This is something I have been working on having previously taken the drug and believe to have experience a negative reaction to it.
Dopamine and Dopamine D2 Receptors and their relationship to depression
http://www.dukemedne...cle.php?id=9153
http://www.medicalne...icles/28280.php
http://www.webmd.com...e-in-depression
"Li-Huei Tsai, Harvard Medical School (HMS) professor of pathology, HMS research fellow Sang Ki Park, and colleagues worked with mice and found a novel function for the molecule Par-4 (prostate apoptosis response 4)--as a binding partner for dopamine receptor D2. When mice deficient in Par-4 were subjected to stress, they showed depression-like behaviors, proposing Par-4-as a molecular link between dopamine signaling and depression. Par-4 was previously implicated as a proapoptotic factor in neurodegenerative diseases such as Alzheimer's disease. These new findings reveal an unexpected role for Par-4 in the dopamine system and present a rare glimpse of molecular mechanisms behind clinical depression."
"In laboratory tests with mice, researchers found prolonged exposure to dopamine through this pathway inactivated a regulatory protein in the brain known as Akt and caused the mice to behave like they were depressed in response to stress."
"The Duke team's previous work suggested that the regulatory protein beta-arrestin 2, normally involved in desensitization of receptor signals, is required for normal dopamine-related behavior. They also found that prolonged stimulation of D2 receptors leads to inactivation of a regulatory protein called Akt.
Furthermore, they showed, Akt inactivation occurred more slowly and was maintained for longer than other similar biochemical events that had previously been observed. However, the mechanism behind that inactivation remained unclear.
In the current study in mice, the Duke team found that Akt inactivation by dopamine involves the formation of a previously unidentified complex containing beta-arrestin 2, Akt and a third protein phosphatase 2A that inactivates Akt. Mice lacking beta-arrestin become less responsive to certain drugs and exhibit abnormalities in behaviors, such as locomotion, associated with dopamine. In addition to the behavioral deficits, the animals also lack normal regulation of Akt, they report.
"These results provide direct physiologically relevant evidence for the emerging concept that beta-arrestin 2 not only controls desensitization but also participates in slow synaptic transmission here by acting as a scaffold for signaling molecules in response to dopamine receptor activation," Caron said.
"The observations also provide an alternative pathway by which dopamine receptor activation leads to the expression of dopamine-associated behaviors." "
Elevated dopamine D2 receptor expression and depression
Am J Psychiatry 163:1594-1602, September 2006
doi: 10.1176/appi.ajp.163.9.1594
© 2006 American Psychiatric Association
Elevated Putamen D2 Receptor Binding Potential in Major Depression With Motor Retardation: An [11C]Raclopride Positron Emission Tomography Study
Jeffrey H. Meyer, M.D., Ph.D., Heather E. McNeely, Ph.D., Sandra Sagrati, B.Sc., Anahita Boovariwala, B.Sc., Krystle Martin, B.Sc., N. Paul L.G. Verhoeff, M.D., Ph.D., Alan A. Wilson, Ph.D., and Sylvain Houle, M.D., Ph.D.
Effect of Major Depressive Episode on Striatal D2 Binding Potential
"As seen in Figure 1, D2 binding potential in depressed subjects was significantly elevated in every striatal region (ANOVA F=4.99–10.23, df=1, 40, p=0.03–0.002; magnitude: 6% to 8%). Somewhat more motor retardation was seen in the depressed subjects (mean=42.6 taps in 10 seconds) than in the healthy subjects (mean=47.0 taps in 10 seconds) (t=1.8, df=38, p=0.08). In the voxel analysis, D2 binding potential in the depressed subjects was elevated in the entire striatum (Figure 2)."
Note: Figures not linked/included
Wellbutrin causes an upregulation of Dopamine D2 Receptors
1: J Recept Res. 1993;13(1-4):341-54.
Regulation of dopamine receptors by bupropion: comparison with antidepressants and CNS stimulants.
Vassout A, Bruinink A, Krauss J, Waldmeier P, Bischoff S.
Research Department, CIBA-GEIGY Ltd., Basel, Switzerland.
