Craving

Alcohol
catechol-O-methyltransferase (COMT) [HGL]
    Catechol-O-methyltransferase (COMT) is an enzyme involved in the metabolism of dopamine, epinephrine, and norepinephrine.  Two alleles of the COMT gene have been identified which result in functional differences in COMT activity.  One allele codes for low (L) activity and the other encodes a high (H) activity enzyme.   The frequency of the L allele was markedly higher in adults with late onset (type 1) alcoholism as compared to the general population, suggesting that the the low activity COMT polymorphism contributes to the development of late-onset alcoholism.  Tiihonen et al., Mol. Psychiatry, 4(3):286-289, 1999.  Family studies also indicated that the L allele was seen observed more frequently in males with early-onset alcoholism, than family members who did not inherit the L allele, suggesting a role in early-onset alcholism, as well.  Wang et al., Mol. Psychiatry, 6:109-111, 2001.

dopamine receptor, subtype 2 (DR2)+ [HGL]
    In a sample of 35 alcoholics, 69% had the A1 allele and 31% had the A2 allele.  In the same number of non-alcoholics, only 20% had the A1 allele and 80% had the A2 allele.  This study suggested that the A1 allele of the dopamine receptor is associated with alcoholism.  Reviewed in Blum et al., American Scientist, March-April, 1996.  However, other studies have found no association between human Taq1 A1 allele and alcoholism.  Town et al., Am. J. Med. Genet., 88:58-461, 1999.

GABA receptor, beta-1 (GABA-R-B1)+ [HGL]
    A polymorphism in GABA receptor, type beta-1 (GABA-R-B1) was associated with type II alcoholism but not controls.  Parsian et al., Am. J. Med. Genetic., 88(5): 533-538, 1999.  Another study of three DNA sequence variants in exons 1a1, 7, and 11 of the GABA-R-BR1 found that none of the genotypes varied significantly among alcoholics and controls.  However, trends towards an excess of the exon 7 and 11 polymorphism was found in the entire sample of alcoholics.  Sander et al., Psychiatr. Genet., 9:69-73, 1999.

GABA receptor, subtype A alpha 6 (GABA-R-A-alpha-6) [HGL]
    A  low level of response to alcohol was associated with a polymorphism GABA receptor, subtype A alpha 6 gene.  Subjects with a Pro/Ser polymorphism in the GABA-R-A-alpha-6 receptor were alcoholics and had the lowest response level to alcohol.  Schuckit et al., Biol. Psychiatry, 45:647-651, 1999.

monoamine oxidase A (MAOA) [HGL]
    A positive correlation was found between two polymorphic markers in the monoamine amine oxidase A gene (a mutation in exon 14 and (CA)n repeat ) and alcoholics with antisocial personality (ASP).  Genomics, 55(3):290-295, 1999.

neuropeptide Y (NPY) [GE]
    Neuropeptide Y (NPY) is a thirty-six amino acid neuromodulator which is expressed throughout the nervous system.  NPY's action is mediated through the Y1, Y2, and Y5 family of receptors, G-protein coupled receptors which inhibit the production of cAMP.  NPY- deficient mice were produced by genetic engineering.  These mice showed an increased preference for ethanol as indicated by a high ethanol consumption.  The sedative effects of ethanol were reduced in NPY-deficient mice as compared to controls.  The increased ethanol consumption in NPY-deficient mice was not related to a preference for other flavored solutions nor was it calorie-driven.  Mice were also genetically-altered to overproduce NPY.  In contrast to mice who were deficient in NPY, overproducers drank significantly less ethanol than controls.  Thus, high levels of NPY are associated with low ethanol consumption and increased sensitivity to ethanol while low, or null, levels of the neuromodulator are correlated with high ethanol consumption and lowered ethanol sensitivity.  Thiele et al., Nature, 396:366-369, 1998.

opiate receptor, type mu [HGL]
    Association between a functional coding variant in the human mu-opiate receptor and alcohol dependency. Town et al., Am. J. Med. Genet., 88:58-461, 1999.

