View Full Version : Your dopamine receptors. . .


Amtram
06-04-13, 04:40 PM
Just out of curiosity, I thought I would hit OMIM to see what I could find about the function (or dysfunction) of different dopamine receptors. atSWIMtooboreds had mentioned that we should consider its role in ADHD, and I thought that maybe it would be good to understand that and a little more.

The DRD1 receptor (http://omim.org/entry/126449?search=DRD1&highlight=drd1):

Lee et al. (2002) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference11) reported that dopamine D1 receptors modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A (138249 (http://omim.org/entry/138249)) and NR2A (138253 (http://omim.org/entry/138253)). While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see 171833 (http://omim.org/entry/171833))-dependent pathway.

Stipanovich et al. (2008) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference15) demonstrated that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kD dopamine- and cAMP-regulated phosphoprotein (DARPP32; 604399 (http://omim.org/entry/604399)). This accumulation is mediated through a signaling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A (see 176915 (http://omim.org/entry/176915)), and dephosphorylation of DARPP32 at ser97 and inhibition of its nuclear export. The nuclear accumulation of DARPP32, a potent inhibitor of protein phosphatase-1 (see 176875 (http://omim.org/entry/176875)), increased the phosphorylation of histone H3 (see 602810 (http://omim.org/entry/602810)), an important component of nucleosomal response. Mutation of ser97 profoundly altered behavioral effects of drugs of abuse and decreased motivation for food, underlining the functional importance of this signaling cascade.

Working memory is a key function for human cognition, dependent on adequate dopamine neurotransmission. McNab et al. (2009) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference14) showed that the training of working memory, which improves working memory capacity, is associated with changes in the density of cortical dopamine D1 receptors. Fourteen hours of training over 5 weeks in 13 volunteers, healthy males aged 20 to 28 years, was associated with changes in both prefrontal and parietal D1 binding potential, as determined by positron emission tomography while the participants were resting before and after training. McNab et al. (2009) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference14) concluded that this plasticity of the dopamine D1 receptor system demonstrates a reciprocal interplay between mental activity and brain biochemistry in vivo.

Lim et al. (2012) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference12) showed that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin-4 receptor (MC4R; 155541 (http://omim.org/entry/155541)). Stress-elicited increases in behavioral measurements of anhedonia, but not increases in measurements of behavioral despair, are prevented by blocking these melanocortin-4 receptor-mediated synaptic changes in vivo. Lim et al. (2012) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference12) concluded that stress-elicited anhedonia requires a neuropeptide-triggered, cell type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression.

The entry also contains links to studies associating DRD1 with systolic blood pressure, nicotine dependence, and schizophrenia.

Amtram
06-04-13, 04:48 PM
The DRD2 Receptor (http://omim.org/entry/126450?search=DRD2&highlight=drd2):

There is very little I can simply copy/paste here. D2 receptors seem to have a lot more problems when accompanied by certain other genes and alleles, and dysfunctions are most highly associated with schizophrenia and dystonias. I think it may be useful to look at the mouse studies, but keep in mind that these do not automatically apply to humans. . .

Balk et al. (1995) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference1) used homologous recombination to generate D2 receptor-deficient mice. Absence of D2 receptors led to animals that were akinetic and bradykinetic in behavioral tests and showed significantly reduced spontaneous movements. The phenotype resembled Parkinson disease. Maldonado et al. (1997) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference37) studied the behavior of DRD2 knockout mice and showed that there was a total suppression of rewarding behavior with morphine. In contrast, these animals showed normal responses when food was used as a reward.

Chronic blockade of dopamine D2 receptors, a common mechanism of action for antipsychotic drugs, downregulates D1 receptors (126449 (http://omim.org/entry/126449)) in the prefrontal cortex and, as shown by Castner et al. (2000) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference6), produces severe impairments in working memory. These deficits were reversed in monkeys by short-term coadministration of a D1 agonist, ABT431, and this improvement was sustained for more than a year after cessation of D1 treatment. Castner et al. (2000) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference6) concluded that pharmacologic modulation of the D1 signaling pathway can produce long-lasting changes in functional circuits underlying working memory. Resetting this pathway by brief exposure to the agonist may provide a valuable strategy for therapeutic intervention in schizophrenia and other dopamine-dysfunctional states.

