D2 Ligands Research Articles

2,4-Disubstituted pyrroles: synthesis, traceless linking and pharmacological investigations leading to the dopamine D4 receptor partial agonist FAUC 356

Solution-phase synthesis and a solid-phase supported approach to piperazinylmethyl substituted pyrroles are described. Receptor binding studies and the measurement of D4 ligand efficacy led to the ethynylpyrrole 1d (FAUC 356) exerting selective D4 binding and substantial ligand efficacy (66%, EC 50=1.9 nM). This activity profile might be of interest for the treatment of ADHD.

Age-related changes in dopamine D2 receptors in rat heart and coronary vessels.

1. The distribution of dopamine D2 receptors in rat heart and coronary vessels and the possible age-related changes in D2 receptor density were studied. The pharmacological characteristics and the anatomical location of dopamine D2-like receptor sites in rat heart and coronary vessels were investigated using combined binding techniques and light microscopy autoradiography. 2. Samples of heart and coronary vessels were harvested from young and old rats. On frozen slices, dopaminergic D2 receptors were labelled by means of a selective D2 ligand, namely [3H]-spiroperidol (spiperone). Inhibition studies were performed using unlabelled agonists and/or labelled and unlabelled antagonists to define pharmacological specificity of the binding. Physiological experiments were performed to demonstrate the selective antagonism between D2 receptors and many dopaminergic drugs. 3. [3H]-Spiroperidol was bound to sections of rat heart and coronary artery (in a manner consistent with the labelling of dopamine D2-like receptors) with an equilibrium dissociation constant of approximately 2.4 +/- 0.7 nmol/L and a maximum capacity of binding sites of 65.8 +/- 4.5 fmol/mg protein. Experiments performed on sections of coronary veins did not allow the evaluation of specific binding. Autoradiography, observed with light microscopy, showed the development of specific silver grains within the whole wall of rat heart and coronary artery. The greater sensitivity to displacement by amisulpride, bromocriptine, domperidone, haloperidol, raclopride and L-sulpiride than to displacement by N-propyl-norapomorphine, quinpirole and clozapine suggests that the binding sites observed in these experiments are likely to belong to the dopamine D2 receptor subtype. 4. Comparing results in young and old rats, we observed numerous significant age-related changes, including a decrease in D2 receptors localized in rat heart and coronary artery wall. These D2 receptors show a specific location, in close relationship with dopaminergic nerve fibres. They decrease with age and their role remains unknown.

Modulation of cocaine and food self-administration by low- and high-efficacy D1 agonists in squirrel monkeys.

Dopamine D1 ligands have been proposed as candidate medications for cocaine abuse. Previous studies have shown that the ability of D1 ligands to modulate the behavioral effects of cocaine may depend on agonist efficacy. This study investigated the role of agonist efficacy in the ability of D1 ligands to modulate the reinforcing effects of cocaine in monkeys. Squirrel monkeys trained to self-administer cocaine under a second-order schedule of reinforcement were treated daily with D1 agonists varying in efficacy from low to high (SKF 83959 < SKF 77434 < or = SKF 81297 < SKF 82958) and the D1 antagonist SCH 39166. D1 ligands, regardless of efficacy, produced dose-dependent reductions in responding maintained by a maximally effective dose of cocaine. Equivalent doses of each D1 ligand reduced responding for food under a similar second-order schedule, suggesting that the suppression was not specific to cocaine self-administration. When studied in combination with a range of cocaine doses, treatment with the agonists SKF 83959, SKF 77434, SKF 81297, and the antagonist SCH 39166 produced overall rightward and downward shifts in the dose-response function for cocaine self-administration. Treatment with the agonist SKF 82958, however, produced an overall suppression of responding, regardless of the dose of cocaine. In contrast to a high-efficacy agonist, low-efficacy D1 ligands modulated the reinforcing effects of cocaine in a manner consistent with at least a partial antagonism of cocaine self-administration. This delineation of the efficacy-dependent profile of effects for D1 ligands should guide research into their utility as cocaine pharmacotherapies.

Design and synthesis of [(2,3-dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as novel ligands selective for the dopamine D3 receptor subtype.

