Biomedical subjects

Steven R Goldberg

Publications and source records attributed to Steven R Goldberg.

At least 19 recordsLinked to original sources

PubMed2007

The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport.

Anandamide is an endogenous ligand for brain cannabinoid CB(1) receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of delta-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and methanandamide were blocked by the CB1 receptor antagonist rimonabant, but not the vanilloid VR1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.

Amidohydrolases↗

PubMed2007

Dopamine D3 receptor ligands for the treatment of tobacco dependence.

This review considers the potential use of the dopamine D(3) receptor (DRD3) as a novel therapeutic target for the treatment of tobacco dependence. Among the 5 dopamine receptors identified, the DRD3 is located in the nucleus accumbens, ventral tegmental area and amygdala: 3 brain structures that are implicated in the motivational control of drug-seeking behaviour and drug-conditioning processes. Although it has been proposed that modulating dopamine transmission would be effective in the treatment of drug dependence, no validation has been provided in humans so far. Several highly selective DRD3 ligands have recently been evaluated in preclinical models of drug dependence. These ligands act as DRD3 antagonists in vivo and are able to decrease the motivation to take various drugs of abuse and reduce the influence of associated drug-conditioned behaviour. Of note is that these effects have been found with nicotine-seeking behaviour and nicotine relapse in rodents, suggesting a potential use of these ligands for the treatment of tobacco smokers. In contrast to nicotine replacement therapy, varenicline and bupropion (which are currently used for the treatment of smokers), DRD3 antagonists do not seem to produce nicotine-like effects in experimental animals and, therefore, may not substitute for nicotine or alleviate nicotine withdrawal symptoms in human smokers. This behavioural profile, which was also reported recently with cannabinoid CB(1) receptor antagonists, may result from effects on specific brain pathways that express DRD3 receptors and are involved in relapse and conditioning processes. These preclinical studies suggest that the clinical evaluation of DRD3 ligands should be performed with clinical trials designed specifically to evaluate the relapse phenomena.

Animals↗

PubMed2006

Blockade of adenosine A2A receptors prevents protein phosphorylation in the striatum induced by cortical stimulation.

Previous studies have shown that cortical stimulation selectively activates extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and immediate early gene expression in striatal GABAergic enkephalinergic neurons. In the present study, we demonstrate that blockade of adenosine A2A receptors with caffeine or a selective A2A receptor antagonist counteracts the striatal activation of cAMP-protein kinase A cascade (phosphorylation of the Ser845 residue of the glutamate receptor 1 subunit of the AMPA receptor) and mitogen-activated protein kinase (ERK1/2 phosphorylation) induced by the in vivo stimulation of corticostriatal afferents. The results indicate that A2A receptors strongly modulate the efficacy of glutamatergic synapses on striatal enkephalinergic neurons.

Adenosine A2 Receptor Antagonists↗

PubMed2006

Previous exposure to THC alters the reinforcing efficacy and anxiety-related effects of cocaine in rats.

The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to other drugs can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. In Experiment 1, THC pre-exposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Experiment 2 examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THC-exposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC pre-exposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effect-which was verified in Experiment 3 using another model of anxiety, the light-dark test-may explain the reduced reinforcing value of cocaine observed in THC-exposed rats in Experiment 1.

Analgesics, Non-Narcotic↗

PubMed2006

Heteromeric nicotinic acetylcholine-dopamine autoreceptor complexes modulate striatal dopamine release.

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D(2) autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D(2) autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-alpha(7) nACh receptor antagonist dihydro-beta-erythroidine or the D(2-3) receptor agonist quinpirole. Local perfusion of the D(2-3) receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro-beta-erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D(2) autoreceptor modulating the efficacy of non-alpha(7) nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between beta(2) subunits of non-alpha(7) nicotinic acetylcholine receptors and D(2) autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-alpha(7) nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.

Animals↗

PubMed2006

Two brain sites for cannabinoid reward.

