Influence of Age and Genetic Background on Ethanol Intake and Behavioral Response Following Ethanol Consumption and During Abstinence in a Model of Alcohol Abuse.

Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40-70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction.

Role of genetic background in the effects of adolescent nicotine exposure on mesolimbic dopamine transmission.

Smoking during adolescence may increase the likelihood to develop nicotine dependence and to abuse other drugs such as cocaine. Despite great efforts to understand underlying neurobiological mechanisms of this progression, less attention has been paid to the role of genetic factors. Here, we investigated the influence of both genetic background and age at first nicotine exposure in the long-lasting effects on mesolimbic dopamine transmission including the increased cocaine-rewarding effect. Mid-adolescent and adult rats of inbred strains Lewis (addiction prone) and Fischer 344 (addiction resistant) were administered nicotine (0.4 mg/kg) or vehicle once daily for 5 days. Changes in dopamine transmission were investigated by in vivo microdialysis and electrophysiology after 30 days of withdrawal, whereas changes in cocaine-rewarding effect were assessed via conditioned place preference paradigm. Nicotine pre-exposure differentially changed mesolimbic dopamine transmission depending on strain and age of pre-exposure. A potentiation of dopamine response to nicotine was observed in nucleus accumbens (NAc) core of both strains and age groups, whereas dopamine response in NAc shell was enhanced exclusively in Lewis rats exposed to nicotine during adolescence. A similar response was observed following cocaine challenge at adulthood. Changes in VTA dopamine cell population and activity were observed only in adolescent nicotine-pretreated Lewis rats, which also showed an increased cocaine-rewarding effect at adulthood. These results highlight the influence of genetic background in the long-lasting effects of nicotine exposure and suggest that exposure during adolescence might increase nicotine and cocaine-rewarding properties in genetically vulnerable individuals, thereby facilitating progression toward dependence.

Immunomodulatory drugs alleviate l-dopa-induced dyskinesia in a rat model of Parkinson's disease.

BACKGROUND: Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model. METHODS: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control. RESULTS: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels. CONCLUSIONS: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.

Neuroinflammation in L-DOPA-induced dyskinesia: beyond the immune function.

Neuroinflammation is a main component of Parkinson's disease (PD) neuropathology, where unremitting reactive microglia and microglia-secreted soluble molecules such as cytokines, contribute to the neurodegenerative process as part of an aberrant immune reaction. Besides, pro-inflammatory cytokines, predominantly TNF-α, play an important neuromodulatory role in the healthy and diseased brain, being involved in neurotransmitter metabolism, synaptic scaling and brain plasticity. Recent preclinical studies have evidenced an exacerbated neuroinflammatory reaction in the striatum of parkinsonian rats that developed dyskinetic responses following L-DOPA administration. These findings prompted investigation of non-neuronal mechanisms of L-DOPA-induced dyskinesia (LID) involving glial cells and glial-secreted soluble molecules. Hence, besides the classical mechanisms of LID that include abnormal corticostriatal neurotransmission and maladaptive changes in striatal medium spiny neurons (MSNs), here we review studies supporting a role of striatal neuroinflammation in the development of LID, with a focus on microglia and the pro-inflammatory cytokine TNF-α. Moreover, we discuss several mechanisms that have been involved in the development of LID, which are directly or indirectly under the control of TNF-α, and might be abnormally affected by its chronic overproduction and release by microglia in PD. It is proposed that TNF-α may contribute to the altered neuronal responses occurring in LID by targeting receptor trafficking and function in MSNs, but also dopamine synthesis in preserved dopaminergic terminals and serotonin metabolism in serotonergic neurons. Therapeutic approaches specifically targeting glial-secreted cytokines may represent a novel target for preventing or treating LID.

Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson's disease.

Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic l-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.

In vivo dopamine agonist properties of rotigotine: Role of D1 and D2 receptors.