The dopamine D3 receptor subtype has been recently targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. However, definitive behavioral investigations have been hampered by the lack of highly selective D3 agonists and antagonists. In an attempt to design a novel class of D3 ligands with which to study this receptor system, a series of chemically divergent compounds that possessed various structural features that exist within several classes of reputed D3 agents was screened and compared to the recently reported NGB 2904 (58b). On the basis of these results, a novel series of compounds was designed that included functional moieties that were required for high-affinity and selective binding to D3 receptors. All the compounds in this series included an aryl-substituted piperazine ring, a varying alkyl chain linker (C3-C5), and a terminal aryl amide. The compounds were synthesized and evaluated in vitro for binding in CHO cells transfected with human D2, D3, or D4 receptor cDNAs. D3 binding affinities ranged from K(i) = 1.4 to 1460 nM. The most potent analogue in this series, 51, demonstrated a D3/D2 selectivity of 64 and a D3/D4 selectivity of 1300. Structure-activity relationships for this class of ligands at D3 receptors will provide new leads toward the development of highly selective and potent molecular probes that will prove useful in the elucidation of the role D3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine.

Rationally based efficacy tuning of selective dopamine d4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213).

Structure dependent efficacy studies in the field of selective D4 ligands led to the 2-aminomethyl substituted azaindole 2 (FAUC 213) that displayed strong D4 binding, high subtype selectivity, and complete antagonist properties in ligand-induced mitogenesis experiments. According to our schematic molecular model, the intrinsic activity of the regioisomers investigated is controlled by the ability of the heterocyclic unit to interact with both elements of the D4 binding-site crevice, the aromatic microdomain in TM6, and a serine residue in TM5.

Quantitative assessment of dopamine D2 antagonist activity using invertebrate ( Planaria) locomotion as a functional endpoint

Introduction: Dopaminergic ligands, including drugs of abuse, modulate the locomotor activity of planarians and induce characteristic abnormal patterns of motility at high doses. It has been presumed that the effect is related to dopamine receptors based on ligand specificity and effects on second messenger levels. However, to date, the measured changes have been mostly qualitative in nature and it is not completely clear that the effect is related to stereospecific receptor mechanisms. Methods: The present study addressed these issues by devising a convenient and sensitive metric (locomotor velocity, pLMV) and applied the method to test Planaria enantiomer-sensitivity to a dopamine D2-receptor antagonist. Results: pLMV was remarkably constant over the observation period and established a stable baseline against which to study and quantitate pharmacologic intervention. Further, S(−)-sulpiride at low doses (10 −10 to 10 −8 M) attenuated pLMV in a dose-dependent manner, but R(+)-sulpiride was only 1/25th as potent. Discussion: The new methodology thus provides a method for quantifying actions of D2 ligands in a simple in vivo system.

N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo

We reported previously that synthetic amides of polyunsaturated fatty acids with bioactive amines can result in substances that interact with proteins of the endogenous cannabinoid system (ECS). Here we synthesized a series of N-acyl-dopamines (NADAs) and studied their effects on the anandamide membrane transporter, the anandamide amidohydrolase (fatty acid amide hydrolase, FAAH) and the two cannabinoid receptor subtypes, CB(1) and CB(2). NADAs competitively inhibited FAAH from N18TG2 cells (IC(50)=19-100 microM), as well as the binding of the selective CB(1) receptor ligand, [(3)H]SR141716A, to rat brain membranes (K(i)=250-3900 nM). The arachidonoyl (20:4 omega 6), eicosapentaenoyl (20:5 omega 3), docosapentaenoyl (22:5 omega 3), alpha-linolenoyl (18:3 omega 3) and pinolenoyl (5c,9c,12c 18:3 omega 6) homologues were also found to inhibit the anandamide membrane transporter in RBL-2H3 basophilic leukaemia and C6 glioma cells (IC(50)=17.5-33 microM). NADAs did not inhibit the binding of the CB(1)/CB(2) receptor ligand, [(3)H]WIN55,212-2, to rat spleen membranes (K(i)>10 microM). N-arachidonyl-dopamine (AA-DA) exhibited 40-fold selectivity for CB(1) (K(i)=250 nM) over CB(2) receptors, and N-docosapentaenoyl-dopamine exhibited 4-fold selectivity for the anandamide transporter over FAAH. AA-DA (0.1-10 microM) did not displace D1 and D2 dopamine-receptor high-affinity ligands from rat brain membranes, thus suggesting that this compound has little affinity for these receptors. AA-DA was more potent and efficacious than anandamide as a CB(1) agonist, as assessed by measuring the stimulatory effect on intracellular Ca(2+) mobilization in undifferentiated N18TG2 neuroblastoma cells. This effect of AA-DA was counteracted by the CB(1) antagonist SR141716A. AA-DA behaved as a CB(1) agonist in vivo by inducing hypothermia, hypo-locomotion, catalepsy and analgesia in mice (1-10 mg/kg). Finally, AA-DA potently inhibited (IC(50)=0.25 microM) the proliferation of human breast MCF-7 cancer cells, thus behaving like other CB(1) agonists. Also this effect was counteracted by SR141716A but not by the D2 antagonist haloperidol. We conclude that NADAs, and AA-DA in particular, may be novel and useful probes for the study of the ECS.