Acute treatment of rats with the antidepressant bupropion increased [3H]spiperone binding to D2 receptors in vivo. This dose- and time-dependent effect was greatest in striatum and minimal in cerebellum and pituitary. A parallel behavioral stimulation occurred in the same rats. Among 21 antidepressants and CNS stimulants tested, only those that activate dopamine (DA) transmission had similar effects: nomifensine, amineptine, methylphenidate, D-amphetamine, amfonelic acid, cocaine, benztropine and GBR 12909. Decreasing DA transmission with reserpine plus alpha-methyl-p-tyrosine prevented the action of bupropion. Finally, bupropion was inactive in vitro and ex-vivo. Therefore, we propose that bupropion and other DA-enhancing agents modify the characteristics of [3H]spiperone binding through the intervention of a dynamic regulation of the D2 receptors by the neurotransmitter itself.
PMID: 8095555 [PubMed - indexed for MEDLINE]
Dopamine D2 and striatal acetylcholine or Wellbutrin potentially makes one dumber via dopamine as well as via direct ACH interactions.
Physiological release of striatal acetylcholine in vivo: modulation by D1 and D2 dopamine receptor subtypes
P DeBoer and ED Abercrombie
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey, USA.
Our experiments assessed the modulation of striatal acetylcholine (ACh) output by dopamine (DA) receptor subtypes under physiological conditions using in vivo microdialysis in awake rats. The degree to which the dopaminergic modulation of striatal cholinergic neurons might vary as a function of local extracellular ACh level also was examined by application of varying concentrations of the acetylcholinesterase (AChE), inhibitor neostigmine (NEO) in the microdialysis perfusate. Under physiological conditions (O NEO), the amount of ACh in the dialysates was 25.1 +/- 2.2 fmol/20-microliters sample (n = 20) whereas values of 67.9 +/- 3.5 (n = 35) and 527.7 +/- 56.1 (n = 13) fmol/20- microliters sample were obtained when the applied NEO concentration was 10 and 100 nM, respectively. In the absence of NEO, a low dose of the indirect DA agonist amphetamine (AMPH; 2 mg/kg i.p.) failed to affect striatal ACh output; a higher AMPH dose (10 mg/kg i.p.) significantly decreased the amount of ACh in dialysates. Under physiological conditions, the direct D2-selective agonist quinpirole (3 mg/kg i.p.) decreased extracellular ACh in striatum to nondetectable levels and the direct D1-selective agonist SKF-38393 (10 mg/kg i.p.) produced a significant increase in this measure. Analysis of the changes in striatal ACh output produced by administration of these DA compounds in the absence vs. presence of local NEO revealed that 10 nM NEO did not qualitatively alter the pharmacological responsivity of this system as compared to the physiological condition. However, in the presence of 100 nM NEO, 2 mg/kg AMPH elicited a significant increase in striatal ACh output. At the 100 nM NEO concentration it also was observed that the amplitude of the quinpirole-induced inhibition of ACh efflux did not increase further in proportion to basal ACh levels whereas the amplitude of the increase in ACh output produced by SKF-38393 was linearly related to basal ACh levels across all NEO concentrations. Under conditions where cholinergic pharmacological responsivity was minimally affected (10 nM NEO), the D2 receptor antagonist haloperidol (1 mg/kg i.p.) increased striatal ACh output by 50% and the D1 receptor antagonist SCH-23390 (0.5 mg/kg i.p.) decreased this variable by 41%. Under these conditions, the inhibitory action of quinpirole on ACh output could be reversed by subsequent administration of AMPH (5 mg/kg i.p.) and this effect of AMPH could then be blocked by administration of SCH-23390. Thus, under physiological or low NEO (10 nM) conditions a prevalent D2-mediated inhibition as well as an opposing D1-mediated excitation of striatal ACh output can be demonstrated. At a higher NEO concentration (100 nM), regulation of the striatal ACh system by DA receptor subtypes is differentially affected such that the D2-mediated inhibitory influence no longer predominates over the D1-mediated excitatory drive. Caution should be exercised when interpreting ACh efflux data obtained using microdialysis under conditions of AChE inhibition.
Volume 277, Issue 2, pp. 775-783, 05/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics
Dopamine D2 receptors and memory impairment in cannibis use - just found this one interesting.
