Striatal Dopamine Receptor Density Research Articles

9.2 BRAIN STRUCTURAL AND NEUROCHEMICAL HETEROGENEITY AND HOMOGENEITY IN PSYCHOTIC DISORDERS: TRANSDIAGNOSTIC PET AND MRI IMAGING FINDINGS IN SCHIZOPHRENIA AND BIPOLAR AFFECTIVE DISORDER

BackgroundPsychosis is seen in a number of disorders and treated with the same drugs. However, there is considerable variability in response to treatment and clinical course. Understanding the neurobiology underlying psychosis across diagnoses and in treatment response is important to help guide the development of new treatments and biomarkers for treatment response. Elevated dopamine synthesis and release capacity and structural brain changes have been consistently associated with schizophrenia, but it remains unknown how variable these are, or how they compare across psychotic disorders.MethodsTwo cohorts of first episode patients, one with a diagnosis of schizophrenia (n=16) and another with a diagnosis of bipolar affective disorder (n=22) received 18F-DOPA PET and [1H]-MR spectroscopy imaging and clinical measures. All patients had experienced a psychotic episode and received clinical follow-up over 18 months to determine diagnostic stability. We then conducted a meta-analysis using a novel meta-analytic approach to quantify variability in measures to investigate structural and neurochemical heterogeneity in schizophrenia and bipolar affective disorder. The entire PubMed, EMBase and PsychInfo databases were searched from inception to identify relevant studies and the natural log of the measures of dispersion and the coefficient of variance.ResultsStriatal dopamine synthesis capacity (Kicer) was significantly elevated in both bipolar (effect size=1.02; p<0.003) and schizophrenia (effect size=0.9; p<0.05) groups, compared to controls. There was no significant difference in dopamine synthesis capacity between bipolar and schizophrenia groups (p>0.4). Kicer was significantly positively correlated with positive psychotic symptom severity in the transdiagnostic group of people with psychosis (r=0.52, p<0.004), and in the bipolar group after adjusting for manic symptom severity (r=0.6, p<0.01). There were no differences in glutamate levels in the anterior cingulate cortex.In the meta-analyses a total of 128 studies were identified including >4000 patients and >4000 controls. Variability ratio was significantly increased in patients relative to controls in gray matter volumes in temporal lobe (VR=1.1, p=0.004) and thalamus (VR=1.16, p<0.001), and in striatal dopamine receptor density (p<0.05) but unaltered in frontal cortex and significantly reduced in the anterior cingulate cortex (VR=0.9, p=0.02)DiscussionElevated dopamine synthesis capacity is associated with psychosis across diagnostic boundaries and linked to the severity of psychotic symptoms, even after adjusting for manic symptom severity. Striatal dopamine receptor density and structural gray matter volumes in a number of cortical and sub-cortical regions show heterogeneity in psychotic disorders, but frontal cortical regions show unaltered and, in the case of the anterior cingulate cortex, reduced heterogeneity, suggesting alterations are homogenous across patients. Taken together these findings striatal dopamine synthesis and structural changes in frontal cortex are common mechanisms linked to psychosis across disorders.

Density of available striatal dopamine receptors predicts trait impulsiveness during performance of an attention-demanding task.

The density (measured at binding potential) of available striatal D2/D3 receptors has been shown to predict trait impulsiveness. This relationship is highly robust and well replicated. In each case, however, the availability of dopamine receptors was measured at rest. More broadly, the extent to which relationships between dopamine receptor availability and behavioral traits hold when participants perform a cognitive task is unclear. Furthermore, the performance of a cognitive task engages fundamentally different neural networks than are maximally engaged during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by two distinct factors. The first is variation in available receptor density, which reflects a stable trait of the individual. The second is variation in context-specific dopamine release, which differentially displaces some dopamine radiotracers (such as raclopride) across individuals. Using an existing data set, we related trait impulsiveness, as measured using the Barratt Impulsiveness Scale (BIS-11), to the density (binding potential) of available striatal D2/D3 receptors as measured using positron emission tomography (PET) with [11C]raclopride. Importantly, the PET scan was completed while participants performed an attention-demanding visual search task. We replicate robust correlations between this measure of receptor availability and trait impulsiveness previously demonstrated during the resting state, extending this relationship to periods of active task engagement. Our results support the idea that this relationship depends on striatal D2/D3 receptor density and not on context-dependent dopamine release.NEW & NOTEWORTHY Several studies have demonstrated a relationship between the density of available striatal D2/D3 receptors and trait impulsiveness. However, in each case, the availability of dopamine receptors was measured during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by either stable variation in receptor density or context-dependent dopamine release. We present evidence uniquely consistent with the former interpretation, providing clarity to the nature of this brain-behavior relationship.

