Striatal Dopamine Receptors Research Articles

Dopamine modulates attentional control of auditory perception: DARPP-32 (PPP1R1B) genotype effects on behavior and cortical evoked potentials

Using a specific variant of the dichotic listening paradigm, we studied the influence of dopamine on attentional modulation of auditory perception by assessing effects of allelic variation of a single-nucleotide polymorphism (SNP) rs907094 in the DARPP-32 gene (dopamine and adenosine 3′, 5′-monophosphate-regulated phosphoprotein 32 kilodations; also known as PPP1R1B) on behavior and cortical evoked potentials. A frequent DARPP-32 haplotype that includes the A allele of this SNP is associated with higher mRNA expression of DARPP-32 protein isoforms, striatal dopamine receptor function, and frontal–striatal connectivity. As we hypothesized, behaviorally the A homozygotes were more flexible in selectively attending to auditory inputs than any G carriers. Moreover, this genotype also affected auditory evoked cortical potentials that reflect early sensory and late attentional processes. Specifically, analyses of event-related potentials (ERPs) revealed that amplitudes of an early component of sensory selection (N1) and a late component (N450) reflecting attentional deployment for conflict resolution were larger in A homozygotes than in any G carriers. Taken together, our data lend support for dopamine's role in modulating auditory attention both during the early sensory selection and late conflict resolution stages.

Prefrontal cortical–striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity

Variation in dopamine receptor levels has been associated with different facets of impulsivity. To further delineate the neural substrates underlying impulsive action (inability to withhold a prepotent motor response) and impulsive choice (delay aversion), we characterised rats in the Differential Reinforcement of Low Rates of Responding task and a delay discounting task. We also measured performance on an effort-based discounting task. We then assessed D1 and D2 dopamine receptor mRNA expression in subregions of the prefrontal cortex and nucleus accumbens using in situ hybridisation, and compared these data with behavioral performance. Expression of D1 and D2 receptor mRNA in distinct brain regions was predictive of impulsive action. A dissociation within the nucleus accumbens was observed between subregions and receptor subtypes; higher D1 mRNA expression in the shell predicted greater impulsive action, whereas lower D2 mRNA expression in the core predicted greater impulsive action. We also observed a negative correlation between impulsive action and D2 mRNA expression in the prelimbic cortex. Interestingly, a similar relationship was present between impulsive choice and prelimbic cortex D2 mRNA, despite the fact that behavioral indices of impulsive action and impulsive choice were uncorrelated. Finally, we found that both high D1 mRNA expression in the insular cortex and low D2 mRNA expression in the infralimbic cortex were associated with willingness to exert effort for rewards. Notably, dopamine receptor mRNA in these regions was not associated with either facet of impulsivity. The data presented here provide novel molecular and neuroanatomical distinctions between different forms of impulsivity, as well as effort-based decision-making.

Motor and nonmotor complications in Parkinson’s disease: an argument for continuous drug delivery?

The complications of long-term levodopa therapy for Parkinson’s disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations—at least equally common, but less well appreciated—in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)—or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated.

Striatal CB1 and D2 receptors regulate expression of each other, CRIP1A and delta opioid systems

Although biochemical and physiological evidence suggests a strong interaction between striatal CB1 cannabinoid (CB1 R) and D2 dopamine (D2 R) receptors, the mechanisms are poorly understood. We targeted medium spiny neurons of the indirect pathway using shRNA to knockdown either CB1 R or D2 R. Chronic reduction in either receptor resulted in deficits in gene and protein expression for the alternative receptor and concomitantly increased expression of the cannabinoid receptor interacting protein 1a (CRIP1a), suggesting a novel role for CRIP1a in dopaminergic systems. Both CB1 R and D2 R knockdown reduced striatal dopaminergic-stimulated [(35) S]GTPγS binding, and D2 R knockdown reduced pallidal WIN55212-2-stimulated [(35) S]GTPγS binding. Decreased D2 R and CB1 R activity was associated with decreased striatal phosphoERK. A decrease in mRNA for opioid peptide precursors pDYN and pENK accompanied knockdown of CB1 Rs or D2 Rs, and over-expression of CRIP1a. Down-regulation in opioid peptide mRNAs was followed in time by increased DOR1 but not MOR1 expression, leading to increased [D-Pen2, D-Pen5]-enkephalin-stimulated [(35) S]GTPγS binding in the striatum. We conclude that mechanisms intrinsic to striatal medium spiny neurons or extrinsic via the indirect pathway adjust for changes in CB1 R or D2 R levels by modifying the expression and signaling capabilities of the alternative receptor as well as CRIP1a and the DELTA opioid system.