In rat/mouse neuronal cell lines, Yujnovsky et al. (2006) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference54) found that Drd2 mediated stimulation of circadian Clock (601851 (http://omim.org/entry/601851)):Bmal1 (602550 (http://omim.org/entry/602550)) activity and increased expression of the Per1 (602260 (http://omim.org/entry/602260)) gene. The response was mediated by the transcriptional coactivator CREB-binding protein (CREBBP; 600140 (http://omim.org/entry/600140)). Clock:Bmal1-dependent activation and light inducibility of Per1 transcription were drastically dampened in the retinas of Drd2-null mice. The findings suggested a physiologic link between photic input, dopamine signaling, and molecular clock machinery.

Dalley et al. (2007) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference9) reported that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine function before drug exposure. Using positron emission tomography, Dalley et al. (2007) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference9) demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of dopamine release. Dalley et al. (2007) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference9) concluded that their data demonstrated that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

Schaefer et al. (2010) (http://omim.org/entry/126450?search=DRD2&highlight=drd2#reference47) generated mice lacking Ago2 (EIF2C2; 606229 (http://omim.org/entry/606229)), which plays a significant role in microRNA (miRNA) generation and miRNA-mediated gene silencing, in Drd2-expressing striatum neurons. These mice had normal neuron and brain morphology. Ablation of Ago2 in Drd2-expressing striatum neurons alleviated cocaine addiction, as manifested by reduced motivation to self-administer the drug. Reduced drug dependence was associated with selective downregulation of a set of miRNAs in Ago2-deficient striatum. Comparison of these Ago2-dependent miRNAs with miRNAs enriched and/or upregulated in Drd2-expressing neurons revealed 23 miRNAs likely to play a role in cocaine addiction. Reporter assays showed that these 23 miRNAs regulated genes important for the development of cocaine addiction, including Cdk5r1 (603460 (http://omim.org/entry/603460)) and the transcription factors Fosb (164772 (http://omim.org/entry/164772)) and Mef2d (600663 (http://omim.org/entry/600663)).

Amtram
06-04-13, 04:53 PM
The DRD3 Receptor (http://omim.org/entry/126451?search=drd3&highlight=drd3):

Molecular Genetics Crocq et al. (1992) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference4) presented data from 2 independent studies carried out in the UK and France, determining frequencies of a BalI polymorphism (S9G; 126451.0001 (http://omim.org/entry/126451#0001)) in the DRD3 gene in patients with schizophrenia (181500 (http://omim.org/entry/181500)). In both studies, more patients than controls were homozygous (p = 0.005, p = 0.008). When pooled data were analyzed, this difference was highly significant (p = 0.0001) with a relative risk of schizophrenia in homozygotes of 2.61 (95% CI = 1.60-4.26). Shaikh et al. (1993) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference17) failed to find similar results when they studied bipolar affective disorder. They believed that this indicated a genetic distinction between the 2 disorders which have been thought by some to be different expressions of the same underlying disturbance. Nothen et al. (1993) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference14) were unable to confirm the finding by Crocq et al. (1992) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference4) of an association between schizophrenia and homozygosity at the DRD3 receptor locus. They pointed out that there was an overrepresentation of heterozygotes in the control groups studied by Crocq et al. (1992) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference4). In a study of 91 Japanese patients and 90 controls, Nanko et al. (1993) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference13) likewise could not confirm the findings of Crocq et al. (1992) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference4). However, Spurlock et al. (1998) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference19) did replicate the findings of Crocq et al. (1992) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference4) as part of the European Multicentre Association Study of Schizophrenia. An excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi(2), 8.54, P = 0.003; odds ratio, 1.64, 95% CI, 1.18-2.29).