Altered brain activation in a reversal learning task unmasks adaptive changes in cognitive control in writer's cramp.

Previous receptor binding studies suggest dopamine function is altered in the basal ganglia circuitry in task-specific dystonia, a condition characterized by contraction of agonist and antagonist muscles while performing specific tasks. Dopamine plays a role in reward-based learning.Using fMRI, this study compared 31 right-handed writer's cramp patients to 35 controls in reward-based learning of a probabilistic reversal-learning task. All subjects chose between two stimuli and indicated their response with their left or right index finger. One stimulus response was rewarded 80%, the other 20%. After contingencies reversal, the second stimulus response was rewarded in 80%. We further linked the DRD2/ANKK1-TaqIa polymorphism, which is associated with 30% reduction of the striatal dopamine receptor density with reward-based learning and assumed impaired reversal learning in A + subjects.Feedback learning in patients was normal. Blood-oxygen level dependent (BOLD) signal in controls increased with negative feedback in the insula, rostral cingulate cortex, middle frontal gyrus and parietal cortex (pFWE < 0.05). In comparison to controls, patients showed greater increase in BOLD activity following negative feedback in the dorsal anterior cingulate cortex (BA32). The genetic status was not correlated with the BOLD activity.The Brodmann area 32 (BA32) is part of the dorsal anterior cingulate cortex (dACC) that plays an important role in coordinating and integrating information to guide behavior and in reward-based learning. The dACC is connected with the basal ganglia-thalamo-loop modulated by dopaminergic signaling. This finding suggests disturbed integration of reinforcement history in decision making and implicate that the reward system might contribute to the pathogenesis in writer's cramp.

Cocaine dependence: a fast-track for brain ageing?

Cocaine-dependent individuals anecdotally appear aged and their mortality rates are estimated up to eight times higher than in the healthy population.1 Psychological and physiological changes typically associated with old age such as cognitive decline, brain atrophy, or immunodeficiency are also seen in middle-aged cocaine-dependent individuals.2,3 These observations raise the question of whether cocaine abuse might accelerate the process of normal ageing. Although this is a little-studied area, there are several reasons for assuming that chronic cocaine exposure interferes with the processes of brain ageing. We compared the effects of age on gray matter volume in 120 individuals aged 18–50 years (Supplementary Information). Half of the sample met the standard diagnostic criteria for cocaine dependence of the DSM-IV-TR;4 whereas the other half had no history of substance misuse disorders or major psychiatric disorders. The two groups were matched for age (t118=−0.12, P=0.905), gender (χ2=2.8, P=0.148), and verbal IQ (t115=−0.36, P=0.716), as described elsewhere.5 All participants underwent a structural MRI brain scan, which was analyzed using voxel-based morphometry5 to produce whole-brain maps of age-related change in gray matter volume. All participants showed a reduction of gray matter volume in cortical and subcortical regions as a linear function of increasing calendar age (Figures 1a and b). However, the annual rate of global gray matter volume loss in cocaine-dependent individuals was almost twice the rate of healthy volunteers (that is, 3.08 ml per year (standard error (s.e.): 0.49 ml) versus 1.69 ml per year (s.e.: 0.41 ml)). Consequently, the rate of age-related gray matter volume loss in cocaine-dependent individuals was significantly greater than in healthy volunteers (F1,116=4.7, P=0.031); this interaction remained significant after excluding 16 individuals with comorbid alcohol dependence (F1,100=6.4, P=0.013). Accelerated ageing in cocaine-dependent individuals was also demonstrated by a significant age-by-group interaction on gray matter volume of the regions affected by age (P<0.001, see Figure 1c). Cocaine-dependent individuals showed a significantly greater-than-normal age-related decline in gray matter in prefrontal and temporal regions compared with healthy controls. By contrast, parts of the striatum appeared resistant to age-related volume decline in the cocaine-using group. Enlarged striatal volume has frequently been reported in stimulant-dependent individuals,5,6 possibly reflecting a marker of reduced dopamine neurotransmission in this dopamine-rich brain region where drugs like cocaine work. Decline in striatal dopamine receptor density has been associated with normal age-related cognitive decline.7 The relative absence of age-related changes in the striatum of cocaine-dependent people may thus reflect another feature of an abnormal brain ageing process. Figure 1 Age-related changes in gray matter volume in 60 healthy volunteers and 60 cocaine-dependent individuals. The brain maps show regions of age-related gray matter volume loss separately in healthy volunteers (a) and cocaine-dependent individuals (b); the ... Abnormal ageing in chronic cocaine users is an emerging public health concern, which has received little attention. Approximately 1% (ref. 8) of the 21 million users of cocaine wordwide,9 are considered to develop cocaine dependence. These individuals may potentially be at risk of premature brain ageing. Young people taking cocaine today need to be educated about the long-term risk of ageing prematurely, specifically at a time when many developed economies are facing the demographic challenge of an ageing population. Our findings also draw attention to the increasing number of older drug users seeking treatment for drug abuse.10 Drug-treatment services, however, mainly target drug use in young people, focusing on prevention and harm reduction; the needs of older drug users are not so well catered for. As the psychological and physiological challenges of ageing may have also accelerated in individuals with long-term drug dependence,11 the effects of cocaine on the process of ageing should be recognized in order to design and administer age-appropriate treatments for older drug users.

