Different roles of dopamine receptor subtypes in footshock stress-induced enhancement of morphine conditioned place preference

The present study investigated the involvement of dopamine mechanism in the effect of intermittent footshock stress on the morphine-induced place preference. A single intermittent footshock session significantly enhanced the place preference induced by 3.0 mg/kg morphine. This enhancing effect was inhibited by selective D₁ receptor antagonist SCH23390 and selective D₂ receptor antagonist sulpiride pretreatment 20 min before footshock session, suggesting dopamine D₁ and D₂ receptors are required for the development of intermittent footshock stress-induced enhancement of morphine-associated place preference. However, different from D₁ and D₂ receptors this enhancing effect was blocked by stimulation of dopamine D₃ receptor with selective D₃ receptor agonist 7-OH-DPAT pretreatment 20 min before footshock session which suggest dopamine D₃ receptor play a negative mediation effect on the intermittent footshock stress-induced this enhancement. These results indicate that dopamine D₁, D₂, and D₃ receptor subtypes play different roles in footshock stress-induced enhancement of morphine conditioned place preference.     

Prostaglandin E2 receptor expression in the rat trigeminal-vascular system and other brain structures involved in pain

Prostaglandin E₂ (PGE₂) is considered to be a key mediator in migraine pathophysiology. PGE₂ acts via four receptors (EP₁-EP₄) but their distribution in the brain districts implicated in migraine has yet to be delineated. We quantified amount of mRNA and protein expression for the EP receptors in both peripheral and central structures involved in pain transmission and perception in migraine: dura mater, cerebral arteries, trigeminal ganglion, trigeminal nucleus caudalis, periaqueductal grey, thalamus, hypothalamus, cortex, pituitary gland, hippocampus and cerebellum. In the trigeminal-vascular system (TVS) we found highest expression of EP₁ and EP₂ protein in the trigeminal nucleus caudalis. EP₃ and EP₄ mRNA expression were highest in the trigeminal ganglion. Within intracranial structures EP₁ mRNA and protein expression were significantly higher in pituitary gland and cerebellum than in dorsal root ganglia (peripheral control), whereas the EP₂ mRNA and protein were highly abundant in the pituitary gland. EP₃ mRNA was mainly found in thalamus and hypothalamus. The most robust mRNA and protein expression for EP₄ receptor was seen in the dorsal root ganglion. In conclusion, all four receptors are located in areas implicated in migraine supporting the possible involvement of PGE₂ in this disease.     

Bifeprunox and aripiprazole suppress in vivo VTA dopaminergic neuronal activity via D2 and not D3 dopamine autoreceptor activation

Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D₂ and D₃ dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D_2/3 receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D₂-like agonistic activities [L. Dahan, H. Husum, O. Mnie-Filali, J. Arnt, P. Hertel, N. Haddjeri, Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour, J. Psychopharmacol. (2009)]. In the present electrophysiological study, selective antagonists of D₂ and D₃ receptors were used to further characterize the inhibitory role of bifeprunox and aripiprazole on the D₂ and D₃ receptors in vivo. Administration of bifeprunox (250 μg/kg, i.v.) or aripiprazole (300 μg/kg, i.v.) reduced the firing activity of VTA DA neurons by 40–50%. The bursting activity was reduced by 95% and 77% by bifeprunox and aripiprazole, respectively. Systemic administration of the preferential D₃ receptor antagonist GR218,231 (200 μg/kg, i.v.) did not modify the inhibitory effect of bifeprunox or aripiprazole, either on the firing or on the bursting activity. On the other hand, the preferential D₂ receptor antagonist L741,626 (500 μg/kg, i.v.) completely blocked the inhibitory effect of both bifeprunox and aripiprazole on the VTA DA neuronal activity. The present study shows that bifeprunox and aripiprazole behave as partial D₂, but not D₃, receptor agonists in vivo, inhibiting the firing activity (preferentially the phasic activity) of VTA DA cells.     

