Selective Changes in Affinity States of Dopamine D-1 receptors in amphetamine sensitization: Implications for Schizophrenia.

Abstract:

In order to elucidate the dopaminergic mechanisms in amphetamine sensitization, we used the radioligand binding technique to measure D-1 and D-2 receptors in the striatum of rats treated with repeated d-amphetamine at 10 mg/kg s.c. twice daily for 10 days. In amphetamine-treated rats, D-1 receptors demonstrated statistically significant enhancement in the binding capacity (Bmax) , and binding affinity (Kd) , with preferential shift towards the high affinity state of D1 receptors (D-1HL) [ p < 0.005 ], as compared with the control group. D-2 receptor function remained unchanged in both the amphetamine sensitized and control groups. Amphetamine-induced D-1-receptor effects in the striatum were reversed by addition of the GTP analogue, 5’-guanylylimidodiphosphate in vitro. The results are discussed within the context of the model of dysregulated G-protein-coupled dopamine receptors in amphetamine sensitization and schizophrenia.

Key words: Amphetamine sensitization, G protein, Dopamine receptors, schizophrenia

Introduction

In rodents, repeated administration of d-amphetamine leads to progressive enhancement of locomotor and stereotyped responses. The phenomenon, characterized as amphetamine sensitization [1] parallels the pattern of amphetamine abuse in humans. Psychostimulant drug abuse results from repeated episodes of amphetamine binges and the gradual escalating dosage of the psychostimulant in seeking for the “speed high”. In vulnerable individuals, chronic amphetamine users experience serious psychotomimetic effects: auditory and visual hallucinations, paranoid delusions and bizarre behavioral disturbances closely resembling paranoid schizophrenia [2]. The exact molecular footprints of the reinforcing actions of the psychostimulant amphetamine and congeners, however, remain incompletely understood
There is ample pharmacological evidence suggesting that dopamine signaling pathway mediates amphetamine sensitization. Amphetamine, when applied through iontophoretic technique, sensitization [3]. enhanced response of dopamine receptors subtype 1 D-(1)-R in the ventral tegmentum area (VTA) is required for the development of behavioral sensitization, the expression of the sensitized response depends upon activation of D-1-R receptors in the nucleus accumbens [ 3, 4, 5 ]. Selective D-1-R antagonist, SCH23390, blocked the inhibitory effect of the D-1-R agonist, SKF 38393, on the sensitized response of the nucleus accumbens neurons. Sulpiride, the D-2-R antagonist, was without any effect. Similarly, amphetamine-induced enhanced locomotor activity and extra-cellular dopamine responses in the nucleus accumbens (ventral striatum) are selectively blocked by D-1-R antagonist, SCH 23390, but not by the selective D-2-R antagonist, sulpiride.
Deletion mutant studies have shed interesting light on the mechanisms of amphetamine sensitization. D-1-R genetically engineered mutant mice are incapable of expressing the transcription factors: cFos or Jun B, and regulating the dynorphins [6, 7]. Haloperidol, the prototypal D-2-R antagonist, remained effective in inducing catalepsy and inducing cFos or JunB in the D-1-R mutant mice. The importance of D-1-R in contributing towards amphetamine response is further shown by the finding that the mutant mice are less sensitive to acute amphetamine stimulation as compared to the wild type mice [8]. Behavioral effects of amphetamine have also been investigated through deleting the selective D-1-a and D-1-b receptor subclasses. Karper et al [9] found that both wild type and D1a knockout manifested amphetamine-induced behavioral sensitization. Pretreatment with D-1-R antagonist, SCH 23390 attenuated the locomotor sensitization in wild-type mice, without affecting the D-1-a deficient mice. The results indicate that while D-1 receptors are necessary for development of amphetamine sensitization in wild type mice, neither D-1a or D-1b receptor subtypes are required for amphetamine behavioral effects in the D-1a knockout mice.
Synergistic interaction of D-1 and D-2 receptors may contribute towards amphetamine sensitization. Concurrent activation of D-1 and D-2 with co-infusion of D-1 agonist, SKF 82958 and D-2 agonist, quinpirole, into the rat ventral-lateral striatum produced vigorous oral movements and sniffing. The behavioral events correlate with marked changes in the firing rate of neurons in substantia nigra pars reticulata [10].
In an attempt to explore further the mechanism of dysregulation of D-1-R and D-2-R in amphetamine sensitization, we used the rodent paradigm of repeated administration of amphetamine treatment, to determine whether specific changes occur in the sensitivity of dopamine receptors subtypes: D-1-R and D-2-R at the level of affinity states of D-1-R and D-2-R. We employed two different binding technqiues: radioligand saturation and agonist/antagnoist competition binding techniques to measure the binding affinities and capacity of D-1-R and D-2-R in the striatum from sensitized rats. Previously, we have shown that amphetamine sensitization is associated with supersensitized adenylate cyclase [11]. In view of the role of G proteins regulate the affinity states of diverse dopamine receptor subtypes through coupling with adenylate cyclase [ 14], we have also examined the differential effects of addition of the non-metabolizable analogue of GTP, 5’-guanylylimidodiphosphate [Gpp(NH)p] in the striatum from amphetamine-sensitized rats, as compared with the control group.