Double Dissociation of Dopamine Genes and Timing in Humans

A number of lines of evidence implicate dopamine in timing [Rammsayer, T. H. Neuropharmacological approaches to human timing. In S. Grondin (Ed.), Psychology of time (pp. 295-320). Bingley, UK: Emerald, 2008; Meck, W. H. Neuropharmacology of timing and time perception. Brain Research, Cognitive Brain Research, 3, 227-242, 1996]. Two human genetic polymorphisms are known to modulate dopaminergic activity. DRD2/ANKK1-Taq1a is a D(2) receptor polymorphism associated with decreased D(2) density in the striatum [Jönsson, E. G., Nothen, M. M., Grunhage, F., Farde, L., Nakashima, Y., Propping, P., et al. Polymorphisms in the dopamine D(2) receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry, 4, 290-296, 1999]; COMT Val158Met is a functional polymorphism associated with increased activity of the COMT enzyme such that catabolism of synaptic dopamine is greater in pFC [Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., et al. Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype. Nature Neuroscience, 8, 594-596, 2005]. To investigate the role of dopamine in timing, we genotyped 65 individuals for DRD2/ANKK1-Taq1a, COMT Val158Met, and a third polymorphism, BDNF Val66Met, a functional polymorphism affecting the expression of brain-derived neurotrophic factor [Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257-269, 2003]. Subjects were tested on a temporal discrimination task with sub- and supra-second intervals (500- and 2000-msec standards) as well as a spontaneous motor tempo task. We found a double dissociation for temporal discrimination: the DRD2/ANKK1-Taq1a polymorphism (A1+ allele) was associated with significantly greater variability for the 500-msec duration only, whereas the COMT Val158Met polymorphism (Val/Val homozygotes) was associated with significantly greater variability for the 2000-msec duration only. No differences were detected for the BDNF Vall66Met variant. Additionally, the DRD2/ANKK1-Taq1a polymorphism was associated with a significantly slower preferred motor tempo. These data provide a potential biological basis for the distinctions between sub- and supra-second timing and suggest that BG are integral for the former whereas pFC is implicated in the latter.