Estrogen receptors and lesion-induced response of striatal dopamine receptors

Neuroprotection by 17β-estradiol and an estrogen receptor (ER) agonist against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion were shown to implicate protein kinase B (Akt) signaling in mice. In order to evaluate the associated mechanisms, this study compared estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) intact or knockout (KO) and wild-type (WT) C57Bl/6 male mice following MPTP treatment of 7, 9, 11mg/kg and/or 17β-estradiol. Striatal D1 and D2 dopamine (DA) receptors were measured by autoradiography with the specific ligands [3H]-SCH 23390 and [3H]-raclopride, respectively and signaling by Western blot for Akt, glycogen synthase kinase 3β (GSK3β) and extracellular-regulated signal kinases (ERK1 and ERK2). Control ERKOβ mice had lower striatal [3H]-SCH 23390 specific binding than WT and ERKOα mice; both KO mice had lower [3H]-raclopride specific binding. Striatal D1 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in ERKOα mice and remained unchanged in WT and ERKOβ mice. Striatal D2 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in WT and ERKOα mice and increased in ERKOβ mice. In MPTP-lesioned mice, 17β-estradiol treatment increased D1 receptors in ERKOα and ERKOβ mice and D2 receptors in WT and ERKOβ mice. MPTP did not affect striatal pAkt/Akt and pGSK3β/GSK3β levels in WT and ERKOα mice, while in vehicle-treated ERKOβ mice these levels were higher and increased with MPTP lesioning. Striatal pERK1/ERK1 and pERK2/ERK2 levels showed to a lesser extent a similar pattern. In conclusion, ERs affected the response of striatal DA receptors to a MPTP lesion and post receptor signaling.

Increased Synaptic Dopamine in the Putamen in Restless Legs Syndrome

Prior studies using positron emission tomography (PET) or single-photon emission computed tomography techniques have reported inconsistent findings regarding differences between patients with restless legs syndrome (RLS) and control patients in the striatal dopamine-2 receptor (D2R) binding potentials (BP). D2R-BP does reflect receptor-ligand interactions such as receptor affinity (K(d)) and density (β(max)) or neurotransmitter synaptic concentrations. Thus, differences in D2R-BP reflect changes in these primary factors. PET techniques are currently available to estimate D2R β(max) and K(d). Separate morning and evening PET scans were performed. The D2R-BP were measured in basal ganglia using [(11)C]raclopride. Academic medical center. Thirty-one patients with primary RLS and 36 age- and sex-matched control patients completed the study. Patients with RLS had lower D2R-BP in putamen and caudate but not the ventral striatum. A subgroups analysis of those RLS patients who had not previously taken dopaminergic medications continued to show a significantly lower D2R-BP in the posterior putamen. D2R-BP did not differ between night and day for either group. D2R β(max) and K(d) did not differ significantly between patients with RLS and control patients but did show a strong and significant increase at night in the ventral striatum. Primary and secondary clinical measures of disease status failed to show any relation to D2R in any brain region. Given the lack of any difference in either β(max) or K(d) and the prior studies supporting an increase in presynaptic dopaminergic activity, the current changes found in D2R-BP likely reflect an increase in synaptic dopamine.

2821 – Dopamine D2/3 receptor availability and human cognitive impulsivity: a high-resolution PET imaging study with [11C]raclopride

: Human impulsivity is a complex multidimensional construct encompassing cognitive, emotional, and behavioral aspects. Previous animal studies have suggested that striatal dopamine receptors play a critical role in impulsivity. In this study, we investigated the relationship between self-reported cognitive impulsiveness and dopamine D2/3 receptor availability in striatal subdivisions in healthy subjects using high-resolution positron emission tomography (PET) with [11C]raclopride. Twenty-one participants completed 3-Tesla magnetic resonance imaging and high-resolution PET scans with [11C]raclopride. The trait of impulsiveness was measured using the Barratt Impulsiveness Scale (BIS-11). Partial correlation analysis was performed between BIS-11 scores and D2/3 receptor availability in striatal subregions, controlling for the confounding effects of temperament characteristics that are conceptually or empirically related to dopamine, which were measured by the Temperament and Character Inventory. The analysis revealed that the non-planning ( p = 0.004) and attentional ( p = 0.007) impulsiveness subscale scores on the BIS-11 had significant positive correlations with D2/3 receptor availability in the pre-commissural dorsal caudate. There was a tendency toward positive correlation between non-planning impulsiveness score and D2/3 receptor availability in the post-commissural caudate. These results suggest that cognitive subtrait of impulsivity is associated with D2/3 receptor availability in the associative striatum that plays a critical role in cognitive processes involving attention to detail, judgment of alternative outcomes, and inhibitory control.