Materials and Methods

Amphetamine sensitization protocol

We used our amphetamine treatment protocol to induce amphetamine sensitization in the rodent species [11]. Under the protocol, we administered d-amphetamine sulfate at the subcutaneous dosage of 10 mg/kg twice daily for 10 days and during the course of the drug treatment, the rats exhibited progressive increase in locomotor counts and supersensitized adenylate cyclase responses.
Male Sprague Dawley rats weighing between 200-250 gm were treated with d-amphetamine sulfate at the dosage of 10 mg /kg s.c., twice daily for ten days. Control animals received equivalent volumes of 0.9 % saline (sodium chloride) for the same period. The animals were sacrificed forty-eight hours after the last treatment day. The dissected striata were stored at -70o C.until use. For the binding assays, we combined the dorsal (caudate nucleus and putamen) and ventral striatum (nucleus accumbens) from the respective control (n = 6) and amphetamine groups (n = 6).
Radioligand binding assays: Radioligands were purchased from New England Nuclear Co., Boston, Mass, USA. We used two methods to evaluate the possible changes in D-1-R and D-2-R binding: saturation binding and agonist/antagonist binding. For charactering saturation binding, D-1 binding studies, we define the specific binding of the radioligand [3H]-SKF-38393 as the difference in total binding in the presence and absence of 10 μM of SCH 23390. For D-2-R saturation binding studies, we used [3H] - NPA (N-propyl-norapomorphine) displaceable with 10 μM haloperidol to characterize saturation binding.
For determination of the relative proportions of high and low affinity states of D-1 R we used [3H]-SCH 23390 binding to compete against unlabelled SKF 38893 [12]. For high and low-affinity states of D-2-R [3H]-spiroperidol competition binding against unlabelled NPA. For D-1 binding, varying concentrations of unlabelled SKF 38393 (10-10 M- 10-5 M) was used to compete for 0.25 nM [3H- SCH- 23390] binding. For D-2 binding, varying concentrations of unlabelled NPA (10-10 M- 10-5 M) were used to compete for 0.25 nM [3 H] spiroperidol binding. All chemical agents were of the highest research grade obtained from Sigma Chem. Co., St. Louis, USA. Radioactivity was determined by Beckman liquid scintillation counter. All samples are run in duplicate.
In addition, competition antagonist / agonist binding were carried out in the presence and absence of 10-µM GTP analogue, 5-guanyl-imidodiphosphate [Gpp (NH) p]. . Both D-1 and D-1 binding assays were conducted in striata from the amphetamine sensitized (AMPH) and control (CONTROL) rats.
Data Analysis: The data were analysed on the IBM-PC computing system with the weighed curve-fitting program (EMF Software, Knoxville, TN, USA): BDATA for the saturation Scatchard analysis (linear model) and the CDATA for the agonist/antagonist competition curve (dual affinity state receptor model: high- and low-affinity sites). The relative proportions of high and low-affinity states of dopamine receptors (D-1 and D-2) were derived from statistical analysis comparing the “goodness of fit” of the one-affinity state with the two-affinity state model.