serotonin receptor, type 1B (5-HT1B) [GE]
    Transgenic mice were engineered which lacked the serotonin receptor, type 1B (5-HT1B).  These null mice showed enhanced aggression.  See, also, Entry under Aggression.  They also showed altered release of serotonin from several, but not all, brain regions.  The receptor-deficient mice were evaluated for their response to ethanol.  Mutant mice voluntarily consumed about twice more ethanol as wild-type mice.  Their intake of food and water, however, was normal.  Mutant mice also took longer to develop ethanol tolerance but showed equivalent response to ethanol withdrawal and metabolism.  These results suggest that the 5-HT1B receptor plays a role in the regulation of ethanol consumption, as well as mediating its ataxic effects.  Crabbe et al., Nature Genetics, 14:98-101, 1996.

serotonin receptor, subtype 2B (5-HT2B)* [HGL]
    No association between two polymorphisms in the 5-HT2B gene and alcoholism. Schuckit et al., Biol. Psychiatry, 45:647-651, 1999.

serotonin receptor, subtype 2C (5-HT2C)* [HGL]
    No association between a polymorphism in the 5-HT2C gene and alcoholism. Schuckit et al., Biol. Psychiatry, 45:647-651, 1999.

serotonin receptor, subtype 3 (5-HT3) [GE]
    A mouse overexpressing the 5-HT3 receptor in the forebrain was created by introducing a 5-HT3 gene under the control of a calmodulin promoter.  Overexpression of the 5-HT3 receptor resulted in a decrease in alcohol consumption and an enhanced sensitivity to the stimulating effects of a low dose of alcohol, without altering its sedating effects or alcohol metabolism.  Engel et al., Psychopharmacology (Berl.), 140:243-248, 1998; Engel and Allan, Psychopharmacology (Berl.), 144:411-415, 1999.

serotonin transporter (5-HTT or SERT) [HGL]
    A  low level of response to alcohol was associated with the LL polymorphism of the 5-HTT gene.  Schuckit et al., Biol. Psychiatry, 45:647-651, 1999.

Cigarette
serotonin transporter (5-HTT or SERT) [H]
    A common 44-base pair polymorphism in the promoter of the serotonin transporter is associated with affective illness and anxiety disorders.  The polymorphism has been designated long (L) and short (S), depending on whether the insertion is present or absent in the promoter region.  The S allele is less active than the L allele.  One study found that people with the short variant, and high levels of neuroticism, found it harder to quit smoking once they started.  However, there was no association between whether a person smoked and the 5-HTT genotype.  Hu et al., Molecular Psychiatry, 5:181-188, March 2000.  Another study found an association between the S allele of the 5-HTT and smoking.  Lerman et al., Molecular Psychiatry, 5:189-192, March 2000.

Cocaine
AMPA receptor
    See, fosB.

cAMP-responsive element binding protein (CREB) [GE]
    Two different strains of rats were produced by microinjecting a viral vector containing the gene of interest into the nucleus accumbens region of the brain, resulting in transient expression of the gene.  One strain of rats overexpressed a normal copy of the CREB gene ("CREB rats"), while another strain overexpressed a dominant negative mutation ("mCREB rats"), which would mask the normal gene's effects.  A place-conditioning test was used to test for the rewarding properties of cocaine.  Normal rats spend significantly more time in envrinoments previously associated with the drug.  In CREB rats, place-conditioning occurred at a much lower dose than oberved in normal rats, sugggesting that CREB increases the rewarding effect of cocaine.  The dominat negative mutation, on the other hand, resulted in place-aversion, with mCREB rats avoiding the placed associated with cocaine admnistration.  These results suggest tht variability in the expression CREB may affect an individual's susceptibility to cocaine and relapse.  Carlezon et al., Science, 282:2272-2275, 1998.

dopamine receptor, type 2 (DR2)
    Using positron emission tomography, the availability of dopamine receptors in the brain was compared between normal subjects and cocaine abusers.  Humans addicted to cocaine showed significant decreases in dopamine receptor availability which persisted for months after detoxification.  These differences were most pronounced in the orbito-frontal cortex and cingulate gyri,  Dopamine dysregulation of these brain areas could lead to the loss of control resulting in compulsive drug-taking behavior.  Volkow et al., Synapse, 14:169-177, 1993.

fosB [GE]
    FosB is a transcription factor.  Mice were genetically-engineered to overexpress FosB in the striatum by placing the gene under the control of a neuron specific promoter.  The gene was also made inducible by utilizing the tetracycline gene-regulation system.  Mice were conceived and raised under conditions in which the fosB transgene was inactive.  Prior to testing, the gene was induced, resulting in selective and increased expression of the FosB protein in the striatum of transgenic mice.  These genetically-altered mice show increased sensitivity to the rewarding properties of cocaine as reflected in enhanced conditioning to cocaine at the lowest dosages tested.  Expression of the GluR2 subunbit of the AMPA  (alpha- amino-3-hydroxy-5-methyl-4-isoxazole) glutamate receptor was enhanced in the transgenic mice, suggesting that it is involved in the increased sensitivity to cocaine.  Keltz et al., Nature, 401:272-76, 1999.