Intravenous progesterone elicits a more rapid induction of lordosis in rats than does SKF38393

In ovariectomized (ovx), estradiol (E)-primed rats, progesterone (P) facilitates sexual receptivity within 2–30 min following intravenous (i.v.) administration. Intracerebroventricular infusion of P or the dopamine receptor type 1-like (D1) agonist, SKF38393, increases lordosis in ovx, E-primed rats, and intracellular progestin receptor (PR) blockers attenuate P and SKF38393’s facilitation of lordosis. The present experiments examined whether P can have effects via Dl receptors and compared the onset of P’s and SKF38393’s induction of lordosis following i.v. administration. Ovx rats (N = 20) with i.v. jugular catheters were primed daily with 2 µg E subcutaneously and were pretested for sexual receptivity. In Experiment 1, rats (n = 10) were repeatedly tested for receptivity 3–7, 15, 30, 60, and 120 min following i.v. infusion of P (2 µg), SKF38393 (100 ng), and propylene glycol vehicle (0.2 cc). Progesterone increased postinfusion lordosis at all test times, whereas SKF38393’s increases in lordosis were not statistically significant until 15 min following i.v. infusion, relative to lordosis following vehicle or pretest conditions in Experiment 1. In Experiment 2, rats (n = 15; 5 from Experiment 1, and 10 new subjects) received infusions of the antiprogestin, RU38486, the D1 antagonist, SCH23390, or vehicle followed by a second P or vehicle infusion. Although both RU38486 and SCH23390 blocked the facilitatory effects of P on lordosis, their effects varied. RU38486 completely blocked P’s effects, whereas SCH23390 did not. In Experiment 3, rats (n = 15, from Experiment 2) received infusions of RU38486, SCH23390, or vehicle followed by a second SKF38393 or vehicle infusion. RU38486 and SCH23390 both effectively blocked the facilitatory effects of SKF38393 on lordosis. In Experiment 4, rats (n = 15, from Experiment 3) received i.v. infusions of P, which rapidly and significantly increased the number of super-threshold spikes in the ventral tegmental area, but not in the ventral medial hypothalamus or in the parietal cortex. These data suggest that actions at intracellular progestin receptors do not account for all of P’s effects to facilitate receptivity. Interestingly, although PRs may be involved in P and D1 ligand’s activation of female sexual behavior, D1 receptors are not required for P’s effects. However, i.v. P rapidly and significantly alters neuronal activity in sites with the greatest concentration of dopamine neurons (ventral tegmental area > ventral medial hypothalamus > cortex).

A solution-phase combinatorial synthesis of selective dopamine D4 ligands.

Utilizing combinatorial synthesis and a preparative LC-MS automated chromatography system we have prepared and purified a library of 4-[2-(1,2,4-oxadiazolyl)]piperidines that were designed to be novel and selective dopamine D4 ligands. In one round of synthesis we identified N-4-chlorobenzyl-4-[2-(3-(2-thienyl)-1,2, 4-oxadiazolyl)]piperidine with a Kd of 5 nM for the human D4 receptor.