Dopamine receptor pruning during the peripubertal period is not attenuated by NMDA receptor antagonism in rat

D 1 and D 2 receptors are overproduced and pruned in the mammalian striatum during the periadolescent period. The mechanism that underlies this process in striatum is unknown. However, previous research has shown that the activity-dependent pruning of dendrites and synapses in somatosensory cortex and the visual fields is mediated by glutamatergic actions via N-methyl- d- aspartate (NMDA) receptor and is prevented by pretreatment with the NMDA antagonist MK-801. In order to test the hypothesis that the pruning of dopamine D 1 and D 2 receptors that occurs in the striatum after puberty (which occurs at approximately 40 days of age; P40), male and female rats were treated with saline vehicle or MK-801 (0.3 mg/kg) for 20 or 40 days and sacrificed immediately after the 20 day treatment (P60), 40 day treatment (P80), or 40 day treatment with 40 day recovery (P120). Analyses of the data reveal that none of these three treatment regimens altered striatal D 1 or D 2 receptor density in males or females relative to vehicle controls. At P60, MK-801 treatment failed to alter either D 1 ( F1,16=0.06, P>0.5) or D 2 receptors ( F1,16=0.39, P>0.5) for either sex. Similarly, MK-801 treatment did not affect D 1 or D 2 receptors at P80 ( P>0.3) or at P120 ( P>0.7). These data suggest that the normal 40% reduction in striatal dopamine receptor density that occurs between puberty and adulthood is not dependent on post-pubertal glutamatergic transmission through NMDA receptors.

Normal IPT and IBZM SPECT in drug-naive and levodopa-treated idiopathic restless legs syndrome.

Fourteen drug-naive and 11 levodopa-treated patients with idiopathic restless legs syndrome (RLS), and 10 controls age-matched to each RLS group separately were examined with polysomnography (PSG), [(123)I]-(N)-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane ((123)I-IPT) SPECT, and [(123)I]-(S)-2-hydroxy-3-iodo-6-methoxy-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide ((123)I-IBZM) SPECT. Drug-naive and levodopa-treated patients with RLS and controls showed similar striatal dopamine transporter and dopamine D(2)-receptor binding, the latter declining with age. The authors conclude that striatal dopamine transporter and receptor density is normal in drug-naive and levodopa-treated patients with RLS.

Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers.

The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [11C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (-141C Del) and high striatal dopamine receptor density (t= 2.32, P= 0.02). In agreement with some previous studies the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t=2.58, P=0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t= 2.58, P= 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.

A Rodent Model of Spontaneous Stereotypy: Initial Characterization of Developmental, Environmental, and Neurobiological Factors

Stereotypies are patterns of motor behavior that are repetitive, excessive, topographically invariant, and that lack any obvious function or purpose. In humans, stereotyped behaviors are associated with psychiatric, neurological, and developmental disorders. In animals, stereotypy has been frequently associated with adverse environmental circumstances and often related to alterations in striatal dopamine. To assess the development of stereotyped behaviors and to test the hypothesis that these behaviors are associated with environmental restriction, deer mice were housed in either standard laboratory cages or larger, enriched cages, and the development of stereotypy was followed from weaning over a 17-week period. Standard-caged deer mice engaged in stereotyped behaviors at a higher rate and developed these behaviors more quickly when compared to animals in enriched caging. Additionally, enriched caging was associated with higher rates of patterned running, whereas jumping and backward somersaulting were typically observed in standard cages. In addition, there was a significant effect of litter, but no effect of sex or cage, on the time to develop stereotypy. No differences were found in the density of either striatal D 1 or D 2 dopamine receptors or the concentration of striatal dopamine or its metabolites as a function of rearing condition or as a function of whether the animals developed stereotypy. These results characterize the development of stereotypies in this species, demonstrate the importance of environmental conditions in the genesis of stereotypy, and suggest that alterations in striatal dopamine content or dopamine receptor density do not account for the expression of stereotyped behaviors in this model.

