Neurogenetics of dopaminergic receptor supersensitivity in activation of brain reward circuitry and relapse: proposing "deprivation-amplification relapse therapy" (DART).
OBJECTIVE
It is well known that after prolonged abstinence, individuals who use their drug of choice experience a powerful euphoria that often precipitates relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed "supersensitivity" might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared with DRD2 A2 allele carriers. Because carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine D2 agonist bromocriptine. Moreover, under chronic or long-term therapy with D2 agonists, such as bromocriptine, it has been shown in vitro that there is a proliferation of D2 receptors. One explanation for this relates to the demonstration that the A1 allele of the DRD2 gene is associated with increased striatal activity of L-amino acid decarboxylase, the final step in the biosynthesis of dopamine. This appears to be a protective mechanism against low receptor density and would favor the utilization of an amino acid neurotransmitter precursor like L-tyrosine for preferential synthesis of dopamine. This seems to lead to receptor proliferation to normal levels and results in significantly better treatment compliance only in A1 carriers.
We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse, including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: "denervation supersensitivity." Rats with unilateral depletions of neostriatal dopamine display increased sensitivity to dopamine agonists estimated to be 30 to 100 x in the 6-hydroxydopamine (6-OHDA) rotational model. Given that mild striatal dopamine D2 receptor proliferation occurs (20%-40%), it is difficult to explain the extent of behavioral supersensitivity by a simple increase in receptor density. Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing amino acid neurotransmitter precursors, enkephalinase, and catechol-O-methyltransferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in reward deficiency syndrome (RDS) probands. If future translational research reveals that dopamine agonist therapy reduces relapse in RDS, it would support the proposed concept, which we term "deprivation-amplification relapse therapy" (DART). This term couples the mechanism for relapse, which is "deprivation-amplification," especially in DRD2 A1 allele carriers with natural D2 agonist therapy utilizing amino acid precursors and COMT and enkepalinase inhibition therapy.
Blum
Kenneth
K
Department of Psychiatry, School of Medicine and McKnight Brain Institute, University of Florida, Gainsville, FL, USA. drd2gene@aol.com
Chen
Thomas J H
TJ
Downs
B William
BW
Bowirrat
Abdalla
A
Waite
Roger L
RL
Braverman
Eric R
ER
Madigan
Margaret
M
Oscar-Berman
Marlene
M
DiNubile
Nicholas
N
Stice
Eric
E
Giordano
John
J
Morse
Siobhan
S
Gold
Mark
M
D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008962:Models, Theoretical; D011110:Polymorphism, Genetic; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics*; D012201:Reward; D055502:Secondary Prevention; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology
D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2