2H-T1 Relaxation and Deuterium Quadrupole Coupling Constants in Transition Metalη2-D2 Complexes

D2ligands differ significantly from classical deuteride ligands in their deuterium quadrupole coupling constants (DQCCs), which were derived from 2H-T1 min measurements on polydeuteride complexes such as [pp3MD2] and [pp3MD(D2)]+ (M = Ru, Os; pp3 = P(CH2CH2PPh2)3). The DQCC of the D2 ligand is much lower than that of the classical deuteride ligand (DQCC values given in kHz below structures in picture).

Probing the motion of the η2-dideuterium ligand by solution and solid-state 2H NMR spectroscopy

Variable temperature 2H NMR is used to measure the T1min values of the η2-D2 and D ligands in trans-[M(η2-D2)(D)(dppe)2]+, M = Ru (1) and Os (2) in solution. The rapid spinning motion of the η2-D2 ligand results in a much longer T1min than that of the terminal deuteride. The quadrupole coupling constant (CQ) for the terminal deuteride is calculated to be 79 kHz for 1 and 81 kHz for 2 while motion-reduced coupling constant (CQeff) for the D in the η2-D2 ligands in 1 and 2 are in the range 19-22 and 27-31 kHz, respectively. The actual CQ for these ligands with short D-D distances (&lt;1 Å) should be at least 2CQeff and probably greater than that of the terminal deuteride but less than that of D2(g), 227 kHz. A fast spinning (&gt;&gt;61 MHz) and tilting of the primary electric field gradient component of between 90° and 60° or between 50° and 40° with respect to the axis of D2 rotation is an explanation for the small CQeff. Therefore neither D-D nor M-D bonding dominates the electric field gradient direction in these M(η2-D2) bonds. The complex [RuD2(C5Me5)(dppm)]+ 3, which exists in solution as a 3.3:1 mixture of Ru(D···D) (3a) and Ru(D)2 (3b) tautomers, has T1min(D) values that provide CQeff values of 66 kHz for 3a and 71 kHz for 3b. The elongated D···D ligand in 3a with d(D···D) ~ 1.10 Å may be "static" compared to the 61.4 MHz 2H spectrometer frequency and therefore have "compressed dihydride" character and display similar Ru-D bonds as in 3b. However, it is more likely that the static CQ for the D of 3a is much larger than that of a terminal Ru-D but averaged to 66 kHz by a 180° flip of the D2 as observed in 7. The complexes trans-[M(D···D)(Cl)(dppe)2]PF6, M = Ru (4), Os (5), and Ru(η2-D2)(dppb)(µ-Cl)3RuCl(dppb) (6) also have motion-reduced CQ values. Some 2H NMR quadrupole echo wide-line spectra of 1, 4, and Os(D···D)(Cl)2(CO)(PiPr3)2 (7) (contaminated with 20% Os(H···D)) were recorded in the solid phase from 293 to 123 K. These also indicate that the CQeff of the D in the D2 ligands are motion-reduced. Simulation of the spectra of 7 are suggestive of a twofold reorientation of a D2 ligand with a static CQ value in the range of 120-167 kHz, a tilt angle of the electric field gradient of about 50°, and an asymmetry parameter near to zero. Significantly, the MAS 2H spectrum of 7 has a broad doublet, possibly due to a non-averaged D-D dipolar/quadrupolar interference phenomenon; this is first time this has been observed. Variable temperature T1 data for solid 7 are also reported, which allow the evaluation of the activation barrier to the twofold flipping motion of the D2; the only other way of quantifying such an energy barrier is by use of an inelastic neutron scattering method.Key words: dihydrogen, deuterium, NMR, ruthenium, osmium, complexes, dynamics, hydride, bonding.

Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex.