Although the precise pathophysiology of schizophrenia is unknown, the dopaminergic hypothesis assumes that the illness results from excessive activity at dopamine synapses in the brain. Because the diagnosis of schizophrenia relies on descriptive behavioral and symptomatic information, a peripheral measurable marker might enable a simpler, more rapid, and more accurate diagnosis and monitoring. Peripheral blood lymphocytes have been found to express several dopamine receptors: D3, D4 (DRD4; 126452 (http://omim.org/entry/126452)), and D5 (DRD5; 126453 (http://omim.org/entry/126453)). It has been suggested, furthermore, that these dopamine receptors found on lymphocytes reflect the receptors found in the brain. Ilani et al. (2001) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference8) demonstrated a correlation between the D3 dopamine receptor on lymphocytes and schizophrenia and showed a significant elevation of at least 2-fold in the mRNA level of the D3, but not of the D4, dopamine receptor in schizophrenic patients. The increase was not affected by different antipsychotic drug treatments. Moreover, nonmedicated patients exhibited the same pattern, indicating that this change was not a result of medical treatment. Ilani et al. (2001) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference8) proposed that increased D3 receptor mRNA on blood lymphocytes can be used as a marker for identification and follow-up of schizophrenia.

Eye movement disturbances occur in most patients with schizophrenia and in many of their healthy first-degree relatives (Holzman, 2000 (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference7)). Rybakowski et al. (2001) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference16) studied fixation and smooth pursuit eye abnormalities in 119 schizophrenic patients and 94 unrelated healthy control subjects in association with the ser9-to-gly polymorphism of the DRD3 gene. They found that both kinds of eye movement abnormalities were higher in individuals with a homozygous ser9 genotype. The ser9/ser9 genotype was more prevalent in patients with a higher intensity of both fixation (58.1 vs 23.9%, P less than 0.001) and smooth pursuit disturbances (52.3 vs 25.8%, P less than 0.02) and the ser9/gly9 genotype frequency was lower in patients with higher fixation disturbances (37.0 vs 60.9%, P less than 0.02). Similarly, genotype frequency of ser9/ser9 was higher in subjects with any degree of eye movement disturbance than in control subjects. Rybakowski et al. (2001) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference16) suggested that the ser9/ser9 polymorphism may contribute to eye movement disturbances, which are used as a marker for schizophrenia.

Lohmueller et al. (2003) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference11) performed a metaanalysis of 301 published genetic association studies covering 25 different reported associations with common disorders. For 8 of these associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. One of these 8 was the DRD3/schizophrenia association (S/S of S9G polymorphism) as first reported by Crocq et al. (1992) (http://omim.org/entry/126451?search=drd3&highlight=drd3#reference4).

Note again the association with schizophrenia - and a specific dystonia limited to eye movements.

Amtram
06-04-13, 05:02 PM
The DRD4 Receptor (http://omim.org/entry/126452?search=drd4&highlight=drd4):

Now we're starting to see more specific ADHD connections with dopamine.


Attention deficit-hyperactivity disorder (ADHD; 143465 (http://omim.org/entry/143465)) is a developmental syndrome expressed along 3 domains: inattention, hyperactive-impulsive, and combined type. Several investigations examined the role of the DRD4 exon 3 repeat polymorphism in ADHD. The long 7R allele of this receptor was shown in population-based and family-based studies (LaHoste et al., 1996 (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference29); Rowe et al., 1998 (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference43); Smalley et al., 1998 (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference49); Swanson et al., 1998 (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference52)), but not in 1 case-control design (Castellanos et al., 1998 (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference3)), to be a risk factor for this disorder. In a family-based study of the DRD4 exon 3 repeat region and ADHD, Eisenberg et al. (2000) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference14) failed to observe preferential transmission of the DRD4 7R allele, and there was no preferential transmission observed when genotypes were compared. The reasons for the conflict with earlier findings were discussed.

Swanson et al. (2000) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference50) evaluated ADHD subgroups defined by the presence or absence of the 7R allele of the DRD4 gene, using neuropsychologic tests with reaction time measures designed to probe attention networks with neuroanatomic foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7R-present subgroup showed normal speed and variability of response, whereas the average reaction times of the 7R-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7R-present subgroup seemed to be free of some of the neuropsychologic abnormalities thought to characterize ADHD. These findings led Swanson et al. (2000) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference50) to reconceptualize the possible association of the DRD4 gene with ADHD.

Ding et al. (2002) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference11) stated that 8 separate replications of the initial observation of an increased frequency of the DRD4 7R alleles in ADHD probands had been reported.