Results:

We used the best-fit method to analyse the binding parameters: binding density (Bmax) and binding affinity (Kd) derived from Scatchard plot. We found that amphetamine sensitized rats demonstrated an increase in the total density of [3-H] SKF-38393 binding to D-1 receptor sites in the striatum (Bmax) as compared with the saline group control. As compared with the control group (n=6), the amphetamine-sensitized rats (n=6) exhibited an increase in Bmax in the striatum (AMPH group: Bmax 884 ± 62 fmoles/mg protein vs CONTROL group Bmax 683 ± 45 fmoles/mg protein). The increase reached statistical significance (two-tailed t-test P < 0.05). The Kd of the AMPH group, however, did not differ significantly from the Control group (AMPH group 3.0 ± 0.4 nM vs CONTROL 3.1 +0.3 nM).
With regard to the saturation binding D-2 ligand, [3H] NPA binding, we failed to detect any significant difference in the binding parameters between the AMPH and CONTROL groups. The Bmax of AMPH and CONTROL groups are similar: AMPH: 690 ± 226 fmoles/mg protein vs CONTROL: 586 ± 141 fmoles/mg protein. The dissociation constant (Kd) of AMPH group: 0.30 ± 0.08 nM did not differ significantly from the CONTROL group: 0.45 ± 0.03 nM.
For both D-1-R and D-2-R saturation binding, we used the D-1-R and D-2-R labelled agonist binding displaceable with unlabelled antagonist to define the specific binding for saturation analysis. While the Scatchard plot of D-1 and D-2 binding provided a global analysis of changes in D-1/D-2 receptors in amphetamine-sensitized rats, when compared with the control, saturation-binding methodology may not be capable of unmasking the high-affinity and low-affinity states of D-1 or D-2 binding.
We next used the D-1-R antagonist/ agonist competition binding method to determine the relative proportions of the high and low affinity states of D-1 receptors (D1HA and D1LA ) and D-2 receptors (D2HA and D2LA). When the SKF-38393/[ 3H ]SCH-23390 D-1 competition binding was analysed with respect to the two- state model (D1HA, D-1LA), we found that there was a difference in the relative proportions of high affinity and low-affinity states of D-1 in the AMPH group as compared with the CONTROL group : AMPH group [17.4 ± 4 % of D-1HA and 83 + 4 % of D-1 LA ] vs CONTROL group [10 ± 3 % D1HA and 90 ± 3 % ]. The difference reached statistical significance (chi square p < 0.05).
The AMPH group exhibited a marked increase in the binding affinity of D-1HA, as reflected by the decrease in dissociation constant (KD), when compared with the CONTROL group: AMPH Kd : 0.12 ± 0.06 nM vs CONTROL Kd : 1.50 ± 0.60 nM. The difference reached statistical significance (P < 0.005). We interpret the finding of changes in the relative proportion and affinity constant of D-1HA in amphetamine-sensitized rats as preferential shift of the conformation state of D-1-R towards the predominant high-affinity state. No difference was found in the low-affinity state of D-1 in the amphetamine-sensitized group as compared with the control group. The dissociation constant (KD) of D-1LA in the AMPH group was similar to the KD from the CONTROL group: AMPH 804.1 ± 103.1 nM vs CONTROL 690.9 ± 145.5 nM.
For D-2 NPA / [3H] spiroperidol, competition binding, no significant difference was found between the AMPH and the CONTROL groups when the data were analysed according to the two-state model. Both the AMPH and CONTROL groups exhibited similar proportions of high-affinity states of D-2: AMPH 86 ± 4 % vs CONTROL 89 ± 6 %. AMPH group did not differ from the CONTROL group regarding the dissociation constant of D-2: AMPH Kd 0. 23 ± 0.84 nM vs CONTROL 0.20 ± 0.56 nM.
During the same series of experiments on D-1-R and D-2-R conducted on the group of AMPH and CONTROL rats, we showed that the enhanced binding capacity and affinity of D-1HA in the AMPH group were reversed by the addition of 10 μm Gpp(NH)p in vitro to the reaction mixture. Gpp (NH) p almost completely abolished the D-1HA in the striatum from both the AMPH group and CONTROL group and the assay failed to detect any D-1 D-1HA in either AMPH or CONTROL groups.
When tested under the D-1-R agonist/antagonist competition binding conditions, Gpp (NH) p did not distinguish between AMPH groups from CONTROL group in its regulatory effects on D-1-R binding. Gpp (NH) p markedly shifted the D-1 high affinity binding towards the D-1-R low affinity state: D-1LA in both the AMPH and CONTROL groups. The Kd of the D-1LA from the AMPH group did not differ significantly from the Kd of D-1LA of the CONTROL group: AMPH 597 ±164 nM vs CONTROL 672 ± 5.5 nM. These results showed the observed shift towards the high affinity state of D-1 receptor binding in AMPH group was reversible. The AMPH sensitized group retained responsiveness towards modulation by GTP analogue in vitro.