Sleep deprivation has been shown to have an antidepressant benefit in a subgroup of depressed patients. Functional imaging studies by the authors and others have suggested that patients with elevated metabolic rates in the anterior cingulate gyrus at baseline are more likely to respond to either sleep deprivation or antidepressant medications than patients with normal metabolic rates. The authors extend their earlier work in a larger group of patients and explore additional brain areas with statistical probability mapping. Thirty-six patients with unipolar depression and 26 normal volunteers were studied with positron emission tomography before and after sleep deprivation. Response to sleep deprivation was defined as a 40% or larger decrease in total scores on the Hamilton Depression Rating Scale. One-third of the depressed patients had a significant response to sleep deprivation. Responders had higher relative metabolic rates in the medial prefrontal cortex, ventral anterior cingulate, and posterior subcallosal gyrus at baseline than depressed patients who did not respond to sleep deprivation and normal volunteers. Lower Hamilton depression scores correlated significantly with lower metabolic rates in the left medial prefrontal cortex. After sleep deprivation, significant decreases in metabolic rates occurred in the medial prefrontal cortex and frontal pole in the patients who responded positively to sleep deprivation. High pretreatment metabolic rates and decreases in metabolic rates after treatment in the medial prefrontal cortex may characterize a subgroup of depressed patients who improve following sleep deprivation and, perhaps, other antidepressant treatments.

Dopamine D3 receptor mutant and wild‐type mice exhibit identical responses to putative D3 receptor‐selective agonists and antagonists

Previous studies using a variety of drugs with different affinities for the dopamine (DA) D3 receptor suggested that this receptor is involved in regulating motor activity and hypothermia. However, the in vivo selectivity of many of these compounds has been repeatedly questioned. To examine the precise roles of the DA D3 receptor in motor activity and hypothermic responses, we used mutant mice lacking the DA D3 receptor to evaluate the in vivo effects of several putative D3 receptor-selective agonists and antagonists. Using automated photocell activity chambers, we observed that the decreases in locomotor activity produced by putative D3 receptor-selective agonists as well as increases in locomotor activity produced by putative D3 receptor antagonists are identical in D3 receptor mutant and wild-type mice. In addition, the hypothermia produced by the putative D3 receptor-selective agonist PD 128907 is identical in both groups of mice. Based on these findings, we propose that D3 receptors are unlikely to be involved in these effects and we caution that the putative D3 ligands that have been used to reach conclusions regarding the functional roles of D3 receptors lack the necessary in vivo selectivity to support such conclusions. Synapse 31:210–215, 1999. © 1999 Wiley-Liss, Inc.

Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys.

The present study used autoradiography to examine the effects of chronic self-administration of cocaine on the density of dopamine D2 receptors in nonhuman primates. Three rhesus monkeys intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months until they were euthanized immediately after a self-administration session. Binding site density of the D2 ligand [3H]raclopride (2 nM) was assessed in these monkeys as well as three untreated controls, using quantitative in vitro receptor autoradiography. As compared to untreated controls, D2 binding site density was significantly lower in the animals that self-administered cocaine in all regions of the striatum rostral to the anterior commissure. These regions include the anterior and central regions of the caudate nucleus, putamen, olfactory tubercle, and both the shell and core of the nucleus accumbens. Within the substantia nigra and ventral tegmental area, by contrast, no differences were found in the density of D2 binding sites. These findings suggest a pervasive effect of cocaine on the regulation of D2 receptors in the striatum. The lack of change within the ventral midbrain, however, suggests a differential regulation of D2 receptors in the striatum and ventral midbrain. This study confirms and extends our knowledge of the neurobiological changes in the mesolimbic dopamine system that result from chronic exposure to cocaine.

Isoindolinone enantiomers having affinity for the dopamine D4 receptor.

PD 108635 (1) was identified as a potent dopamine D4 ligand and we wanted to replace the benzylic alcohol with a metabolically more stable moiety. Investigations led to the discovery of a series of isoindolinones having D4 affinity.

Mapping of D1 dopamine receptor mRNA by non-radioactive in situ hybridization.