The recent findings that Delta9tetrahydrocannabinol (Delta9THC), the active agent in marijuana and hashish, (1) is self-administered intravenously, (2) potentiates the rewarding effects of electrical brain stimulation, and (3) can establish conditioned place preferences in laboratory animals, suggest that these drugs activate biologically primitive brain reward mechanisms. Here, we identify two chemical trigger zones for stimulant and rewarding actions of Delta9THC. Microinjections of Delta9THC into the posterior ventral tegmental area (VTA) or into the shell of the nucleus accumbens (NAS) increased locomotion, and rats learned to lever-press for injections of Delta9THC into each of these regions. Substitution of vehicle for drug or treatment with a cannabinoid CB1 receptor antagonist caused response cessation. Microinjections of Delta9THC into the posterior VTA and into the posterior shell of NAS established conditioned place preferences. Injections into the core of the NAS, the anterior VTA, or dorsal to the VTA were ineffective. These findings link the sites of rewarding action of Delta9THC to brain regions where such drugs as amphetamines, cocaine, heroin, and nicotine are also thought to have their sites of rewarding action.

Analysis of Variance↗

PubMed2006

Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers.

The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.

Animals↗

PubMed2006

Stimulation of adenosine receptors selectively activates gene expression in striatal enkephalinergic neurons.

In the striatum, adenosine A2A and dopamine D2 receptors exert reciprocal antagonistic interactions that modulate the function of GABAergic enkephalinergic neurons. We have previously shown that stimulation of adenosine A1 receptors allows the stimulation of A2A receptors to overcome a tonic inhibitory effect of D2 receptors and induce striatal expression of c-fos. In the present work, by studying co-localization of c-Fos immunoreactivity and preproenkephalin and preprodynorphin transcripts, we show that co-administration of the A1 receptor agonist CPA and the A2A receptor agonist CGS 21680 increases the striatal expression of c-fos in GABAergic enkephalinergic but not in GABAergic dynorphinergic neurons. Co-administration of CPA and CGS 21680 also induced a significant increase in the striatal expression of preproenkephalin. The results underscore the role of adenosine in the activation of gene expression in the GABAergic enkephalinergic neuron.

Adenosine↗

PubMed2006

Nicotine pre-exposure does not potentiate the locomotor or rewarding effects of Delta-9-tetrahydrocannabinol in rats.

This study assessed the effects of nicotine pre-exposure on subsequent locomotor and rewarding effects of repeated Delta-9-tetrahydrocannabinol administration in Sprague-Dawley rats. Repeated administration of the same dose of Delta-9-tetrahydrocannabinol (0.01-2 mg/kg) did not produce significant tolerance or behavioral sensitization to Delta-9-tetrahydrocannabinol's locomotor effects. An unbiased place conditioning paradigm was then used to obtain a measure of the rewarding effects of Delta-9-tetrahydrocannabinol. Rats received an injection of either Delta-9-tetrahydrocannabinol (0.01-2 mg/kg) before being placed in one compartment (three trials) or saline before being placed in the other compartment (three trials) of a two-compartment apparatus. Control rats received saline injections associated with both compartments. Significant conditioned place preferences developed with 0.1 mg/kg Delta-9-tetrahydrocannabinol in control rats, but not in nicotine pre-exposed rats. Surprisingly, significant place aversions developed at higher 1 and 2 mg/kg doses of Delta-9-tetrahydrocannabinol in nicotine pre-exposed rats. To the extent that behavioral sensitization may reflect reward processes in drug dependence, the lack of behavioral sensitization on repeated Delta-9-tetrahydrocannabinol administration is consistent with the difficulties usually encountered in demonstrating rewarding or reinforcing effects of Delta-9-tetrahydrocannabinol in rats. The present findings suggest, moreover, that nicotine pre-exposure alters the qualitative nature of rewarding effects and accentuates aversive effects of Delta-9-tetrahydrocannabinol.

Animals↗

PubMed2006

Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats.