Discussion:

The major finding of our present study indicates that amphetamine sensitized rats, D-1-R exhibited preferential shift towards higher proportion of high-affinity states (D-1-RHA) in the striatum. The biochemical findings provide evidence for selective activation of D-1-R associated with GTP-sensitive conformational changes in D-1-R in amphetamine sensitization. Our findings are consistent with earlier data from electrophysiological and behavioral studies of D-1-R signaling changes as the pivotal event underlying neuro-adaptation in psychostimulant sensitization. [Three, 4]. Behavioural sensitization is generalized to categories of psychostimulants besides amphetamine and congeners. Supersensitivity of D-1-R signaling pathway has also been reported with cocaine [13]. We interpret the preferential locking of D-!-R in the high affinity state has significant consequences on the coupling of D-1-R to the effector adenylate cyclase (AC) via the stimulatory G-protein: G(s) alpha subunit [14] in the nucleus accumbens. In humans, evidence is available on the effect of amphetamine binge on AC response. Tong et al [15] recently reported in the postmortem human striatum from chronic methamphetamine abusers, there were 25-30 % reduction in the maximal effect of dopamine stimulation of adenylate cyclase, and while the basal or Gpp (NH) p stimulated enzyme activities were unaffected. Dopamine receptors (DR-1) become less responsive towards dopamine stimulation during the amphetamine withdrawal syndrome.
The finding of our study on selective conformational changes of D-1-R without concomitant changes in D-2 receptor density and affinity differs from the study by Seeman et al using [3H] raclopride binding in label D-2 receptors in vivo [16]. Seeman et al [16] found that amphetamine sensitized rats exhibited a 29% decrease in [3 H] raclopride binding. The addition of Gpp(NH)p, the amphetamine sensitized group resulted in a four-fold increase in the high affinity states of D-2 receptors as compared with the control group. In Seeman’s study [16] D-2-R binding was conducted 4 weeks after the last injection of amphetamine. In our study, we carried out the study 48 hours after the last injection of amphetamine. Methodological differences in in vivo binding, technique, the nature of the radioligand, and amphetamine treatment protocols, can explain the discrepant findings from the two studies.
We interpret the proposed model of dysregulation of D-1 receptor through assuming the high affinity “locked-in” conformation, while sparing the D-2-R changes. The absence of amphetamine effect on D-2 receptor binding parameters, however, must not be construed to interpret that D-1 activation is entirely independent of D-2 receptor function. Synergistic interaction of D-1 and D-2 receptors may be equally important for modulating the function and plasticity of dopamine signaling systems
G protein couples the D-1 receptors to adenylate cyclase and modulates the affinity of D-1 receptors. Hence, G-protein coupling constitutes the initial step of D-1/D-2 receptor-activated cascade events leading to diverse downstream responses, including prolonged phosphorylation of cyclase response element binding protein (CREB) [14]. Genetic deletions of stimulatory G-protein: Gαolf [17] and the inhibitory G-protein: Gαo [18] and the effector adenylase cyclase (AC5) [19] have further clarified the physiological relevance of coupling of dopamine receptors to adenylate cyclase. In general, D1-R is coupled positively to AC5 via Gs and D-2R is coupled negatively to AC5 via Gi in the brain. The striatum differs from other brain regions in that coupling to G9olf) alpha, a close relative to G(s) alpha appears to mediate D-1 signaling in the striatum [17].