D2 dopamine receptors enable Δ9-tetrahydrocannabinol induced memory impairment and reduction of hippocampal extracellular acetylcholine concentration
F Nava,1* G Carta,2 A M Battasi,1 and G L Gessa1,2
11Laboratory of Neuropsychopharmacology, Department of Neuroscience ‘B.B. Brodie', University of Cagliari, Cagliari, Italy
22Neuroscience S.c.a.r.l., Cagliari, Italy
*Author for correspondence: Email: lgessa@unice.it
Received September 15, 1999; Revised March 30, 2000; Accepted April 5, 2000.
Small right arrow pointing to: This article has been cited by other articles in PMC.
Abstract
* The systemic administration of Δ9-tetrahydrocannabinol (2.5–7.5 mg kg−1) reduced hippocampal extracellular acetylcholine concentration and impaired working memory in rats.
* Both effects were antagonized not only by the CB1 cannabinoid receptor antagonist SR141716A (0.5 mg kg−1, i.p.) but also unexpectedly by the D2 dopamine receptor antagonist S(−)-sulpiride (5, 10 and 25 mg kg−1, i.p.). Conversely, Δ9-tetrahydrocannabinol-induced memory impairment and inhibition of hippocampal extracellular acetylcholine concentration were potentiated by the subcutaneous administration of the D2 dopamine receptor agonist (−)-quinpirole (25 and 500 μg kg−1). The inhibition of hippocampal extracellular acetylcholine concentration and working memory produced by the combination of (−)-quinpirole and Δ9-tetrahydrocannabinol was suppressed by either SR141716A or S(−)-sulpiride.
* Our findings suggest that impairment of working memory and inhibition of hippocampal extracellular acetylcholine concentration are mediated by the concomitant activation of D2 dopamine and CB1 cannabinoid receptors, and that D2 dopamine receptor antagonists may be useful in the treatment of the cognitive deficits induced by marijuana.
Keywords: Δ9-Tetrahydrocannabinol, D2 dopamine receptors, working memory, acetylcholine
Methylphenidate reduces/normalizes D2 expression - would chronic wellbutrin use have the same effect since I have not been able to locate any studies to this effect?
Is increased D2 receptor availability associated with response to stimulant medication in ADHD
Developmental Medicine & Child Neurology 2001, 43: 755–760
N Ilgin*Ass. Prof., Department of Nuclear Medicine;
S Senol Assoc. Prof., Department of Child Psychiatry;
K Gucuyener Assoc. Prof., Department of Paediatric
Neurology;
N Gokcora Assoc. Prof.;
S Atavci, Ass. Prof., Department of Nuclear Medicine;
S Sener Prof., Department of Child Psychiatry, Gazi
University, Ankara, Turkey.
*Correspondence to first author at PK 61 Bahcelievler,
06500 Ankara, Turkey.
E-mail: nese@med.gazi.edu.tr
"Interestingly, the finding reported by Volkow and colleagues
(1997) regarding different effects of methylphenidate
on regional brain glucose metabolism in healthy humans
may be applied to the group with ADHD as the basis of the
therapeutic intervention. In this previous study, regional
brain glucose metabolism in healthy humans was investigated
and the relation of this effect to dopamine D2 receptors
was reported where frontal and temporal metabolism
increased in those with high D2 receptors and decreased in
those with low D2 receptors. Another study by the same
author reported that normally developing participants who
liked the effects of methylphenidate had significantly lower
D2 receptor levels than those who disliked its effects
(Volkow et al. 1998). Moreover, the higher the D2 levels were
found, the more intense were methylphenidate’s unpleasant
effects. They concluded that these results provided preliminary
evidence that D2 receptor levels predict response to
psychostimulants. Similarly, we believe that our data may
also suggest the preliminary evidence that D2 receptor levels
predict response to therapy in non-drug treated patients
with ADHD, and our hypothesis is that the best responders to
methylphenidate in ADHD may be the ones with the highest
initial D2 binding levels. However, the necessity of further
studies with larger sample sizes remains."
"Conclusion
In conclusion, the results of this study indicate that in nondrug
treated children with ADHD, higher D2 receptor availability
is observed at baseline which is down-regulated back to
reported near-normal values after methylphenidate therapy.