Striatal dopamine D1 receptors are involved in the dissociation of learning based on reward-magnitude

Here we investigate the contribution of striatal dopamine receptors (D1) to the influence of reward-magnitude on learning. Pigeons (Columba livia) were trained on a discrimination-task with two pairs of stimuli; correct discrimination resulted in a large reward in one pair of stimuli and in a small reward in the other pair. Acquisition of the discrimination-task was accompanied by intracranial injections to the medial striatum, either of a dopamine-antagonist (Sch23390) or of vehicle. In the control-condition the rate of learning was modulated by the magnitude of the reward; discrimination was learned faster if contingent rewards were large and learning was slower if contingent rewards were small. Following injections of D1 antagonist this effect vanished even though the ability to discriminate between the rewards was unaffected. Interestingly, the mean rate of learning was indistinguishable between the control and antagonist conditions. Consequently, it appears that not learning per se but the effect of reward-magnitude on learning is mediated through D1 receptors in the striatum.We argue that the injections of dopamine-antagonist cause a shift in strategy underlying learning. In the control-condition animals rely on positive feedback and thus learning is affected by the magnitude of the contingent reward; in the antagonist-condition, however, learning might rely on negative feedback and is thus insensitive to reward-magnitude.

Experimental reappraisal of continuous dopaminergic stimulation against L‐dopa‐induced dyskinesia

The concept of ‘‘continuous dopaminergic stimulation’’ (498 occurrences on PubMed, of which 46 feature these words in their title) emerged in the 1980s primarily for managing the complex fluctuations in motor performances 1‐3 that are the major problem in the long-term management of Parkinson’s disease. Although motor fluctuations were the first targeted issues of the concept (and its pharmacological consequences), levodopa-induced dyskinesia was rapidly encompassed as a possible manifestation controllable by continuous dopaminergic stimulation. 4 The short plasma half-life of levodopa and the ensuing pulsatile stimulation of striatal dopamine receptors were thought to underlie the propensity of the drug to induce dyskinesia. Late-stage parkinsonian patients indeed benefit from continuous dopaminergic stimulation with notable improvement of established dyskinesia, 5 but large trials in de novo parkinsonian patients with either continuous delivery of levodopa in early Parkinson’s disease using Sinemet CR (CR-FIRST) 6 or the combination of levodopa with the C-O-methyltransferase inhibitor entacapone (STRIDE-PD) 7 failed to reduce the risk of dyskinesia induction. Because the experimental evidence on continuous dopaminergic stimulation has been skeletal, Papathanou et al report in this issue of Movement Disorders on the effect of duodenal compared with intraperitoneal levodopa administration on the induction and expression of abnormal involuntary movements in 6-hydroxydopamine (6-OHDA)‐lesioned rats. Their experimental data confirm that more continuous delivery of levodopa by intraduodenal infusion can exert a beneficial effect on the expression of established dyskinesia. Probably more interesting is their second claim: that continuous dopaminergic stimulation may not reduce the risk of dyskinesia induction, at least in this rodent model. This second claim contradicts both the concept of providing continuous dopaminergic stimulation for preventing dyskinesia incidence and the conclusions made by previous experimental studies obtained in the very same 6-OHDA-lesioned rat model 8 and in the MPTP-treated marmoset model of dyskinesia. 9 Those studies indeed showed that levodopa combined with entacapone delayed the onset of abnormal involuntary movements or dyskinesia, respectively and reduced their severity. 8,9 The question thus arises as to why the previous and current studies reached different conclusions, if they actually did. Two studies were performed in the medial forebrain bundle 6-OHDA-lesioned rat model 8,10 that produced extensive nigrostriatal lesions (more than 90%). They differed in their screening method, with one challenging the unlesioned hemisphere with amphetamine 10 and the other priming the

Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO

A number of addictions have been linked with decreased striatal dopamine (DA) receptor availability and DA release. Stress has a key role in cannabis craving, as well as in modulation of dopaminergic signaling. The present study aimed to assess DA release in response to a laboratory stress task with [(11)C]-(+)-PHNO positron emission tomography in cannabis users (CU). Thirteen healthy CU and 12 healthy volunteers (HV) were scanned during a sensorimotor control task (SMCT) and under a stress condition using the validated Montreal imaging stress task (MIST). The simplified reference tissue model (SRTM) was used to obtain binding potential (BP(ND)) in striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). Stress-induced DA release (indexed as a percentage of reduction in [(11)C]-(+)-PHNO BP (ND)) between CU and HV was tested with analysis of variance. SMCT BP(ND) was significantly higher in CU compared with HV in the AST (F=10.38, p=0.003), LST (F=4.95, p=0.036), SMST (F=4.33, p=0.048), and whole striatum (F=9.02, p=0.006). Percentage of displacement (change in BP(ND) between SMCT and MIST PET scans) was not significantly different across groups in any brain region, except in the GP (-5.03±14.6 in CU, compared with 6.15±12.1 in HV; F=4.39, p=0.049). Duration of cannabis use was significantly associated with stress-induced [(11)C]-(+)-PHNO displacement by endogenous DA in the LST (r=0.566, p=0.044), with no effect in any other brain region. In conclusion, despite an increase in striatal BP(ND) observed during the control task, chronic cannabis use is not associated with alterations in stress-induced DA release.

Early deficits in declarative and procedural memory dependent behavioral function in a transgenic rat model of Huntington's disease

In Huntington's disease (HD) cognitive deficits co-exist with motor impairments, both contributing to the overall disease symptomology. Despite short-term and working memory impairments, learning and other non-motoric behavioral deficits arising from the damage to frontostriatal loop being common in HD patients, most of the experimental work with transgenic animals focuses on motor symptoms. The transgenic rat model (tgHD) recapitulates many hallmark HD-like symptoms, such as huntingtin aggregates, cellular loss and dysfunction, and motor, and some cognitive deficits. In the current study we tested tgHD rats in two different cognitive, water maze competition paradigms to learn more about the impact of the transgene on learning and memory processing using hippocampal- and striatal-based memory systems. The tgHD rats had early and robust cognitive deficits in learning and memory function in both paradigms. Specifically, the transgenic animals were impaired in task acquisition and committed more procedural errors with the strongest phenotype amongst the homozygote tgHD. Although the transgenic animals were capable of using both procedural and declarative memory, their response patterns were distinct from wild-type animals. Wide spread huntingtin aggregates were observed at 13 months, but neither PET nor autoradiography indicated neuronal loss or dysfunction in striatal dopamine receptor population. In summary, the homozygote tgHD showed a robust learning and memory impairment prior to any clear motor deficits, or striatal dysfunction. However, the data were not conclusive regarding how the memory systems were compromised and the precise nature and underlying mechanism of the cognitive deficit in the tgHD model requires further investigation.

Levodopa infusion does not decrease the onset of abnormal involuntary movements in parkinsonian rats

The short duration of effect of levodopa is linked to pulsatile stimulation of striatal dopamine receptors and dyskinesia induction. However, the recent introduction of intraduodenal (i.d.) infusions and novel oral controlled release formulations of l-dopa may prevent dyskinesia induction and reduce the severity of established involuntary movements. We have compared the effects of twice-daily intraperitoneal (i.p.) administration and daily i.d. infusion of l-dopa on the induction and expression of abnormal involuntary movements in 6-hydroxydopamine (6-OHDA)-lesioned rats. Animals were treated with either twice-daily i.p. administration of l-dopa/carbidopa (7.85/12.5 mg/kg) or an 8-hour i.d. infusion of l-dopa/carbidopa (20/5 mg/mL; infusion rate: 0.04 mL/h) for 14 days, after which treatments were switched between groups and continued for a further 14 days. Pulsatile i.p. administration of l-dopa induced moderate to severe abnormal involuntary movements, which gradually increased in severity over the 14 days, but i.d. infusion of l-dopa induced abnormal involuntary movements of a similar severity. Switching from continuous i.d. to pulsatile i.p. administration of l-dopa continued to provoke severe abnormal involuntary movements expression. Switching from pulsatile i.p. to continuous i.d. l-dopa administration did not alter the peak abnormal involuntary movement severity but tended to reduce their duration. Treatment with less pulsatile l-dopa administration using i.d. infusion does not reduce the risk of the appearance of dyskinesia. By contrast, the duration of established dyskinesia can be reduced by more continuous l-dopa delivery in agreement with clinical experience.