Langley et al. (2004) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference30) found that in children with ADHD, possession of the DRD4 7R allele appeared to be associated with an inaccurate, impulsive response style on neuropsychologic tasks that was not explained by ADHD symptom severity. Children with the 7R allele had significantly more incorrect responses and shorter mean reaction times for incorrect responses, and displayed higher activity levels as measured by actigraphy compared to children without the allele.

Lynn et al. (2005) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference34) investigated the link between ADHD in adults, novelty-seeking temperament, and the DRD4 7R allele in 171 parents from 96 families with ADHD-affected sib pairs. Of the parents, 56 (33%) had a lifetime history of ADHD with 28 (50%) continuing to meet DSM-IV criteria. Novelty seeking and the 7R variant were associated with a lifetime history of ADHD; however, novelty seeking and ADHD did not appear to be due to the DRD4 7R variant.

Leung et al. (2005) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference31) noted that the DRD4 7R allele associated with ADHD varies in prevalence across ethnic groups and is very low in Asian populations. Leung et al. (2005) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference31) studied 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate responders and observed no evidence of 7R alleles. Instead, they found a 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically matched controls (20%) (p = 0.015). This 1.65-fold increase in the 2R allele was close to the increase of the 7R allele observed in ADHD children of European ancestry. Leung et al. (2005) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference31) postulated that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD.

Manor et al. (2002) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference36) noted that polymorphisms (specifically the short exon 3 allele) of the DRD4 gene have been associated with ADHD in some studies, but that 2 Israeli studies (Eisenberg et al., 2000 (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference14); Kotler et al., 2000 (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference26)) failed to observe this association. Manor et al. (2002) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference36) studied 178 Israeli triads using the transmission disequilibrium test (TDT). Preferential transmission of the short allele was associated with ADHD. Study of the same triad using the Test of Variables of Attention (TOVA) revealed that individuals with the short allele of the exon 3 repeat performed significantly worse on the TOVA measured both by errors of commission and response time variable. A dosage effect was observed in that increasing repeat size was accompanied by a reduced number of errors of commission and a significant difference was observed between the 2 versus 7 repeats.

McCracken et al. (2000) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference37) found significant preferential transmission of a 240-bp (long) allele of the DRD4 120-bp repeat promoter polymorphism (126452.0003 (http://omim.org/entry/126452#0003)) in 371 children with ADHD, and further analyses strengthened the evidence for linkage.

D'Souza et al. (2004) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference8) studied the function of the 120-bp tandem duplication sequence of the DRD4 gene by using transient transfection in 4 human cell lines and luciferase reporter gene assays. The longer allele had lower transcriptional activity than the shorter allele. Lower levels of transcriptional activity observed with the long form of the polymorphism could result in lower levels of expression of the DRD4 gene which may affect levels of dopamine in the synaptic cleft. The authors noted that their findings supported the hypothesis of McCracken et al. (2000) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference37) that the 240-bp allele was a risk factor for ADHD.

The Attention Network Test (ANT) uses the flanker task to measure conflict and shows strong activation in the dorsal anterior cingulate on neuroimaging studies. Because the cingulate is modulated by the ventral tegmental dopamine system, Fossella et al. (2002) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference16) tested 200 normal individuals with the ANT and genotyped them for 4 genes related to the dopamine system. Polymorphisms in the DRD4 and MAOA (309850 (http://omim.org/entry/309850)) genes were significantly related to the efficiency of conflict. To examine whether this genetic variation contributed to differences in brain activation within the anterior cingulate cortex, Fan et al. (2003) (http://omim.org/entry/126452?search=drd4&highlight=drd4#reference15) genotyped 16 subjects for the DRD4 and MAOA genes who had been scanned during the ANT. In each of the 2 genes they identified a polymorphism in which persons with the allele associated with better behavioral performance showed significantly more activation in the anterior cingulate while performing the ANT than those with the allele associated with worse performance. The 2 polymorphisms were the -1217G insertion/deletion in the upstream region of DRD4 and a 3-repeat allele of the 30-bp repeat in the MAOA promoter (309850.0002 (http://omim.org/entry/309850#0002)). The results demonstrated how genetic differences among individuals can be linked to individual differences in neuromodulators and in the efficiency of the operation of an appropriate attentional network.