Rotigotine acts in vitro as a full agonist of dopamine D1 receptors at concentrations almost superimposable to those at which it acts on D2 receptors. However in vivo evidence of the differences between the agonist activity of rotigotine at D1 receptors from that on the D2 receptors has not been provided yet. In order to test the ability of rotigotine to stimulate dopamine D1 and D2 receptors in vivo, we studied the effect of SCH39166 and eticlopride, selective dopamine D1 and D2/D3 receptor antagonists respectively, on rotigotine-induced contralateral turning behavior in 6-hydroxydopamine lesioned rats. Furthermore, the expression of the immediate-early gene c-fos in the caudate-putamen, was evaluated. As a comparison, we tested the D2/D3 agonist pramipexole. In primed rats, rotigotine (0.035, 0.1 and 0.35mg/kg) induced dose-dependent contralateral turning. Turning induced by 0.1mg/kg of rotigotine was reduced by pretreatment with the D1 antagonist SCH39166 and the D2 antagonist eticlopride. In drug-naive rats, rotigotine was less effective in eliciting turning but SCH39166 still reduced turning induced by rotigotine (0.35mg/kg). Pramipexole induced contralateral turning only in primed rats. SCH39166 potentiated and eticlopride abolished pramipexole-induced turning. Rotigotine induced Fos expression in the caudate-putamen and SCH39166 completely blocked it. Pramipexole failed to induce Fos. These results indicate that rotigotine acts in vivo as an agonist of D1 and D2 receptors while pramipexole is devoid of D1 activity in vivo. Given their differing DA receptor profiles, rotigotine and pramipexole might differ in their spectrum of application to the therapy of Parkinson's disease.

Role of nucleus accumbens µ opioid receptors in the effects of morphine on ERK1/2 phosphorylation.

RATIONALE: Despite the critical role attributed to phosphorylated extracellular signal regulated kinase (pERK1/2) in the nucleus accumbens (Acb) in the actions of addictive drugs, the effects of morphine on ERK1/2 phosphorylation in this area are still controversial. OBJECTIVES: In order to investigate further this issue, we studied (1) the ability of morphine to affect ERK1/2 phosphorylation in the shell (AcbSh) and core (AcbC) of Sprague-Dawley and Wistar rats and of CD-1 and C57BL/6J mice and (2) the role of dopamine D1 and µ-opioid receptors in Sprague-Dawley rats and CD-1 mice. METHODS: The pERK1/2 expression was assessed by immunohistochemistry. RESULTS: In rats, morphine decreased AcbSh and AcbC pERK1/2 expression, whereas in mice, increased it preferentially in the AcbSh compared with the AcbC. Systemic SCH 39166 decreased pERK1/2 expression on its own in the AcbSh and AcbC of Sprague-Dawley rats and CD-1 mice; furthermore, in rats, SCH 39166 disclosed the ability of morphine to stimulate pERK1/2 expression. Systemic (rats and mice) and intra-Acb (rats) naltrexone prevented both decreases, in rats, and increases, in mice. CONCLUSIONS: These findings confirm the differential effects of morphine in rats and mice Acb and that D1 receptors exert a facilitatory role on ERK1/2 phosphorylation; furthermore, they indicate that, in rats, removal of the D1-dependent pERK1/2 expression discloses the stimulatory influence of morphine on ERK1/2 phosphorylation and that the morphine's ability to decrease pERK1/2 expression is mediated by Acb µ-opioid receptors. Future experiments may disentangle the psychopharmacological significance of the effects of morphine on pERK1/2 in the Acb.

Strain dependence of adolescent Cannabis influence on heroin reward and mesolimbic dopamine transmission in adult Lewis and Fischer 344 rats.