Alternatively, D-1 activation in amphetamine sensitization can be linked to a novel class of regulators of G-protein signaling (RGS) [20]: mRNA expression of RGS is in turn modulated by the sensitivity of D-1 receptors. The RGS are thought to modulate G-protein coupled receptor signaling by activating GTPase through accelerating the rate of GTP hydrolysis of G-protein. RGS play a vital role in mediating the rapid turnoff of G-Protein Coupled Receptor (GPCR) pathway. A previous study showing that subtypes of RGS (RGS2,3,5 ) are differentially regulated in amphetamine sensitization [21 ] There is good evidence suggesting that RGS-2 regulates the coupling of D-1 receptors to adenylate cyclase 5 through Galphaolf and RGS-4 regulates the coupling of D-2 receptors to adenylate cyclase 5 through Galphao [ 22 ].
Deficits in sensorimotor gating have been found in both amphetamine sensitization and in schizophrenia in humans, suggesting that common neurobiological substrates underlie both conditions [23]. Interestingly enough, in schizophrenia similar changes in RGS-4 mRNA occurred in postmortem human brain [24]. In contrast to earlier study on reduced striatal D-1-R binding in postmortem schizophrenia brain [25], we found that similar conversion of D-1 receptors towards the high affinity state occurred in the caudate nucleus [9]. Seeman et al found evidence for disruption of the link between D-1 and D-2 receptors in postmortem schizophrenia brain [26]. Domyo et al [27] recently found an increase in [3 H] -SCH23390 binding in the medial and inferior cerebral cortex and superior parietal cortex, in postmortem schizophrenic brains, independent of the medication status. In vivo imaging PET (Positron Emission Tomography) imaging studies yielded mixed results. Okubo et al [28] found evidence for down-regulation of D-1 receptors in the prefrontal cortex subserving the working memory impairment in schizophrenia. Karlsson [29] found in antipsychotic-naïve schizophrenia subjects, negative symptoms of schizophrenia correlated with the changes in D-1-R binding in the right frontal cortex. A very recent PET study of D-1-R in twins discordant for schizophrenia found that high D-1-R density in the medical prefrontal cortex, superior temporal gyrus and heteromodal association cortex was associated with increased genetic risk for schizophrenia [30].
In summary, our finding of preferential activation of D-1 receptors through shifting towards the high affinity state, in amphetamine-sensitized rats highlights the significance of the dynamics of G-protein-coupled-dopamine receptors in amphetamine abuse and dependence. These considerations implicate common neurobiological substrates drive both schizophrenia and amphetamine abuse and dependence.

Authors

*Simon S. Chiu MD PhD, ** Mortimer Mamelak MD, # Ram K. Mishra PhD
* Regional Mental Health Care, St. Thomas, Ontario; Department of Psychiatry, N5P 3V9; University of Western Ontario, London, Ontario, Canada.
** Department of Psychiatry, University of Toronto, Ontario, Canada.
#Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario N6G 3T3, Canada.
@The study was conducted at Neuropharmacology Laboratory, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario N6G 3T3 Canada.

To whom correspondence to be directed:
Simon S. Chiu MD, PhD
Regional Mental Health Care, St. Thomas site,
467 Sunset Drive, St. Thomas, Ontario N5P 3V9 Canada
Fax: 1-519-471-3207
Phone: 1-519-631-8510 ext. 49655

Acknowledgements:

The study was funded by Canadian Psychiatric Research Foundation. The authors would like to express their appreciation to Ms. Samina B. Bajwa for her excellent technical assistance and Ms. Liz Goble for her manuscript preparation.

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First published March 2008

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