In order to improve the identification and characterization of dopaminoceptive neurons, the rat brain was mapped for D1 dopamine receptor mRNA by non-radioactive in situ hybridization (ISH) with a 45mer digoxigenin-labeled oligonucleotide probe. The specificity of the results was controlled with the help of a 396-bp D1 receptor riboprobe. Labeled hybrids were visualized with an alkaline phosphatase-coupled anti-digoxigenin antibody. The high resolution obtained permitted individual labeled cells to be identified and to distinction between cell bodies and processes. D1 mRNA was largely confined to neurons. With the exception of ependymal cells, glial cells were not distinctly labeled. Subcellularly, D1 mRNA was localized to perikarya but not to dendrites or axons. D1 receptor-expressing neurons were present in all of the known terminal fields of mesencephalic or diencephalic dopaminergic neurons. However, D1 message was also detected in brain areas which are not known to contain D1 ligand binding sites or in which the presence or the cellular source of this receptor subtype had previously not been unequivocally established, such as the hippocampus or cerebellar cortex. Moreover, labeled neurons were present in regions not known to receive dopaminergic projections, such as the thalamic and some brainstem nuclei. We conclude that this ISH technique provides a considerable gain in sensitivity and resolution with regard to neurotransmitter receptor mapping.

Is schizophrenia an autoimmune disease?

Changes in D2-like dopamine (DA) receptor binding in rat brain regions were compared by quantitative in vitro receptor autoradiography after 21-d treatment with a typical (fluphenazine), atypical (clozapine), or candidate atypical antipsychotic (S[+]-N-n-propylnorapomorphine, [+]-NPA). Fluphenazine treatment significantly increased binding of the D2,3,4 radioligands [3H]nemonapride and [3H]spiperone in caudate-putamen (CPu: 22%, 32%), nucleus accumbens (ACC: 67%, 52%), olfactory tubercle (OT: 53%, 43%), and medial prefrontal cerebral cortex (MPC: 46%, 47%) but not dorsolateral frontal cortex (DFC). D2-like binding in MPC was also increased by (+)-NPA (49%, 39%) and clozapine (60%, 40%), but not in DFC, CPu, ACC, or OT. Binding of D2,3-selective [3H]raclopride increased less after fluphenazine in ACC (27%) and CPu (16%) than with the nonselective radioligands, and not after clozapine or (+)-NPA. D3-selective binding of [3H]R(+)-7-OH-DPAT was not changed with any treatment or region including islands of Calleja. Binding of [3H]nemonapride or [3H]spiperone under D4-selective conditions (with 300 nM S[−]-raclopride and other masking agents, at sites occluded by D4 ligand L-745,870), was increased by fluphenazine, (+)-NPA, clozapine in ACC (120%, 76%, 70%, respectively), and CPu (54%, 37%, 35%), but not in OT, DFC or MPC. These results support the hypothesis that cerebrocortical D2-like and striatolimbic D4-like receptors contribute to antipsychotic actions of both typical and atypical drugs and encourage further consideration of S(+)aporphines as potential atypical antipsychotics.

Mapping of Dopamine D3 Receptor Binding Site by Pharmacological Characterization of Mutants Expressed in Cho Cells with the Semliki Forest Virus System

Nine mutants and the wild-type human dopamine D3 receptor were expressed at high levels in BHK and CHO cells using the Semliki Forest virus system and were analysed for receptor binding with several structurally different dopamine D3 ligands. The mutation His349Leu showed a significant decrease in pKi values for raclopride, dopamine and GR218231, but an increase in affinity for GR99841. Thr369Val had an increase in pKi for both GR99841 and 7-OH-DPAT. The receptor modelling based on sequence alignment with bacteriorhodopsin indicated that Thr369 and His349 are located on the inside of the ligand binding pocket and the effect of the mutagenesis was therefore expected. The change in binding affinity for Thr369Val could be due to the location in the transmembrane domain VII close to the aspartate residue in domain III, the postulated counter ion for dopamine.

Effect of cocaine self‐administration on striatal dopamine D1 receptors in rhesus monkeys

An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D1 family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18–22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D1 ligand [3H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D1 binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D1 binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D1 receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use. Synapse 28:1–9, 1998. © 1998 Wiley-Liss, Inc.

Effect of cocaine self-administration on striatal dopamine D1 receptors in rhesus monkeys.

An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D1 family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D1 ligand [3H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D1 binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D1 binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D1 receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use.