In addition, there follow many other studies associating this receptor with novelty-seeking and risk-taking behavior, one on alcoholism, and one on unipolar depression.

Impaired function of this receptor can lead to autonomic nervous system disorders, and may be responsible for reaction to or resistance to certain psychiatric medications.

Amtram
06-04-13, 05:08 PM
The DRD5 Receptor (http://omim.org/entry/126453?search=drd5&highlight=drd5):

This one is again strongly associated with ADHD, but also with blepharospasm (eye muscle spasms.) It is extremely similar to the DRD1 receptor, but has a higher affinity for dopamine than D1 does.

Misbahuddin et al. (2002) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference11) performed association studies between focal dystonia blepharospasm (606798 (http://omim.org/entry/606798)) and 10 previously reported polymorphisms within the dopamine transporter (DAT) gene (SLC6A3; 126455 (http://omim.org/entry/126455)) and dopamine receptor genes D1-5. Allele 2 of the dinucleotide repeat in the D5 receptor gene was found to have an increased frequency in blepharospasm cases compared with controls (606798.0001 (http://omim.org/entry/606798#0001)). The same allele had been found in association with another form of focal dystonia, primary cervical dystonia (Placzek et al., 2001 (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference12)). Among 100 German and 121 French patients with idiopathic focal dystonia, including blepharospasm and torticollis, Sibbing et al. (2003) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference15) found no association with allele 2 or allele 6 of the DRD5 polymorphism.

Daly et al. (1999) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference2) reported a significant association between attention-deficit/hyperactivity disorder (ADHD; 143465 (http://omim.org/entry/143465)) and the 148-bp allele of a microsatellite located 18.5 kb 5-prime to the DRD5 gene. Subsequent studies of this (CA)n repeat marker showed nonsignificant trends toward association with the same allele. Although there was no evidence to suggest that the D5 microsatellite is itself functional, the association reported by Daly et al. (1999) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference2) was in the opinion of Lowe et al. (2004) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference10) too strong to be ignored. Therefore, they hypothesized that if the association with ADHD were true, the microsatellite may be in linkage disequilibrium (LD) with 1 or more functional variants. To this end, they invited all known groups with samples based on parent-proband trios to genotype their samples for the marker and present their data for analysis. Fourteen independent samples were analyzed individually and, in the absence of heterogeneity, analyzed as a joint sample. The joint analysis showed association with the DRD5 locus (P = 0.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appeared to be confined to the predominantly inattentive and combined clinical subtypes.

.0002 ATTENTION DEFICIT-HYPERACTIVITY DISORDER, SUSCEPTIBILITY TO
DRD5, (CA)n MARKER
Daly et al. (1999) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference2) and Lowe et al. (2004) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference10) demonstrated an association between ADHD (143465 (http://omim.org/entry/143465)) and a common 148-bp allele of a microsatellite (CA)n marker located 18.5 kb 5-prime of the DRD5 gene. They considered it unlikely that this was a functional variant and that it was more probable that the microsatellite is in linkage disequilibrium with the true functional variant (or variants) located in or close to the DRD5 gene.

Kustanovich et al. (2004) (http://omim.org/entry/126453?search=drd5&highlight=drd5#reference7) genotyped a large multiplex sample of ADHD-affected children and their parents for polymorphisms in genes reported to be associated with ADHD, including DRD5, and analyzed the results using the transmission disequilibrium test. The dinucleotide repeat polymorphism near the DRD5 gene showed an association with ADHD, with biased nontransmission of the 146-bp allele and a trend toward excess transmission of the 148-bp allele. The DRD5 146-bp allele showed an estimated genotype relative risk of 1.7.

DcGonzo
06-04-13, 05:23 PM
umm...

atSWIMtooboreds
06-04-13, 05:26 PM
That 2R/7R thing is really interesting. Do you happen to know if those alleles are similarly heritable?

Amtram
06-04-13, 05:42 PM
It looked like it from what I was seeing. The nice thing about OMIM is that it has clickable links to the PubMed papers all over, and if you go to the site itself and enter the name of the alleles, it'll bring up all of the related papers as well. Cross-references like mad.