Striatal dopamine receptors modulate the expression of insulin receptor, IGF-1 and GLUT-3 in diabetic rats: Effect of pyridoxine treatment

The incidence of type 2 diabetes mellitus is rising at alarming proportions. Central nervous system plays an important part in orchestrating glucose metabolism, with accumulating evidence linking dysregulated central nervous system circuits to the failure of normal glucoregulatory mechanisms. Pyridoxine is a water soluble vitamin and it has important role in brain function. This study aims to evaluate the role of pyridoxine in striatal glucose regulation through dopaminergic receptor expressions in streptozotocin induced diabetic rats. Radio receptor binding assays for dopamine D1, D2 receptors were done using [3H] 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol and [3H] 5-chloro-2-methoxy-4-methylamino-N-[-2-methyl-1-(phenylmethyl)pyrrolidin-3-yl]benzamide. Gene expressions were done using fluorescently labeled Taqman probes of dopamine D1, D2 receptor, Insulin receptor, Insulin like growth factor-1(IGF-1) and Glucose transporter-3 (GLUT-3). Bmax of dopamine D1 receptor is decreased and Bmax of dopamine D2 was increased in diabetic rats compared to control. Gene expression of dopamine D1 receptor was down regulated and dopamine D2 receptor was up regulated in diabetic rats. Our results showed decreased gene expression of Insulin receptor, IGF-1 and increased gene expression of GLUT-3 in diabetic rats compared to control. Pyridoxine treatment restored diabetes induced alterations in dopamine D1, D2 receptors, Insulin receptor, IGF-1, GLUT-3 gene expressions in striatum compared to diabetic rats. Insulin treatment reversed dopamine D1, D2 receptor, GLUT-3 mRNA expression, D2 receptor binding parameters in the striatum compared to diabetic group. Our results suggest the potential role of pyridoxine supplementation in ameliorating diabetes mediated dysfunctions in striatal dopaminergic receptor expressions and insulin signaling. Thus pyridoxine has therapeutic significance in diabetes management.

Reinforcing properties of Pramipexole in normal and parkinsonian rats

Striatal D2 and D3 dopamine receptors are involved in mediating the reinforcing properties of natural rewards and drugs. In Parkinson's disease, while D2/3 dopamine agonists alleviate motor symptoms, behavioral addictions and withdrawal syndrome are reported in up to 15% of patients. The origin of such adverse effects is poorly understood but suggests that D2/3 agonists could possess reinforcing properties. We evaluated the reinforcing properties of the widely used D2/3 agonist, Pramipexole (PPX), in normal and parkinsonian rats. Intracerebroventricular injections of 6-OHDA induced a bilateral loss of tyrosine hydroxylase-positive cells in the substantia nigra (−51%) and ventral tegmental area (−31%). The animals were then allowed to self-administer intravenous PPX under fixed ratio and progressive ratio (PR) reinforcement schedules before being tested for extinction of PPX seeking. While parkinsonian were slower than sham rats in acquiring self-administration behavior, they later reached the same level of intake. The reinforcing value of PPX, as assessed during PR and extinction, was moderate in both groups. PPX heightened ∆FosB expression in dorsal striatum of lesioned rats and similar PR results involved different striatal subregions between groups. Altogether, our results show that drug-naïve rats self-administer PPX and that the dopaminergic lesion does not affect its reinforcing effects. While PPX reinforcing value was moderate in most rats, a subset of animals displayed a high number of responses and appeared to be particularly sensitive to this drug. These data suggest that PPX may not be responsible for the reported side-effects but rather call for further investigating the differential vulnerability among individuals.