A fetal nigral graft prevents behavioral supersensitivity associated with repeated injections of l-dopa in 6-ohda rats. Correlation with D1 and D2 receptors

The effect of repeated administration of l-3,4-dihydroxyphenylalanine was studied behaviorally and biochemically in grafted versus non-grafted rats with a 6-hydroxydopamine unilateral lesion of the dopaminergic nigro-striatal pathway. Non-grafted rats receiving 14 injections of l-3,4-dihydroxyphenylalanine increased their contraversive circling while grafted rats did not, even after fourteen injections. The density of striatal dopamine receptors was examined by autoradiography using the ligands [ 3H]SCH 23390 for dopamine D1 receptors and [ 3H]-spiperone for D2 receptors. In rats with a lesion of the nigro-striatal dopaminergic pathway, an increase of [ 3H]-SCH 23390 and [ 3H]-spiperone binding in the lesioned striatum was observed when compared with the striatum on the intact side. Chronic treatment with l-3,4-dihydroxyphenylalanine led to a further increase in D1 receptor density in the lesioned as well as the intact side. A similar pattern was observed for D2 receptors although the change did not reach significance. A graft of fetal nigral neurons brought the density of both Dl and D2 receptors on the lesioned side back to the level of the intact side. This is observed both in acutely or chronically l-3,4-dihydroxyphenylalanine treated rats. This study suggests that nigral grafts protect the striatum against l-3,4-dihydroxyphenylalanine-induced supersensitivity. It appears that the graft preserves the symmetry of the striatum even though there is an increase of D1 dopamine receptors. These results suggest that a fetal nigral graft could prevent the induction of 3–4-dihydroxyphenylalanine-induced dyskinesia in parkinsonian patients.

Dopamine supersensitivity and D1/D2 synergism are unrelated to changes in striatal receptor density.

Experiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D1/D2 synergism (i.e., the requirement of concomitant stimulation of D1 and D2 receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D1/D2 synergism was found to be independent of striatal D1 or D2 receptor density in rats as: (1) increasing striatal D1 and/or D2 receptor density (as confirmed by quantitative receptor autoradiography) by chronic treatment with SCH 23390 (0.5 mg/kg/day for 21 days) and/or haloperidol (0.5 mg/kg/day for 21 days) did not alter the normal pattern of D1/D2 synergism as determined by behavioral responsiveness to agonist stimulation of D1 or D2 receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D1 or D2 receptor density, induced a breakdown in D1/D2 synergism (i.e., behavior was elicited by independent stimulation of D1 or D2 receptors). In addition, the density of striatal D2 binding sites was not indicative of behavioral sensitivity to D2 agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D2 agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6-hydroxy-dopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D2 density. This enhanced sensitivity to quinpirole was no greater than that observed in neurologically intact rats treated concomitantly with a maximally stimulating dose of SKF 38393. Furthermore, rats with unilateral 6-hydroxydopamine lesions that were treated chronically with eticlopride continued to rotate contralateral to the lesion in response to quinpirole despite having hemispheric symmetry of striatal D2 receptor binding. By contrast, when rats with unilateral 6-hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity. The results support the hypothesis that two distinct types of dopamine supersensitivity exist: a modest one associated with increased D2 density, and a more profound one associated with a breakdown in D1/D2 synergism and independent of D2 density.

Social isolation and cohabitation with haloperidol- treated partners: Effect on density of striatal dopamine D 2 receptors in the developing rat brain

The influence of the social environment on striatal dopamine D 2 receptor density in the developing rat brain was investigated. Social isolation of rats from 20 to 60 days of age was associated with a decrease in the density of striatal dopamine receptors. Daily handling of the animals did not attenuate this effect. Chronic haloperidol treatment increased striatal dopamine receptor density to normal control values. Cohabitation with haloperidol-treated rats from 20 to 60 days of age was also associated with a decrease in the density of striatal dopamine D 2 receptors in nondrugged animals similar to that seen in animals housed in isolation. The contribution of early life experiences to the development of normal receptor functioning is discussed.