One of the things that was crossing my mind as I was looking at these before (I've used OMIM before putting together this thread) is how these neurotransmitters each do so many different things, depending on which receptors are using them, and how the genes can cause symptoms that may have nothing whatsoever to do with the brain.

In a couple of the dopamine receptors descriptions, you'll see references to kidney function, and we know that there's a connection between serotonin and liver function, so in layperson mode it's interesting to speculate whether we'd be able to narrow down which receptor is causing a problem by looking for symptoms elsewhere in the body.

i.e., I am always having trouble with eye twitching. . .could that mean that my D5 receptor is causing more trouble than my D4? If it does, what does that mean for my risk of developing Parkinson's later on?

Would it be possible at some point to test kidney function or liver enzymes or various endocrine functions to find out what's going on with the brain in a less invasive and more conclusive way? Those are the kind of speculative possibilities I find fascinating.

Amtram
06-04-13, 05:52 PM
I pulled up a search on that 7R allele and realized that I'd read a lot of papers on this years ago - all of them trying to find the link with ADHD. They weren't very certain early on, but I'm looking at a couple from 2004 that seem to show heritability and a strong correlation between that particular repeat in the DRD4 allele and ADHD.

simondoll
07-19-13, 03:37 AM
Just out of curiosity, I thought I would hit OMIM to see what I could find about the function (or dysfunction) of different dopamine receptors. atSWIMtooboreds had mentioned that we should consider its role in ADHD, and I thought that maybe it would be good to understand that and a little more.

The DRD1 receptor (http://omim.org/entry/126449?search=DRD1&highlight=drd1):

Lee et al. (2002) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference11) reported that dopamine D1 receptors modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A (138249 (http://omim.org/entry/138249)) and NR2A (138253 (http://omim.org/entry/138253)). While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see 171833 (http://omim.org/entry/171833))-dependent pathway.

Stipanovich et al. (2008) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference15) demonstrated that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kD dopamine- and cAMP-regulated phosphoprotein (DARPP32; 604399 (http://omim.org/entry/604399)). This accumulation is mediated through a signaling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A (see 176915 (http://omim.org/entry/176915)), and dephosphorylation of DARPP32 at ser97 and inhibition of its nuclear export. The nuclear accumulation of DARPP32, a potent inhibitor of protein phosphatase-1 (see 176875 (http://omim.org/entry/176875)), increased the phosphorylation of histone H3 (see 602810 (http://omim.org/entry/602810)), an important component of nucleosomal response. Mutation of ser97 profoundly altered behavioral effects of drugs of abuse and decreased motivation for food, underlining the functional importance of this signaling cascade.

Working memory is a key function for human cognition, dependent on adequate dopamine neurotransmission. McNab et al. (2009) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference14) showed that the training of working memory, which improves working memory capacity, is associated with changes in the density of cortical dopamine D1 receptors. Fourteen hours of training over 5 weeks in 13 volunteers, healthy males aged 20 to 28 years, was associated with changes in both prefrontal and parietal D1 binding potential, as determined by positron emission tomography while the participants were resting before and after training. McNab et al. (2009) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference14) concluded that this plasticity of the dopamine D1 receptor system demonstrates a reciprocal interplay between mental activity and brain biochemistry in vivo.

Lim et al. (2012) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference12) showed that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin-4 receptor (MC4R; 155541 (http://omim.org/entry/155541)). Stress-elicited increases in behavioral measurements of anhedonia, but not increases in measurements of behavioral despair, are prevented by blocking these melanocortin-4 receptor-mediated synaptic changes in vivo. Lim et al. (2012) (http://omim.org/entry/126449?search=DRD1&highlight=drd1#reference12) concluded that stress-elicited anhedonia requires a neuropeptide-triggered, cell type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression.

The entry also contains links to studies associating DRD1 with systolic blood pressure, nicotine dependence, and schizophrenia.

Awesome information.. Thanks for sharing links.. Links are very helpful so thanks again

SB_UK
07-19-13, 08:01 AM
... ... showed that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin-4 receptor (MC4R; 155541 (http://omim.org/entry/155541)). Stress-elicited increases in behavioral measurements of anhedonia ... ... are prevented by blocking these melanocortin-4 receptor-mediated synaptic changes in vivo ... ...