Association of harm avoidance with dopamine D2/3 receptor availability in striatal subdivisions: a high resolution PET study

We examined the relationship between the personality trait of harm avoidance (HA) and the dopamine D_2/3 receptor availability in striatal subdivisions using high resolution positron emission tomography (PET) with [¹¹C]raclopride. Twenty-one healthy subjects completed 3 T magnetic resonance imaging and high resolution PET scans with [¹¹C]raclopride in order to measure D_2/3 receptor availability in subregions of the striatum. The D_2/3 receptor availability was obtained on the basis of the Logan graphical method. The Temperament and Character Inventory was used to measure the biogenetic temperament of HA. The analysis revealed that the HA score had significant negative correlations with D_2/3 receptor availability in the pre-commissural dorsal caudate and post-commissural putamen, suggesting that HA is associated with D_2/3 receptor availability in the associative and sensorimotor subdivisions of the striatum, which are mainly involved in cognition and locomotion. Further research is required to determine if pathological states have similar dopaminergic mechanisms in specific striatal subdivisions.     

Interaction between dopamine D1 and D2 receptors in modulation of the immune response

The interaction between dopamine D₁ and D₂ receptors plays a role in immunomodulation. The results of thus interaction depends on the degree of receptor activation with selective agonists in different doses. Combined treatment with agonists of D₁ and D₂ receptors in high doses had a synergistic effect in the mechanisms of immunomodulation. Receptor agonists in low doses suppressed the immune response. Our results suggest that weak activation of one of these receptors is accompanied by inactivation of the other receptor type. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 141, No. 5, pp. 488–490, May, 2006     

Chronic passive exposure to aggression decreases D2 and 5-HT1B receptor densities

It has been recently reported that passive exposure to aggression induces aggressive behavior in a rodent model. However, it remains unclear whether this response is correlated with neurochemical changes that correspond either to stress-induced aggression or non-stressed, learned aggression. Stress-induced aggression has been shown to result in increased brain dopamine D₂ receptor and serum corticosterone levels. In contrast, learned aggression is probably associated with reward deficiency syndrome, characterized by low dopamine D₂ receptor levels, without stress effects (i.e., high corticosterone levels). We hypothesized that chronic passive exposure to aggression would produce learned aggression, represented by low levels of dopamine D₂ receptor binding but normal levels of stress hormone. The present study additionally focused on serum testosterone and serotonin 5-HT_1B receptor density that has been associated with aggression/reward circuits. Hormonal results indicated that there were no differences between the “observer” rats that had been passively exposed to aggression and non-aggression for 10 min/day for 23 consecutive days. However, receptor binding autoradiography identified lower densities of dopamine D₂ receptors in the cortical-accumbal regions (shell of the nucleus accumbens and cingulate and motor cortices) and lower 5-HT_1B receptor densities in the tegmental regions (ventral tegmental area, substantia nigra pars compacta, and periaqueductal gray) among observers exposed to aggression, compared to controls. Changes in dopamine D₂ receptor densities due to chronic exposure to aggression do not resemble those patterns reported for stress-induced aggressive behavior. Our evidence suggests that the development of aggressive behavior among passive observers occurs through a learned, and not a stress-induced, mechanism.     

Involvement of dopamine D<Subscript>1</Subscript> and D<Subscript>2</Subscript> receptors in the rat nucleus accumbens in immunostimulation

Analysis of the nature of changes in the immune response in operated Wistar rats showed that electrolytic lesioning of the nucleus accumbens, the site of the greatest density of dopamine D₁ and D₂ receptors, led to suppression of the immune response in animals immunized with sheep erythrocytes. Administration of SKF 38393 (20 mg/kg) and quinpirol (1 mg/kg), selective agonists of dopamine D₁ and D₂ receptors respectively, to sham-operated rats induced significant increases in immune responses. However, no immunostimulation was seen on administration of the selective dopamine D₂ agonist quinpirol to animals with lesions to the nucleus accumbens as compared with controls. At the same time, treatment of animals with nucleus accumbens lesions using the dopamine D₁ receptor agonist SKF 38393 had no effect on the immune response as compared with that in sham-operated animals given the D₁ receptor agonist. These data provide evidence that dopamine D₂ receptors in the nucleus accumbens have a role in the mechanisms of immunostimulation, though D₂ receptors in other brain structures may also make some contribution to this process; D₁ receptors in the nucleus accumbens make no significant contribution to controlling the immune response. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 91, No. 11, pp. 1281–1287, November, 2005.     