Reduction of motor behavioural deficits in senescence via chronic prolactin or estrogen administration: time course and putative mechanisms of action

The effects of chronic estrogen (E 2), rat prolactin (rPRL), or modified ovine prolactin (mPRL) administration on motor behavior (inclined screen performance) and striatal dopamine (DA) (D 2subtype) receptor concentrations were examined in senescent (>24 months of age) female rats. mPRL possesses no lactotrophic activity. Administration of either E 2 or rPRL was effective in improving both inclined screen performance (increased time that the animal could remain on the screen by 95 and 413 s, respectively, compared to highest pre-injection performance) and striatal D 2 receptor concentrations (14 and 20% respectively). These were indications, however, from separate analyses that improvements in inclined screen performance were seen prior to any increases in striatal D 2 receptor concentrations. These early performance increases seemed instead to be the result of improved muscarinic receptor control over striatal DA autoreceptor function. Later improvements in inclined screen performance (at 6–7 days after the E 2 injections were begun) were more dependent on increased striatal DA receptor concentrations. A second set of experiment which involved the injection of E 2 into senescent male as well as female rats indicated that there were no sex differences in improvements in inclined screen performance, and that once the E 2 injections were discontinued, performance returned to preadministration levels. The results are discussed in terms of two important processes that may be involved in mediating enhanced inclined screen performance following E 2 administration: (1) enhancement of muscarinic receptor regulation of DA autoreceptor function; and (2) increases in striatal DA receptor density.

Striatal dopamine innervation and receptor density: regional effects of the weaver mutation

Mice homozygous for the autosomal recesive gene weaver ( wv) exhibit a regionally specific depletion of forebrain dopamine (DA). DA is reduced approximately 70% in the dorsal striatum of homozygotes ( wv/wv) relative to heterozygous (+/ wv) controls while DA content in ventral striatum is relatively unchanged. The goal of the present study was to determine the regional effects of the weaver mutation on striatal DA receptors and DA uptake sites using quantitative autoradiography. Catecholamine histofluorescence was used to examine midbrain DA-containing cell bodies. Compared to behaviorally normal (+/-) littermates, the binding of [ 3H]spiroperidol to D 2 sites was significantly increased in the dorsal but not ventral striatum of wv/wv mice. Binding of the D 1 ligand, [ 3H]SCH23390, was significantly decreased throughout the striatum of wv/wv mice. The binding of [ 3H]mazindol to DA uptake sites was dramatically reduced in all wv/wv striatal regions except the ventrolateral portion. Compared to +/-littermates, wv/wv mice had far fewer fluorescent cell bodies in the substantia nigra and a less pronounced reduction of ventral tegmental area fluorescent somata. These findings support the hypothesis that heterogeneities exist in the genetic control of the mesotelencephalic DA system. The results underscore the usefulness of the weaver mouse in the study of mesostriatal sub-systems, receptor regulation, and potentially as a model of human neuropathologies that affect distinct populations of cells in the mesotelecephalic system.

Effect of ethanol administration of striatal D1 and D2 dopamine receptors.

Chronic in vivo exposure of rats to ethanol in a complete liquid diet for 14 or 21 days produced a behavioral tolerance to the acute injection of ethanol. After 21 days, but not 14 days, of chronic exposure, there was a significant increase in the maximum density of striatal D1 and D2 dopamine receptors without a change in these receptors' affinities. A 24-h withdrawal from the 21-day exposure did not alter the observed increase in density. Both the level and duration of ethanol exposure appear to be important variables for demonstration of an increase in striatal D1 and D2 dopamine receptors.

Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modifications induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17β-estradiol (E 2) at both low (0.1 μg/kg) and high (20 μg/kg) doses confirmed its ability to increase the number of striatal 3H-Spiperone ( 3H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E 2, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophyseal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusion: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of its antiestrogenic activity.

Down-regulation of haloperidol-induced striatal dopamine receptor supersensitivity by active analogues of L-prolyl-L-leucyl-glycinamide (PLG)