Assessment of Striatal Dopamine D2/D3 Receptor Availability with PET and 18F-Desmethoxyfallypride: Comparison of Imaging Protocols Suited for Clinical Routine

Assessment of striatal dopamine receptor availability with (18)F-desmethoxyfallypride PET is of high diagnostic utility in parkinsonism. The present study was undertaken to define the optimal clinical scan protocol with regard to quantification accuracy and scan time. Fourteen patients with parkinsonian syndromes underwent (18)F-desmethoxyfallypride PET over 90 min. Volume-of-interest analyses were performed after spatial normalization, with the right and left caudate nuclei and putamina as target regions and the cerebellum as reference region. The estimate of target region binding potential (relative to nondisplaceable radioligand in tissue) (BP(ND)) provided by the 2-step simplified reference tissue model (SRTM2) served as the reference standard. Additional analyses included the multilinear reference tissue model 2 (MRTM2), noninvasive graphical analyses, and single-scan analyses (peak-equilibrium analysis at 35-65 min [PEA]; pseudoequilibrium analysis at 60-90 min [PsEA]). SRTM2 and MRTM2 yielded virtually identical results (mean BP(ND) difference = 0.1% ± 0.5%, r(2) = 1.0). Noninvasive graphical analyses with and without inclusion of the k(2)' term were affected by a small BP(ND) bias (2.5% ± 3.6% and -5.0% ± 6.7%, respectively), although correlations with SRTM2 were still excellent (r(2) = 1.0 and 0.98, respectively). In turn, single-scan analyses suffered from limited precision (PEA, mean BP(ND) bias = 0.7% ± 13.0%, r(2) = 0.90) or a considerable positive bias (PsEA, 19.2% ± 7.1%, r(2) = 0.98). Shortening scan time to 70 and 60 min resulted in an acceptable average BP(ND) change (<5% decline) for SRTM2/MRTM2 and graphical analysis with inclusion of the k(2)' term, respectively. Kinetic reference tissue model analyses of (18)F-desmethoxyfallypride PET data offer the least biased results at a well-tolerable scan duration and should thus be pursued whenever possible. Single-scan analyses may be pragmatic alternatives that, however, suffer from a relevant positive bias (PsEA) or limited precision (PEA).

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.

Early postnatal striatal gene expression networks in rat: relevance to schizophrenia

Abnormal striatal development is thought to play an important role in a number of diseases, including schizophrenia. In humans, stress during the second trimester of pregnancy leads to increased risk for schizoaffective disorders in the offspring. This is period of active development of the striatum and corresponds to the second postnatal week of striatal development in rat. We show that during the first two postnatal weeks in rat an entire gene expression network becomes down‐regulated and replaced by a mature gene expression network. Using subtractive hybridization, we identified 31 additional genes involved in this process, including 12 novel transcripts with strict developmental expression. We show that in an established schizophrenia model in rat, this developmental process is altered and results in overexpression of the dopamine 2 receptor (D2R) during the second postnatal week, with no change in expression of D1R or other genes. This may play an important role in the development of a schizophrenia‐like phenotype, as striatal D2R upregulation has been shown to cause dysregulation of the prefrontal cortex.

Antipsychotic-Induced Euprolactinemic Galactorrhea in an Adolescent Girl

Antipsychotic-Induced Euprolactinemic Galactorrhea in an Adolescent Girl

Role of Serotonin Neurons in L-DOPA- and Graft-Induced Dyskinesia in a Rat Model of Parkinson's Disease

L-DOPA, the most effective drug to treat motor symptoms of Parkinson's disease, causes abnormal involuntary movements, limiting its use in advanced stages of the disease. An increasing body of evidence points to the serotonin system as a key player in the appearance of L-DOPA-induced dyskinesia (LID). In fact, exogenously administered L-DOPA can be taken up by serotonin neurons, converted to dopamine and released as a false transmitter, contributing to pulsatile stimulation of striatal dopamine receptors. Accordingly, destruction of serotonin fibers or silencing serotonin neurons by serotonin agonists could counteract LID in animal models. Recent clinical work has also shown that serotonin neurons are present in the caudate/putamen of patients grafted with embryonic ventral mesencephalic cells, producing intense serotonin hyperinnervation. These patients experience graft-induced dyskinesia (GID), a type of dyskinesia phenotypically similar to the one induced by L-DOPA but independent from its administration. Interestingly, the 5-HT1A receptor agonist buspirone has been shown to suppress GID in these patients, suggesting that serotonin neurons might be involved in the etiology of GID as for LID. In this paper we will discuss the experimental and clinical evidence supporting the involvement of the serotonin system in both LID and GID.

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.