The effect of methylphenidate on D2 receptor levels in patients
with ADHD is similar to that observed in healthy adults: a
down-regulation phenomenon within 0 to 30%. In addition,
initially higher values of D2 availability seem to indicate a better
response to methylphenidate therapy in ADHD. Further
studies are warranted using larger groups of non-drug treated
patients with ADHD and using tracers labelling presynaptic
and postsynaptic markers for the delineation of the pathophysiology
and response to therapy in ADHD."
All of these seem to indicate Wellbutrin clearly has the potential to cause/make worse depression as well as effecting cognition in a negative fashion. Feedback?
And another thing I found interesting as it makes bupropion more than just an NDRI - which I suppose it was more than that already.
Wellbutrin stimulates the release of dopamine as well as blocking the reuptake - much like most amphetamine-type compounds.
1: J Neurosci Res. 1994 Sep 1;39(1):11-22.Links
Dopamine transporter mediated release of dopamine: role of chloride.
Sitges M, Reyes A, Chiu LM.
División de Investigaciones Clínicas, Instituto Mexicano de Psiquiatría, SSA, Mexico.
Using a rapid (0.5 ml/min) flow rate superfusion system, the dopamine (DA) transporter mediated release of DA is further explored, and compared to the depolarization evoked release of DA in rat striatal synaptosomes preloaded with radioactive DA (3H-DA). In this system external DA in the low microM range efficaciously releases the preloaded transmitter, the maximal response being reached at 3 microM DA. The external DA stimulated release is Ca(2+)-independent, Cl(-)-dependent, and blocked by both bupropion and nomifensine. The atypical antidepressant bupropion inhibits 3H-DA accumulation to rat striatal synaptosomes with a calculated IC50 of 1.3 x 10(-6) M. Among DA uptake blockers some are known to act as DA releasing agents. Here we found that the DA uptake blocker nomifensine (30 microM) is unable to modify the baseline release of 3H-DA, whereas bupropion (10 microM) clearly elevates the baseline release of 3H-DA in a Ca(2+)-independent and Cl(-)-dependent manner. The non releasing agent nomifensine blocks the release of 3H-DA induced by bupropion. The Ca(2+)-dependent, high K+ depolarization evoked release of 3H-DA is not modified by nomifensine and does not depend on the external Cl- concentration. When the depolarizing medium contains DA the carrier mediated release of 3H-DA induced by the external DA is additive to the high K+ induced response. A drastic drop in the external Cl- concentration induces 3H-DA release. This release of 3H-DA induced by low external Cl- levels is completely blocked by nomifensine, which only slightly diminished the release of 3H-DA induced by the absence of external Na+. On the basis of these results, it is concluded that: 1) Rapid perfusion flow rates eliminate DA reuptake. 2) DA uptake inhibitors either with or without DA releasing capabilities block the release of DA induced by microM levels of external DA. 3) By preventing translocation of the DA transporter mobile moiety, nomifensine may inhibit the release of DA induced by external DA or bupropion and by drastic drops in the external Cl- concentration. 4) In the absence of nomifensine, the DA transporter works under both resting and depolarized conditions, but in contrast to the GABA transporter (Sitges et al.: Neurochem Res 18:1081-1087, 1993), the DA transporter does not contribute to the amount of the DA released by depolarization. 5) Reversal of the DA uptake carrier is favored by conditions increasing the internal DA levels. 6) Cl- rather than Na+ is a major determinant in 3H-DA movements through the DA transporter.
PMID: 7807588 [PubMed - indexed for MEDLINE]
And I wonder about that chlorine attached to the ring in the meta- position and if it lends any 'neurotoxcity' to the compound. Admittedly though bupropion doesn't have much of an affinity for any of the monoamine pumps nor dopamine, noradrenaline, or serotonin receptors so this may mitigate any neurotoxicity that is lended to the compound via the chlorine atom. The tert-butyl group may also help to mitigate neurotoxicity of it as well. See "MARK S. KLEVEN, LEWIS S. SEIDEN (1992) Methamphetamine-induced Neurotoxicity: Structure Activity Relationships
Annals of the New York Academy of Sciences 654 (1) , 292–301"