Tardive dyskinesia, a clinical syndrome, is one of the major side effects of protracted treatment with neuroleptics in schizophrenic patients. Functional supersensitivity of striatal dopamine receptors is believed to contribute to the pathogenesis of schizophrenia and tardive dyskinesia. In a rodent model of neuroleptic-induced dopamine receptor supersensitivity, we investigated the efficacy of structurally modified analogues of PLG to down-regulate the striatal dopamine receptor supersensitivity as determined by alterations in [ 3H]spiroperidol binding to striatal membranes in vitro. The PLG analogue, L-prolyl-L-leucyl-(+)-thiazolidine-2-carboxamide-HCl, when given at the dose of 10 mg/kg IP for 5 days prior to haloperidol (3 mg/kg IP 21 days) significantly prevented the up-regulation of striatal dopamine receptor supersensitivity, thus demonstrating a prophylactic effect. Two other analogues, L-prolyl-L-leucyl-5-aminomethyltetrazole and L-prolyl-L-leucyl-glycine-dimethylamide at a dose of 10 mg/kg IP when given concurrently with haloperidol for 21 days, suppressed the development of dopamine receptor supersensitivity. None of the analogues tested in the post-haloperidol session reversed the haloperidol-induced increase in the density of striatal dopamine receptors. Active PLG analogues hold promise as potential therapeutic agents for the amelioration of tardive dyskinesia.

Differential recovery rates of rat D2 dopamine receptors as a function of aging and chronic reserpine treatment following irreversible modification: a key to receptor regulatory mechanisms

The density of D2 dopamine receptors identified by 3H-spiperone binding was significantly lower in the striatum of senescent (28-month-old) than in mature (4-month-old) Fischer 344 rats. The time course of recovery of 3H-spiperone binding to D2 dopamine receptors following irreversible receptor modification by a single injection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was significantly slower in senescent than in mature rats. The kinetics of D2 dopamine receptor repopulation could be adequately described by a model assuming a constant rate of receptor production and a rate of degradation that was dependent on receptor concentration. Both the production rate and degradation rate constant of D2 dopamine receptors were lower in the senescent rats compared to mature rats. The changes in receptor density that occur as a function of development and aging are the result of changes in both the receptor production rate and receptor degradation rate constant, which, while both are reduced, tend to maintain receptor density. That is, receptor density decreased by 26% from 4 to 28 months of age, although the receptor production rate and degradation rate constant decreased by 40-50%. Chronic treatment of rats with reserpine produced a 21% increase in the density of striatal D2 dopamine receptors of mature, but not senescent, rats, accompanied by an increase in the initial recovery rate of 3H-spiperone binding sites following EEDQ treatment. It might have been expected that the reduced formation of agonist-bound receptors would have lead to a decrease in the receptor degradation rate constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Persisting subsensitivity of the striatal dopamine system after fetal exposure to β-endorphin

Fetal exposure of rats to β-endorphin during the third trimester, either alone or with β-MSH, resulted in mild developmental delay and significant decreases in striatal dopamine receptor density (subsensitivity) persisting through maturity. The apparent paradoxical down-regulation of dopamine receptors in the presence of β-endorphin was consistent with fetal exposure to dopamine receptor antagonists and synthesis inhibitors. These findings suggest biophysical properties of receptors which are unique to fetal development including loss of plasticity after exposure to antagonists. Permanent, down-regulation of the striatal dopamine system may be one mechanism underlying delayed development after fetal exposure to β-endorphin which may accompany hypoxia. Even though there were no statistically significant differences between males and females in density of the dopamine receptor, the behavioral profile after peptide treatment was sexually demorphic. Behaviorally, female rats appeared sensitized to perinatal α-MSH and males to α-endorphin.

Hypophysectomy may non-selectively alter pharmacokinetic parameters to enhance the ability of haloperidol to increase striatal dopamine receptor density in the rat

We have investigated the effect of a range of doses of haloperidol (0.625–5.0 mg/kg/day) or saline, administered for 14 days, followed by a 3 day drug washout period, to sham operated or hypophysectomized rats. Haloperidol increased the number of specific striatal 3H-spiperone binding sites ( B max) in sham-operated animals at doses of 2.5 and 5.0 mg/kg/day, and in hypophysectomized animals at all doses used (0.625–5.0 mg/kg/day). The inhibition of locomotor activity produced by haloperidol was greater in hypophysectomized than sham-operated animals. Plasma and striatal haloperidol levels after equivalent doses were greater in hypophysectomized than in sham-operated animals. We conclude that hypophysectomy may enhance the ability of haloperidol to induce striatal dopamine receptor supersensitivity in the rat, and that this may be due to differences in the pharmacokinetic handling of haloperidol between sham-operated and hypophysectomized animals.