Hmmm ... ... 'I was looking for a job and I found a job, and Heaven knows I'm miserable now'.


The point is to be happy - but you gotta' know how ... ...

Amtram
01-19-14, 10:01 PM
As I have come to discover, there are not only neural pathways that are related to functions (the most obvious being the ones that control voluntary movement, involuntary functions, vision, and hearing) but also pathways that are related to specific neurotransmitters. These pathways are as relevant to treatment as identification of the functions of the individual synapses. Psychopharmacology Institute provides a number of tutorial slideshows and videos for free. You can watch them even if you don't subscribe, and they won't harass you. Here's the presentation on dopaminergic pathways on YouTube:

https://www.youtube.com/watch?v=5wM2oqQJhV4

This (http://psychopharmacologyinstitute.com/antipsychotics-videos/dopamine-pathways-antipsychotics-pharmacology/) is the site link for the transcript and links to more explanatory information.

mildadhd
01-19-14, 10:41 PM
The SEEKING/desire system

This extensive network confluent with the medial forebrain bundle (MFB) is traditionally called the “brain reward system.” In fact, this is a general-purpose appetitive motivational system that is essential for animals to acquire all resource needs for survival, and it probably helps most other emotional systems to operate effectively. It is a major source of life “energy”, sometimes called “libido.” In pure form, it provokes intense and enthusiastic exploration and appetitive anticipatory excitement/learning. When fully aroused, SEEKING25 fills the mind with interest and motivates organisms to effortlessly search for the things they need, crave, and desire. In humans, this system generates and sustains curiosity from the mundane to our highest intellectual pursuits. This system becomes underactive during addictive drug withdrawal, chronic stress, and sickness, and with accompanying feelings of depression. Overactivity of this system can promote excessive and impulsive behaviors, along with psychotic delusions and manic thoughts. All antipsychotics reduce arousability of this “reality-creating” mechanism of the brain. The term “reality-creating” is used to highlight the fact that this system appears to generate causal convictions about the nature of the world from the perception of correlated events (for a full discussion see Chapter 8 of Affective Neuroscience 3).


Neuroanatomically, SEEKING circuitry corresponds to the extensive medial forebrain bundle and major dopamine-driven, self-stimulation “reward” circuitry coursing from ventral midbrain to nucleus accumbens and medial frontal cortex, where it can promote frontal cortical functions related to planning and foresight. Rather than being a “pleasure or reinforcement system,” SEEKING coaxes animals to acquire resources needed for survival. It promotes learning by mediating anticipatory eagerness, partly by coding predictive relationships between events. It promotes a sense of engaged purpose in both humans and animals, and is diminished in depression and the dysphoria of withdrawal from addictive drugs. This is further highlighted by the simple fact that bilateral lesions of the system produce profound amotivational states in animals (all appetitive behaviors are diminished) and the elevated threshold for self-stimulation reward probably reflects the dysphoria state.

Brain research supports the existence of at least seven primary-process (basic) emotional systems - SEEKING, RAGE, FEAR, LUST, CARE, GRIEF (formerly PANIC), and PLAY - concentrated in ancient subcortical regions of all mammalian brains.

In sum, affective neuroscientific analysis of basic emotions is based on several highly replicable facts: (i) Coherent emotional-instinctual behaviors can be aroused by electrically stimulating very specific subcortical regions of the brain; (ii) Wherever one evokes emotional action patterns with ESB, there are accompanying affective experiences. Again, the gold standard for this assertion is the fact that the brain stimulations can serve as “rewards” when positive-emotions are aroused - eg, SEEKING, LUST, CARE, and aspects of PLAY. When negative emotions are aroused - RAGE, FEAR, GRIEF - animals escape the stimulation; (iii) The above behavioral and affective changes are rarely, if ever, evoked from higher prefrontal neocortical regions, suggesting that higher brain areas may not have the appropriate circuitry to generate affective experiences, although the neocortex can clearly regulate (eg, inhibit) emotional arousals and, no doubt, prompt emotional feelings by dwelling on life problems.


The emotional primes are summarized in several monographs, with another appearing soon.24 Thumbnail descriptions are provided below, with one key reference for each.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181986/#!po=2.00000