Although endogenous cannabinoid systems have been implicated in the modulation of the rewarding effects of abused drugs and food, little is known about the direct effects of endogenous ligands for cannabinoid receptors on brain reward processes. Here we show for the first time that the intravenous administration of anandamide, an endogenous ligand for cannabinoid receptors, and its longer-lasting synthetic analog methanandamide, increase the extracellular dopamine levels in the nucleus accumbens shell of awake, freely moving rats, an effect characteristic of most drugs abused by humans. Anandamide produced two distinctly different effects on dopamine levels: (1) a rapid, transient increase that was blocked by the cannabinoid CB1 receptor antagonist rimonabant, but not by the vanilloid VR1 receptor antagonist capsazepine, and was magnified and prolonged by the fatty acid amide hydrolase (FAAH) enzyme inhibitor, URB597; (2) a smaller delayed and long-lasting increase, not sensitive to CB1, VR1 or FAAH blockade. Both effects were blocked by infusing either tetrodotoxin (TTX, 1 microm) or calcium-free Ringer's solution through the microdialysis probe, demonstrating that they were dependent on the physiologic activation of dopaminergic neurotransmission. Thus, these results indicate that anandamide, through the activation of the mesolimbic dopaminergic system, participates in the signaling of brain reward processes.

Amidohydrolases↗

PubMed2005

Metabolic transformation plays a primary role in the psychostimulant-like discriminative-stimulus effects of selegiline [(R)-(-)-deprenyl].

l-Deprenyl [selegiline, (R)-(-)-deprenyl] is a selective inhibitor of monoamine oxidase B (MAO-B) used in the treatment of Parkinson's disease and proposed as an antidepressant and an aid for cigarette-smoking cessation and treatment of psychostimulant abuse. Beneficial therapeutic effects of (R)-(-)-deprenyl may also result from indirect actions. Brain levels of dopamine and beta-phenylethylamine (beta-PEA), a behaviorally active endogenous trace amine, increase after (R)-(-)-deprenyl treatment due to MAO-B blockade and (R)-(-)-deprenyl is metabolized to (R)-(-)-methamphetamine and (R)-(-)-amphetamine, suggesting that (R)-(-)-deprenyl may have psychostimulant-like behavioral effects. Indeed, (R)-(-)-deprenyl produces psychostimulant-like discriminative-stimulus effects in experimental animals. Here, we tested the hypothesis that psychostimulant-like behavioral effects of (R)-(-)-deprenyl are mainly mediated by its metabolites. Male Fisher F344 rats were trained to discriminate i.p. injection of 1.0 mg/kg (S)-(+)-methamphetamine or 10.0 mg/kg cocaine from injection of saline using two-lever choice schedules of food delivery or stimulus shock termination. When (R)-(-)-deprenyl was tested by substitution, it had (S)-(+)-methamphetamine- and cocaine-like discriminative-stimulus effects, but only at doses of 10 to 30 mg/kg, doses 10 to 20 times higher than those selective for MAO-B inhibition. Ro 16-6491 [N-(2-aminoethyl)-4-chlorobenzamide hydrochloride], a selective inhibitor of MAO-B enzyme activity without psychoactive metabolites, had no psychostimulant-like discriminative effects. In addition, blockade of (R)-(-)-deprenyl's metabolism with SKF 525A (beta-DEAE-diphenylpropylacetate hydrochloride; 50 mg/kg i.p.) reduced or eliminated (R)-(-)-deprenyl's psychostimulant-like discriminative effects. When beta-PEA synthesis was blocked by NSD 1015 (m-hydroxy-benzyl-hydrazine; 30 mg/kg i.p.), there was a modest reversal of (R)-(-)-deprenyl's psychostimulant-like discriminative effects under some conditions, indicating a facilitatory modulation of the psychostimulant-like discriminative effects of (R)-(-)-deprenyl metabolites by elevated levels of beta-PEA under certain conditions.

Animals↗

PubMed2005

A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors.

RATIONALE: There is no consensus on the contribution of adenosine A(1) and A(2A) receptor blockade to motor-activating effects of caffeine. OBJECTIVE: Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A(1) and A(2A) receptor antagonists. METHODS: The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A(2A) receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A(1) receptor agonist N (6)-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined. RESULTS: The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3. CONCLUSIONS: The results indicate a predominant role for A(1) receptors in the motor-activating effects of acutely administered caffeine.