SKF 83566 attenuates the effects of ghrelin on performance in the object location memory task

Increasing research implicates ghrelin, a metabolic signaling peptide, in memory processes including acquisition, consolidation, and retention. The present study investigated the effects of ghrelin on spatial memory acquisition by utilizing the object location memory task paradigm. Given the co-expression of ghrelin and dopamine D₁ receptors within hippocampal neurons, we examined a potential interaction between these two systems on memory performance. When injected into the dorsal third ventricle (D3V) of male Sprague-Dawley rats, proximal to hippocampal tissue, ghrelin (500 pmol) increased the amount of time spent with objects in novel locations. This effect was completely reversed by the D₁ antagonist SKF 83566 (100 μg/kg IP), although when administered alone, the antagonist had no effect on task performance (10-100 μg/kg). We also examined the feeding effects of D3V ghrelin and found that the peptide reliably increased food intake (500 pmol) but that this effect was not blocked by SKF 83566 (100 μg/kg). When given alone, SKF 83566 did not alter food intake (10-100 μg/kg). Our findings indicate that, in addition to an orexigenic effect, ghrelin improves acquisition of spatial location memories. Furthermore, D₁ receptor activation is necessary for ghrelin to improve the encoding of spatial memories but does not impact the increase in food intake elicited by the peptide.     

The effects of dopaminergic drugs in the ventral hippocampus of rats in the nicotine-induced anxiogenic-like response

Nicotine an active alkaloid of tobacco has dopaminergic properties. The drug alters anxiety-like behavior in rodents. Ventral hippocampus (VHC) may be a site for modulation of anxiety-like behaviors. The possible involvement of ventral hippocampal dopaminergic receptor mechanism in the nicotine influence on anxiogenic-like response has been investigated in the present study. The effects of apomorphine, sulpiride and SCH23390 on nicotine response in elevated plus maze in rats have been investigated. Intraperitoneal administration of nicotine (0.6 mg/kg) decreased percentage of open arm time (%OAT) but not percentage of open arm entries (%OAE) and locomotor activity, indicating an anxiogenic-like response. Intra-hippocampal injection (intra-VHC) of apomorphine, a D₁/D₂ dopamine receptor agonist (0.1 and 0.2 μg/rat) also caused anxiogenic-like effects, but the drug blocked that of nicotine. Intra-VHC administration of the D₂ receptor antagonist, sulpiride (1, 2.5 and 5 μg/rat) or the D₁ receptor antagonist, SCH23390 (0.01, 0.1 and 1 μg/rat) did not elicit any response. However, pretreatment with sulpiride (1 μg/rat) or SCH23390 (0.1 μg/rat) decreased nicotine's effect. The results may indicate a modulatory effect for the D₁ and D₂ dopamine receptors of VHC in the anxiogenic-like response induced by nicotine.     

Cyclooxygenase inhibitors suppress the expression of P2X3 receptors in the DRG and attenuate hyperalgesia following chronic constriction injury in rats