serotonin receptor, subtype 1B (5-HTR1B) [GE]
    Serotonin-1B receptor is involved in the vulnerability to cocaine addiction.  Knock-out mice for the serotonin-1B receptor and wild-type littermates were trained to self-administer cocaine by pressing a lever. Once trained, the authors increased the number of times the lever had to be pressed to receive drug delivery. They found that as the workload increased, the knockout mice were more willing to continue to respond to cocaine by pushing the lever. They also showed that knockout mice sensitized to lower doses of cocaine than wild-type littermates. Knockout mice also exhibited increased basal levels of fos-related proteins; in contrast, these proteins are found in wild-type littermates only after cocaine stimulation. The results suggest that the serotonin-1B receptor normally acts as a brake on the brain's "want" system; its removal leads to increased sensitivity to cocaine addiction.  Lack of the 1B receptor may also have consequential effects on the dopamine system. Roche et al., Nature, 393:175-178, 1998.

Food
obese
    Leptin, a polypeptide hormone coded for by the obese gene, is produced by fats cells.  Rodents with mutations in the obese gene exhibit profound obesity.  Administration of leptin to such rodents reverses the obsesity syndrome, stimulating fat metabolism and reducing food intake.  The reduction in food intake produced by leptin administration appears to be caused by decreasing the reward value of food.  Fulton et al., Science, 287:125-128, 7 Jan. 2000.

Gambling
monoamine oxidase A (MAOA) [HGL]
    Pathological gambling has been described as an impulse control disorder similar to substance addictions, but without the substance.  Three different alleles (A, B, and C) of monoamine oxidase A (MAOA) were studied.  The B or B/B genotype was found in significantly more male gamblers having the most severe pathology as compared to a male control group, suggesting that the B allele may play a role in impulse control susceptibility.  This correlation did not exist in the group of female gamblers studied.  Ibanez et al., Molecular Psychiatry, 5:105-109, 2000.

monoamine oxidase B (MAOB)* [HGL]
    No correlation between monoamine oxidase B (MAOB) and gambling.   Ibanez et al., Molecular Psychiatry, 5:105-109, 2000.

Opiate
ß-arrestin-2 [GE]
    ß-arrestin-2 is a regulatory protein that interacts with G-protein coupled heptahelical receptors, such as the mu-opiate receptor.  Knockout mice homozygous deficient for ß-arrestin-2 were produced ("ßarr2-KO").  After being administered morphine, these mice showed enhanced and prolonged tolerance to pain.  See, Entry under Pain for ß-arrestin-2.  However, ßarr2-KO mice did not become tolerant to the antipain effects of morphine as did their wild-type littermates.  They exhibited the same responsiveness to morphine after both acute and chronic administration.  Despite the failure to become tolerant to morphine's effects, ßarr2-KO still developed physical dependence on morphine after chronic administration via morphine pellet implantation.  These mice experienced withdrawal symptoms like their wild-type littermates.  Thus, morphine tolerance does not appear to be required to develop physical dependence.  Biochemical studies showed that desensitization of the mu-opiate receptor occurred in wild-type mice, but not in ßarr2-KO mice, indicating that desensitization contributes to the development of morphine antinociception tolerance.  On the other hand, adenyl cyclase activity in the brains of mice chronically administered morphine increased significantly in both ßarr2-KO and wild-type littermates.  This suggest that increased cyclase activity plays a role in physical dependence, but not on morphine tolerance.  Bohn et al., Nature, 408:720-723, 7 Dec. 2000.

cannabinoid (CB1) receptor [GE]
    The reinforcing properties of morphine and the severity of opiate withdrawal symptoms were reduced in mice lacking the CB1 receptor, suggesting a role of the CB1 in opiate addiction.  Ledent et al., Science, 283:401-404, 1999.

dopamine receptor, subtype D2 [GE]
    Lack of the receptor in mice does not prevent physical dependence on a drug but abolishes its rewarding effects.  A total suppression of the rewarding effect of morphine.  Maldonado et al., Nature, 388:586-589, 1997.