Adenosine↗

PubMed2005

Nicotine as a typical drug of abuse in experimental animals and humans.

RATIONALE AND BACKGROUND: Tobacco use through cigarette smoking is the leading preventable cause of death in the developed world. Nicotine, a psychoactive component of tobacco, appears to play a major role in tobacco dependence, but reinforcing effects of nicotine often are difficult to demonstrate directly in controlled laboratory studies with animal or human subjects. OBJECTIVE: To review the major findings obtained with various procedures developed to study dependence-related behavioral effects of nicotine in experimental animals and humans, i.e., drug self-administration, conditioned place preference, subjective reports of nicotine effects and nicotine discrimination, withdrawal signs, and ratings of drug withdrawal. RESULTS: Nicotine can function as an effective reinforcer of drug-seeking and drug-taking behavior both in experimental animals and humans under appropriate conditions. Interruption of chronic nicotine exposure produces withdrawal symptoms that may contribute to relapse. Difficulties encountered in demonstrating reinforcing effects of nicotine under some conditions, relative to other drugs of abuse, may be due to weaker primary reinforcing effects of nicotine or to a more critical contribution of environmental stimuli to the maintenance of drug-seeking and drug-taking behavior with nicotine than with other drugs of abuse. Further experiments are also needed to delineate the role other chemical substances inhaled along with nicotine in tobacco smoke play in sustaining smoking behavior. CONCLUSION: Nicotine acts as a typical drug of abuse in experimental animals and humans.

Animals↗

PubMed2005

Ethanol does not affect discriminative-stimulus effects of nicotine in rats.

The effects of ethanol were evaluated in rats trained to discriminate 0.4 mg/kg of nicotine from saline under a fixed-ratio 10 schedule of food delivery. Ethanol (0.1-1 g/kg, i.p.) did not produce any nicotine-like discriminative effects and did not produce any shift in the dose-response curve for nicotine discrimination. Thus, the ability to discriminate nicotine's effects does not appear to be altered by ethanol administration. However, the high dose of 1 g/kg ethanol, given either alone or in combination with nicotine, markedly depressed food-maintained responding. This later effect was associated in some rats with an attenuation of the discriminative-stimulus effects of the training dose of nicotine. This suggests that previous reports of increased tobacco smoking following ethanol consumption in humans are connected, in some way, with an increase in motivation to consume nicotine that is produced by ethanol, rather than with a decrease in the subjective response to nicotine.

Analysis of Variance↗

PubMed2005

The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys.

Anandamide, an endogenous ligand for brain cannabinoid CB(1) receptors, produces many behavioral effects similar to those of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Reinforcing effects of THC have been demonstrated in experimental animals, but there is only indirect evidence that endogenous cannabinoids such as anandamide participate in brain reward processes. We now show that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also show that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we show that the reinforcing effects of both anandamide and methanandamide are blocked by pretreatment with the cannabinoid CB(1) receptor antagonist rimonabant (SR141716). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB(1) receptors by anandamide could be part of the signaling of natural rewarding events.

Animals↗

PubMed2005

Neuropeptide Y protects against methamphetamine-induced neuronal apoptosis in the mouse striatum.

Methamphetamine (METH) is an illicit drug that causes neuronal apoptosis in the mouse striatum, in a manner similar to the neuronal loss observed in neurodegenerative diseases. In the present study, injections of METH to mice were found to cause the death of enkephalin-positive projection neurons but not the death of neuropeptide Y (NPY)/nitric oxide synthase-positive striatal interneurons. In addition, these METH injections were associated with increased expression of neuropeptide Y mRNA and changes in the expression of the NPY receptors Y1 and Y2. Administration of NPY in the cerebral ventricles blocked METH-induced apoptosis, an effect that was mediated mainly by stimulation of NPY Y2 receptors and, to a lesser extent, of NPY Y1 receptors. Finally, we also found that neuropeptide Y knock-out mice were more sensitive than wild-type mice to METH-induced neuronal apoptosis of both enkephalin- and nitric oxide synthase-containing neurons, suggesting that NPY plays a general neuroprotective role within the striatum. Together, our results demonstrate that neuropeptide Y belongs to the class of factors that maintain neuronal integrity during cellular stresses. Given the similarity between the cell death patterns induced by METH and by disorders such as Huntington's disease, our results suggest that NPY analogs might be useful therapeutic agents against some neurodegenerative processes.

