci 1995; 7: 15–22[Abstract/Free Full Text]
  27. George MS, Anton RF, Bloomer C et al. Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues. Arch Gen Psychiatry 2001; 58: 345–52[Abstract/Free Full Text]
  28. Schneider F, Habel U, Wagner M et al. Subcortical correlates of craving in recently abstinent alcoholic patients. Am J Psychiatry 2001; 158: 1075–83[Abstract/Free Full Text]
  29. Jacobsen LK, Giedd JN, Gottsschalk C, Kosten TR, Krystal JH. Quantitative morphology of the caudate and putamen in patients with cocaine dependence. Am J Psychiatry 2001; 158: 486–9[Abstract/Free Full Text]
  30. Franklin TR, Acton PD, Maldjjan JA et al. Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients. Biol Psychiatry 2002; 51: 134–42[CrossRef][ISI][Medline]
  31. Lim KO, Choi SJ, Pomara N, Wolkin A, Rotrosen JP. Reduced frontal white matter integrity in cocaine dependence: a controlled diffusion tensor imaging study. Biol Psychiatry 2002; 51: 890–5[CrossRef][ISI][Medline]
  32. Kaufman MU, Levin JM, Maas LC et al. Cocaine decreases relative cerebral blood volume in humans: a dynamic susceptibility contrast magnetic resonance imaging study. Psychopharmacology (Berl) 1998; 138: 76–81[CrossRef][Medline]
  33. Volkow ND, Mullani N, Gould KL, Adler S, Krajewski K. Cerebral blood flow in chronic cocaine users: a study with positron emission tomography. Br J Psychiatry 1988; 152: 641–8[Abstract/Free Full Text]
  34. Ernst T, Chang L, Oropilla G, Gustavson S, Speck O. Cerebral perfusion abnormalities in abstinent cocaine abusers: a perfusion MRI and SPECT study. Psychiatry Res 2000; 99: 63–74[ISI][Medline]
  35. Wolkin A, Angrist B, Wolf A et al. Effects of amphetamine on local cerebral metabolism in normal and schizophrenic subjects as determined by position emission tomography. Psychopharmacology (Berl) 1987; 92: 241–6[Medline]
  36. de Wit H, Metz J, Cooper M. Effects of ethanol, diazepam and amphetamines on cerebral metabolic rate: PET studies using FDG. NIDA Res Monogr 1991; 105: 61–7[Medline]
  37. Volkow ND, Fowler JS, Wolf AP et al. Changes in brain glucose metabolism in cocaine dependence and withdrawal. Am J Psychiatry 1991; 148: 621–6[Abstract/Free Full Text]
  38. Chang L, Ernst T, Speck O et al. Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users. Psychiatry Res 2002; 114: 65–79[CrossRef][ISI][Medline]
  39. Volkow ND, Wang G-J, Fowler JS et al. Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction. Amm J Psychiatry 1999; 156: 19–26[Abstract/Free Full Text]
  40. Paulus MP, Hozack NE, Zauscher BE et al. Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects. Neuropsychopharmacology 2002; 26: 53–63[CrossRef][ISI][Medline]
  41. Volkow ND, Wang G-J, Fischman MW et al. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature (Lond) 1997; 386: 827–30[CrossRef][Medline]
  42. Schlaepfer TE, Pearlson GD, Wong DF, Marenco S, Dannals RF. PET study of competition between intravenous cocaine and [11C]-raclopride at dopamine receptors in human subjects. Am J Psychiatry 1997; 154: 1209–13[Abstract]
  43. Laruelle M, Abi-Dargham A, van Dyck CH et al. SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med 1995; 36: 1182–90[Abstract/Free Full Text]
  44. Volkow ND, Ding YS, Fowler JS et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 1995; 52: 456–63[Abstract]
  45. Volkow ND, Fowler JS, Wang GJ et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 1993; 14: 169–77[CrossRef][ISI][Medline]
  46. Volkow ND, Wang G-J, Fowler JS et al. Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry 1999; 156: 1440–3[Abstract/Free Full Text]