Adolescent Cannabis exposure has been hypothesized to act as a gateway to opiate abuse. In order to investigate the role of genetic background in cannabinoid-opiate interactions, we studied the effect of Δ(9) -tetrahydrocannabinol (THC) exposure of adolescent Lewis and Fischer 344 rats on the responsiveness of accumbens shell and core dopamine (DA), as monitored by microdialysis, to THC and heroin at adulthood. Heroin reward and reinstatement by heroin priming were studied by conditioned place preference (CPP) and cognitive and emotional functions by object recognition, Y maze and elevated plus maze paradigms. THC stimulated shell DA in Lewis but not in Fischer 344 rats. Adolescent THC exposure potentiated DA stimulant effects of heroin in the shell and core of Lewis and only in the core of Fischer 344 rats. Control Lewis rats developed stronger CPP to heroin and resistance to extinction compared with Fischer 344 strain. In Lewis rats, THC exposure did not affect heroin CPP but potentiated the effect of heroin priming. In Fischer 344 rats, THC exposure increased heroin CPP and made it resistant to extinction. Lewis rats showed seeking reactions during extinction and hedonic reactions in response to heroin priming. Moreover, adolescent THC exposure affected emotional function only in Lewis rats. These observations suggest that long-term effects of Cannabis exposure on heroin addictive liability and emotionality are dependent on individual genetic background.

Acquisition and expression of conditioned taste aversion differentially affects extracellular signal regulated kinase and glutamate receptor phosphorylation in rat prefrontal cortex and nucleus accumbens.

Conditioned taste aversion (CTA) can be applied to study associative learning and its relevant underpinning molecular mechanisms in discrete brain regions. The present study examined, by immunohistochemistry and immunocytochemistry, the effects of acquisition and expression of lithium-induced CTA on activated Extracellular signal Regulated Kinase (p-ERK) in the prefrontal cortex (PFCx) and nucleus accumbens (Acb) of male Sprague-Dawley rats. The study also examined, by immunoblotting, whether acquisition and expression of lithium-induced CTA resulted in modified levels of phosphorylation of glutamate receptor subunits (NR1 and GluR1) and Thr(34)- and Thr(75-Dopamine-and-cAMP-Regulated) PhosphoProtein (DARPP-32). CTA acquisition was associated with an increase of p-ERK-positive neurons and phosphorylated NR1 receptor subunit (p-NR1) in the PFCx, whereas p-GluR1, p-Thr(34)- and p-Thr(75)-DARPP-32 levels were not changed in this brain region. CTA expression increased the number of p-ERK-positive neurons in the shell (AcbSh) and core (AcbC) but left unmodified p-NR1, p-GluR1, p-Thr(34)- and p-Thr(75-DARPP-32) levels. Furthermore, post-embedding immunogold quantitative analysis in AcbSh revealed that CTA expression significantly increased nuclear p-ERK immunostaining as well as p-ERK-labeled axo-spinous contacts. Overall, these results indicate that ERK and NR1, but not GluR1 and DARPP-32, are differentially phosphorylated as a consequence of acquisition and expression of aversive associative learning. Moreover, these results confirm that CTA represents an useful approach to study the molecular basis of associative learning in rats and suggest the involvement of ERK cascade in learning-associated synaptic plasticity.

Pharmacological characterization of 50-kHz ultrasonic vocalizations in rats: comparison of the effects of different psychoactive drugs and relevance in drug-induced reward.

Significant evidence suggests that ultrasonic vocalizations (USVs) may index the emotional state in rats, and 50-kHz USVs have been proposed as a tool to investigate the rewarding properties of drugs. Apart from the evidence on some psychostimulants, little is known about the effects of other drugs with rewarding properties on emission of 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs and their relevance in drug-induced reward, this study characterized the effects of different drugs possessing rewarding properties on 50-kHz USVs in adult male rats. Rats received the acute administration of 3,4-methylenedioxymethamphetamine (MDMA, 5-15 mg/kg, i.p.), methylphenidate (2.5-10 mg/kg, i.p.), morphine (1-5 mg/kg, s.c.), or nicotine (0.1-0.4 mg/kg, s.c.). The number and acoustic features of 50-kHz USVs and their subtypes were then measured. As a comparison, additional rats received the acute administration of amphetamine (2 mg/kg, i.p.), which strongly stimulates the emission of 50-kHz USVs. Methylphenidate, similar to amphetamine, increased the total number of 50-kHz USVs emitted by rats, and also modified their acoustic features. Conversely, MDMA, morphine, and nicotine did not elevate the total number of 50-kHz USVs. However, these drugs modified the acoustic features of 50-kHz USVs, as well as the number and acoustic features of specific subtypes of vocalizations. This study demonstrates that major differences exist in the effects of psychoactive drugs on 50-kHz USVs in rats. These findings provide a better understanding of psychoactive properties of drugs with rewarding properties and usefulness of 50-kHz USVs in assessment of these properties.