Animals↗

PubMed2005

Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats.

RATIONALE: Caffeine is a non-selective adenosine receptor antagonist in vitro, but involvement of different adenosine receptor subtypes, particularly adenosine A1 and A 2A receptors, in the central effects of caffeine remains a matter of debate. OBJECTIVE: Investigate the role of adenosine A1 and A 2A receptors in the discriminative-stimulus effects of caffeine. METHODS: Rats were trained to discriminate an injection of 30 mg/kg (i.p.) caffeine from saline. The selective A1 receptor antagonist CPT, the selective A 2A receptor antagonist MSX-3 and the non-selective adenosine receptor antagonist DMPX were assessed for their ability to produce caffeine-like discriminative effects. The ability of CPT, MSX-3, the A1 receptor agonist CPA and the A 2A receptor agonist CGS21680 to reduce the discriminative effects of caffeine was also tested. Radioligand binding experiments with membrane preparations from rat striatum and transfected mammalian cell lines were performed to characterize binding affinity profiles of the different adenosine antagonists used in the present study (caffeine, DMPX, CPT and MSX-3) in relation to all known adenosine receptors (A1, A 2A, A 2B, A3). RESULTS: DMPX and CPT, but not MSX-3, produced significant caffeine-like discriminative effects. MSX-3, but not CPT, markedly reduced the discriminative effects of caffeine and the caffeine-like discriminative effects of CPT. Furthermore, the A1 receptor agonist CPA, but not the A 2A agonist CGS21680, reduced caffeine's discriminative effects. CONCLUSIONS: Adenosine A1 receptor blockade is involved in the discriminative-stimulus effects of behaviorally relevant doses of caffeine; A 2A receptor blockade does not play a central role in caffeine's discriminative effects and counteracts the A1 receptor-mediated discriminative-stimulus effects of caffeine.

Adenosine A1 Receptor Antagonists↗

PubMed2005

The dopamine D3 receptor and drug dependence: effects on reward or beyond?

Abused drugs (alcohol, heroin, cocaine, tetrahydrocannabinol and nicotine) elicit a variety of chronically relapsing disorders by interacting with brain reward systems. All of these drugs increase dopamine levels in the shell of nucleus accumbens, a structure that has been involved in their hedonic and reinforcing properties. Dopamine D(3) receptors (DRD3) are predominantly expressed in the nucleus accumbens, but also in the ventral tegmental area and in the amygdala, brain structures implicated in drug dependence. Moreover, converging pharmacological, human post-mortem and genetic studies have suggested the involvement of the DRD3 in drug dependence. Based on early studies using non-selective DRD3 ligands, the DRD3 was proposed as having a direct role in the rewarding effects of psychostimulants. However, recent studies using highly selective DRD3 ligands and the DRD3-deficient mice have revealed that the DRD3 is not implicated in the direct reinforcing effects of drugs of abuse. In contrast, the DRD3 appears to be implicated in the motivation to self-administer drugs under schedules where the response requirements are high. This is consistent with a behavioral economic analysis, with the effects of DRD3 ligands revealed only in situations with high prices for drug. Drug-self administration and relapse are strongly controlled by environmental stimuli. The DRD3 strongly modulates the influence of these environmental stimuli on drug-seeking behavior. DRD3 blockade disrupts the reactivity to drug-associated stimuli in various paradigms, such as second-order schedules of drug-self administration, conditioned place preference and Pavlovian conditioning procedures. In several paradigms, the involvement of the DRD3 has been confirmed by using DRD3-deficient mice. On the contrary, reactivity to stimuli associated with natural reinforcers, such as food, appears unaffected by modulation of the DRD3. All these findings suggest that DRD3 ligands may represent a useful strategy for decreasing relapse in abstinent drug-abusers.

Animals↗