  47. McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]-WIN-35,428. J Neurosci 1998; 18: 8417–22[Abstract/Free Full Text]
  48. Volkow ND, Chang L, Wang GJ et al. Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 2001; 158: 377–82[Abstract/Free Full Text]
  49. Sekine Y, Iyo M, Ouchi Y et al. Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 2001; 158: 1206–14[Abstract/Free Full Text]
  50. Grant S, London ED, Newlin DB et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA 1996; 93: 12040–5[Abstract/Free Full Text]
  51. Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP. Limbic activation during cue-induced cocaine craving. Am J Psychiatry 1999; 156: 11–8[Abstract/Free Full Text]
  52. Garavan H, Pankiewicz J, Bloom A et al. Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 2000; 157: 1789–98[Abstract/Free Full Text]
  53. Wexler BE, Gottschalk CH, Fulbright RK et al. Functional magnetic resonance imaging of cocaine craving. Am J Psychiatry 2001; 158: 86–95[Abstract/Free Full Text]
  54. Breiter HC, Gollub RL, Weisskoff RM. Acute effects of cocaine on human brain activity and emotion. Neuron 1997; 19: 591–611[CrossRef][ISI][Medline]
  55. McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]-WIN-35,428. J Neurosci 1998; 18: 8417–22[Abstract/Free Full Text]
  56. Semple DM, Ebmeier KP, Glabus MF, O'Carroll RE, Johnstone EC. Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (‘Ecstasy’) users. Br J Psychiatry 1999; 175: 63–9[Abstract/Free Full Text]
  57. Reneman L, Boojj J, de Bruin K et al. Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons. Lancet 2001; 358: 1864–9[CrossRef][ISI][Medline]
  58. Nutt DJ, Daglish MR. Structural and functional neuroimaging of the effects of opioids. In: Massaro EJ. (ed) Handbook of Neurotoxicology Vol II. Totowa, NJ: Humana, 2002; 397–412
  59. Firestone LL, Gyulai F, Mintun M, Adler LJ, Urso K, Winter PM. Human brain activity response to fentanyl imaged by positron emission tomography. Anesth Analg 1996; 82: 1247–51[Abstract]
  60. Schlaepfer TE, Strain EC, Greenberg BD et al. Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects. Am J Psychiatry 1998; 155: 470–3[Abstract/Free Full Text]
  61. Kling MA, Carson RE, Borg L et al. Opioid receptor imaging with positron emission tomography and [18F]-cyclofoxy in long-term, methadone-treated former heroin addicts. J Pharmacol Exp Ther 2000; 295: 1070–6[Abstract/Free Full Text]
  62. Zubieta J, Greenwald MK, Lombardi U et al. Buprenorphine-induced changes in mu-opioid receptor availability in male heroin-dependent volunteers: a preliminary study. Neuropsychopharmacology 2000; 23: 326–34[CrossRef][ISI][Medline]
  63. Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001; 81: 299–343[Abstract/Free Full Text]
  64. Daglish MRC, Lingford-Hughes A, Williams T et al. Brain opioid receptor changes in early abstinence from methadone. Addiction Biol 2002; 7: 334–5
  65. Wang GJ, Volkow ND, Fowler JS et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology 1997; 16: 174–82[CrossRef][ISI][Medline]
  66. Daglish MRC, Weinstein A, Malizia AL et al. Changes in regional cerebral blood flow elicited by craving memories in abstinent opiate-dependent subjects. Am J Psychiatry 2001; 158: 1680–6[Abstract/Free Full Text]
  67. Sell LA, Morris JS, Bearn J, Frackowiak RSJ, Friston KJ, Dolan RJ. Neural responses associated with cue evoked emotional states and heroin in opiate addicts. Drug Alcohol Depend 2000; 60: 207–16[CrossRef][ISI][Medline]

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ALCOHOL AND GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM
Alcohol Alcohol., January 1, 2005; 40(1): 63 - 75.
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