Recent evidence suggests that P2X₃ receptors express abundantly in nociceptive sensory neurons and play an important role in neuropathic pain. Upregulation of prostaglandin E2 (PGE2) after nerve injure is involved in the pathogenesis of neuropathic pain. An increase of P2X₃ receptors after chronic constriction injury (CCI) to the sciatic nerve has also been reported, the mechanisms are not known clearly. In this study, we examined the effects of systemic administration of cyclooxygenase (COX) inhibitors on analgesia and the expression of P2X₃ receptors in the dorsal root ganglia (DRG) in CCI rats. Rats received 0.9% saline, the nonselective COX inhibitor ibuprofen (40 mg kg⁻¹ day⁻¹) or the selective COX-2 inhibitor celecoxib (30 mg kg⁻¹ day⁻¹) by gavage twice daily from 3 to 14 days after surgery. Mechanical allodynia and thermal hyperalgesia induced by CCI were markedly attenuated by celecoxib from 5 to 14 days after surgery, and relieved by ibuprofen treatment from 7 to 10 days after surgery. The increase of P2X₃ receptors in the DRG in CCI rats on day 14 after surgery was also significantly inhibited; the effect of ibuprofen was stronger than that of celecoxib. These results demonstrate that up-regulated COX/PGE2 after nerve damage may play an important role in neuropathic pain. They are highly involved in the expression of P2X₃ receptors in the DRG in CCI rats.     

Inhibitory action of dopamine involves a subthreshold Cs+-sensitive conductance in neostriatal neurons

Intracellular recordings in in vitro slice preparations of rat brain were used to compare the actions of dopamine and dopamine receptor agonists on the subthreshold membrane properties of neostriatal neurons. A reproducible response for dopaminergic agonists was evoked after firing produced by current ramp injections that induced a subthreshold voltage displacement. Dopamine (10–100 M) decreased both firing rate and membrane slope input resistance in virtually all cells tested. Input resistance change appeared as an increase in inward rectification. Approximate reversal potential was around -87 mV. The D₁ receptor agonists SKF 38393 and C1-APB (1–10 M) mimicked both dopamine effects with a reversal potential around -89 mV. The effects were blocked by the presence of 5–10 M caesium (Cs⁺) but not by 1 M tetrodotoxin, suggesting that main D₁ effects on input resistance are due to subthreshold Cs⁺ sensitive conductances. cAMP analogues mimicked the actions of D₁ receptor agonists. The D₂ agonist, quinpirole (1–10 M), did not produce any input resistance change, nonetheless, it still produced a decrease in firing rate. This suggests that the main D₂ effect on firing is due to actions on suprathreshold ion conductances. All effects were blocked by D₁ and D₂ antagonists, respectively. D₁ or D₂ effects were found in the majority of cells tested.     

Characterization of thromboxane A2 receptor and TRPV1 mRNA expression in cultured sensory neurons

Thromboxane A₂ (TxA₂) is an arachidonic acid metabolite that stimulates platelet aggregation and vasoconstriction when released from platelets and other cell types during tissue trauma. More recent research has demonstrated that TxA₂ can also stimulate vagal and spinal sensory nerves. The purpose of this study was twofold. One, we compared the expression of the TxA₂ receptor (TxA2R) in neurons from two sensory ganglia: the nodose ganglion (NG) containing cell bodies of vagal afferent nerves and the thoracic dorsal root ganglion (DRG) containing cell bodies of spinal afferent nerves. Two, we determined if TxA2R co-localizes with mRNA for the nociceptive marker, TRPV1, which is the receptor for the noxious substance capsaicin. We found a greater percentage of neurons in the NG that are positive for TxA2R expression than in the DRG. We also found that there was no correlation of expression of TxA2R with TRPV1. These data suggest that while TxA2R is expressed in both vagal and spinal neurons, TxA₂ may elicit stronger vagal or parasympathetic reflexes in the rabbit when released during tissue trauma depending on the location of release. Our data also indicate that TxA₂ is likely to stimulate both nociceptive and non-nociceptive neurons thereby broadening the types of neurons and reflexes that it may excite.     

Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up,relation to gender,age, tumor grade,and recurrence

Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D₂ receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6±14.3 years) who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D₂ receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%), II (n=13, 8.3%), or grade III (n=3, 1.9%). Dopamine D₂ receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D₂ receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas.     