Pharmacological therapy of Parkinson's disease: current options and new avenues.

Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed.

Conditioned saccharin avoidance and sensitization to drugs of abuse.

Saccharin avoidance conditioned by drugs of abuse (CSA) has been interpreted as an expression of the appetitive, dopamine-dependent, properties of the drug. Repeated exposure to these drugs induces an increase (sensitization) of their motor stimulant properties associated with differential changes in DA transmission in the NAc shell and core. The present study investigated the changes in drug CSA induced by schedules of repeated drug exposure that induce behavioral sensitization. CSA was performed in a two-bottle choice paradigm with two saccharin-drug associations in rats previously sensitized to morphine, cocaine, amphetamine and nicotine. In control rats morphine (1 and 5mg/kg s.c.), cocaine (5 and 10mg/kg i.p.), amphetamine (0.25 and 0.5mg/kg s.c.) and nicotine (0.4 mg/kg s.c.) induced dose-dependent CSA. Sensitization to morphine, cocaine and nicotine, which is known to reduce the responsiveness of NAc shell DA to the same drugs, also reduced CSA. In contrast, sensitization to amphetamine, that does not affect the responsiveness of NAc shell DA to the drug, failed to affect CSA. The results are consistent with the hypothesis that NAc shell DA is a substrate of the appetitive properties of drugs of abuse.

Impulse control disorders and dopamine dysregulation syndrome associated with dopamine agonist therapy in Parkinson's disease.

Over the last decade, evidence has emerged linking disorders in the impulsive-compulsive spectrum in Parkinson's disease to dopamine receptor agonist treatment. These disorders include hypersexuality, gambling and, to a minor extent, compulsive shopping and eating, as well as dopamine dysregulation syndrome, characterized by an addictive pattern toward dopamine replacement therapy and stereotyped behaviors, such as punding. These syndromes, which have only recently been recognized and are still underdiagnosed, have deleterious social consequences that warrant interventions at the clinical level and promotion of research at the preclinical level. In this review, we first provide a summary of features of Parkinson's disease and current pharmacological therapies associated with the development of dopamine dysregulation syndrome and impulsive-compulsive disorders. We also examine the dopamine receptors and brain areas important in reward and compulsive behaviors. We then critically examine the neuroadaptations in dopaminergic circuitries and the literature concerning gambling, hypersexuality, and other addictive behaviors in parkinsonian patients. Finally, we focus on suggestions pointing to a role for dopamine D(3) receptors and sensitization phenomena as the main factors which may be the origin of these disorders.

Differential involvement of dopamine D1 receptors in morphine- and lithium-conditioned saccharin avoidance.