Regulatory role of 1, 25-dihydroxyvitamin D3 and vitamin D receptor gene variants on intracellular granzyme A expression in pulmonary tuberculosis

Vitamin D receptor (VDR) genotypes have been shown to be associated with differential susceptibility or resistance to tuberculosis. The influence of FokI, BsmI, ApaI and TaqI variants of VDR gene on 1, 25(OH)₂ D₃ modulated granzyme A expression of cytotoxic lymphocytes induced by culture filtrate antigen (CFA) of Mycobacterium tuberculosis was studied in 40 pulmonary tuberculosis (PTB) patients and 49 normal healthy subjects (NHS) by flow cytometry. In both the study groups, addition of 1, 25(OH)₂ D₃ (10^− 7M) significantly reduced the percentage of granzyme A positive cells in both unstimulated (NHS, p < 0.0001; PTB, p = 0.02) and stimulated culture conditions (CFA, NHS, p < 0.0001; PTB, p = 0.0001) which correlated positively with the IFN-γ levels (unstimulated, p = 0.01; CFA stimulated, p = 0.004) in NHS. The ApaI aa genotype and bbaaTT extended genotype were associated with a significantly decreased percentage of granzyme A positive cells in NHS (p < 0.05). Our results suggest that 1, 25(OH)₂ D₃ suppresses granzyme A probably by down-regulating Th1 cytokine response. Moreover, the VDR gene variants might regulate cytotoxic T-cell response via 1, 25(OH)₂ D₃ mediated suppression of granzyme A expression in tuberculosis.     

The human trigeminal ganglion: c-kit positive neurons and interstitial cells

Objectives

The presence of c-kit positive neurons in sensory ganglia has been verified in various species but not in humans. Our aim has been to identify whether human primary trigeminal neurons label with c-kit/CD117 and thus, whether data gathered in animal studies can be extrapolated to humans. We also intended to establish whether, and which non-neuronal cells also label with c-kit in the trigeminal ganglion.

Methods

Human adult trigeminal ganglia from eight cadavers were processed for immunohistochemistry on paraffin embedded samples using monoclonal antibodies for CD117/c-kit, and three additional trigeminal ganglia were used for transmission electron microscopy (TEM). To evaluate which neuronal type (A or B) was labeled with c-kit, we evaluated the same neurons on adjacent sections labeled with antibodies for neurofilaments (NF).

Results

c-kit has labeled trigeminal neurons (TNs), mast cells and interstitial cells (ICs) within the trigeminal ganglion. c-kit + TNs were NF-and thus were strongly presumed to be nociceptive, as such neurons are known to be NF-poor. c-kit + ICs with long and moniliform processes intermingled with the satellite glial cells (SGCs) of the neuronal envelopes. TEM evaluations confirmed this mixed composition of the neuronal envelopes and demonstrated that the perineuronal ICs are in fact interstitial Cajal-like cells (ICLCs) and/or telocytes.

Conclusions

c-kit + TNs were objectified in humans and strongly presumed to be nociceptive. TNs envelopes mostly consist of SGCs, but are also combined with ICLCs/telocytes.     

Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin

Nobiletin isolated from citrus peels up-regulates synaptic transmission and improves memory impairment in rodents. This study investigated the antidepressant-like effect of nobiletin in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of nobiletin in mice were also assessed. Nobiletin (25, 50 and 100 mg/kg, p.o.) decreased the immobility time in both the FST and TST without locomotor alterations in the open-field test (OFT). The anti-immobility effect of nobiletin (50 mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1 mg/kg, s.c., a serotonin 5-HT_1A receptor antagonist), cyproheptadine (3 mg/kg, i.p., a serotonin 5-HT₂ receptor antagonist), prazosin (62.5 μg/kg, i.p., an α₁-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist) or propranolol (5 mg/kg, i.p., a β-adrenoceptor antagonist) did not block the antidepressant-like effect of nobiletin in the TST. Taken together, the data demonstrated that nobiletin produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. Thus, the present study suggests the therapeutic potential of this dietary flavonoid for the treatment of depression.     

Dopamine induces contraction in the proximal,but relaxation in the distal rat isolated small intestine

In the gut, dopamine is released by enteric neurons and modulates motility of small intestine smooth muscle cells. Here, we systematically analyzed the dopamine-induced effects on the longitudinal smooth muscle of different sections of the rat isolated small intestine. We found that exogenous dopamine had biphasic effects and could lead to both an early contraction and a late relaxation, depending on the region of small intestine. Thus, dopamine-induced early contractions were commonly observed in the duodenum, but less frequently in the jejunum, and rarely in the ileum. The amplitudes of these early contractions showed a striking regional dependence (duodenum > jejunum > ileum) and were significantly blocked by SCH23390 and raclopride. Conversely, dopamine-induced late relaxations were regularly obtained in the ileum and in the jejunum, but less frequently in the duodenum. Interestingly, the amplitudes of these relaxations showed an inverse regional dependence (ileum > jejunum > duodenum), and were insensitive to dopamine receptor antagonists. Rather, they were significantly inhibited by propranolol and prazosin. We conclude that dopamine exerts differential effects on smooth muscle motility in different regions within the rat small intestine. In proximal parts, dopamine predominantly causes D₁ and D₂ dopamine receptor-dependent contraction, whereas it leads to α and β adrenoceptor-dependent relaxation in more distal parts.     

Age-related changes in dorsal root ganglia,circulating and vascular calcitonin gene-related peptide (CGRP) concentrations in female rats: Effect of female sex steroid hormones

The aim of the present study is to investigate whether immunoreactive (I) calcitonin gene-related peptide (CGRP) content is decreased in plasma and mesenteric arteries (resistance arteries) in middle-aged rats and if so, whether sex steroid hormones enhance I-CGRP in middle-aged female rats. We also examined whether vascular CGRP receptor components, calcitonin receptor like receptor (CRLR) and receptor activity modifying protein 1 (RAMP₁) are elevated by sex steroid hormones treatment in middle-aged female rats. Young adult (3 months old) and middle-aged (10–12 months old) ovariectomized rats were treated subcutaneously with estradiol-17β (E₂; 2 mg), progesterone (P₄; 5 mg), E₂ + P₄ (2 mg + 20 mg) or placebo (control). Radioimmunoassay and Western blot analysis were performed to measure I-CGRP content and CGRP receptor components in dorsal root ganglia (DRG), in resistance arteries and in plasma. Immunofluorescent staining methods were employed to determine cellular localization of CRLR, RAMP₁ in resistance arteries. Our data demonstrated that I-CGRP content was significantly (p < 0.05) lower in the plasma and resistance arteries of middle-aged female rats compared to young controls. Both RAMP₁ and CRLR were concentrated in vascular endothelium and the underlying smooth muscle cells. RAMP₁ but not CRLR appeared to be decreased in middle-aged rat vasculature. Chronic perfusion of sex steroid hormones to ovariectomized rats: (1) significantly (p < 0.05) elevated I-CGRP in the DRG and in the plasma, and (2) significantly elevated RAMP₁ (p < 0.05) but did not alter CRLR in resistance arteries. These data suggest that female sex steroid treatment enhances I-CGRP and its receptors, and thus regulate the blood pressure in aged female rats.     

Dopamine D1 receptors and age differences in brain activation during working memory

In an fMRI study, 20 younger and 20 healthy older adults were scanned while performing a spatial working-memory task under two levels of load. On a separate occasion, the same subjects underwent PET measurements using the radioligand [¹¹C] SCH23390 to determine dopamine D₁ receptor binding potential (BP) in caudate nucleus and dorsolateral prefrontal cortex (DLPFC). The fMRI study revealed a significant load modulation of brain activity (higher load > lower load) in frontal and parietal regions for younger, but not older, adults. The PET measurements showed marked age-related reductions of D₁ BP in caudate and DLPFC. Statistical control of caudate and DLPFC D₁ binding eliminated the age-related reduction in load-dependent BOLD signal in left frontal cortex, and attenuated greatly the reduction in right frontal and left parietal cortex. These findings suggest that age-related alterations in dopaminergic neurotransmission may contribute to underrecruitment of task-relevant brain regions during working-memory performance in old age.