Conditioned saccharin avoidance (CSA) can be produced when either lithium chloride (LiCl) or a reinforcing drug, such as morphine, is administered following exposure to the taste of saccharin. In this study we investigated the involvement of dopamine (DA) transmission in the acquisition of morphine and LiCl-CSA. CSA was evaluated in a two-bottle choice paradigm with two conditioning pairings between saccharin and morphine or LiCl as unconditioned stimulus (US). Morphine hydrochloride (7.5 mg/kg s.c.) or LiCl (40 mg/kg i.p.), administered 45 and 120' respectively after saccharin-drinking session, induced strong CSA. The DA D(1) receptor antagonist, SCH 39166 (0.1 mg/kg s.c.), impaired morphine-CSA if administered 15' and, to a lesser extent, 30' but not 45' before the drug (i.e immediately after saccharin drinking). In contrast SCH 39166 reduced LiCl-CSA when administered 45' before the drug and even more so when administered 105' before LiCl i.e. immediately after saccharin drinking. Therefore SCH 39166 impaired morphine-CSA when given shortly before the drug, while it impaired LiCl-CSA when given shortly after saccharin. Raclopride, a specific antagonist of D(2) receptors, failed to affect LiCl- and morphine-CSA. These results are consistent with the idea that DA, acting on D(1) receptors, plays a differential role in morphine- and LiCl-CSA. In LiCl-CSA DA is necessary for the processing (consolidation) of the short-term memory trace of the saccharin taste to be associated with the lithium-induced aversive state, while in morphine CSA contributes to mediate the appetitive properties of the drug.

Blockade of globus pallidus adenosine A(2A) receptors displays antiparkinsonian activity in 6-hydroxydopamine-lesioned rats treated with D(1) or D(2) dopamine receptor agonists.

We have recently demonstrated how antagonism of adenosine A(2A) receptors within the globus pallidus (GP) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor L-DOPA in 6-hydroxydopamine-lesioned hemiparkinsonian rats. To further characterize the influence of pallidal A(2A) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation, hemiparkinsonian rats were infused with the water-soluble A(2A) antagonist SCH BT2 in the GP, alone or in combination with systemic administration of either SKF 38393 or quinpirole, to stimulate dopamine D(1) or D(2) receptors, respectively. SCH BT2 alone (5 mug/1 mul) neither altered motor behavior nor produced postural asymmetry. In contrast, the contralateral rotations elicited by SKF 38393 (1.5 mg/kg) as well as quinpirole (0.05 mg/kg) were potentiated by the concomitant intrapallidal infusion of SCH BT2. The results of this study demonstrate that blockade of pallidal A(2A) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D(1) or D(2) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A(2A) receptor antagonists.

Involvement of globus pallidus in the antiparkinsonian effects of adenosine A(2A) receptor antagonists.

An involvement of globus pallidus (GP) in the antiparkinsonian effects of A(2A) receptor antagonists has been proposed on the basis of the selective localization of A(2A) receptors on the striatopallidal pathway. In order to investigate this possibility, the present study evaluated rotational behavior in unilaterally 6-hydroxydopamine-lesioned rats following infusion of the water-soluble A(2A) receptor antagonist SCH BT2 into GP. SCH BT2 (5 microg/1 microl) altered neither motor behavior nor produced postural asymmetry by itself. However, when infused concomitantly with a parenteral subthreshold dose of l-DOPA (3 mg/kg i.p.) capable of inducing modest contralateral rotational behavior (34.7 +/- 20.7/1 h), SCH BT2 significantly potentiated the number of contraversive rotations (167.4 +/- 16.3/1 h). These results suggest that A(2A) receptors located in the globus pallidus may be involved in the antiparkinsonian effects of A(2A) antagonists.

Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease.

Preclinical evidence strongly indicate that adenosine A(2A) receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A(2A) receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A(2A) antagonist SCH 58261 dose-dependently reduced the magnitude of perioral tremor induced by the acetylcholinesterase inhibitor tacrine (2.5 mg/kg). Furthermore, intrastriatal infusion of SCH BT2 (5 microg/microl), a water-soluble analogue of SCH 58261, antagonized tacrine-induced jaw movements with a maximal effect in the ventrolateral striatum. On the other hand, SCH 58261 (5 mg/kg) was ineffective in blocking tremulous jaw movements stimulated by the direct muscarinic agonist pilocarpine (1 mg/kg). Taken together, these results indicate that A(2A) antagonists reduce parkinsonian tremor stimulated in rats by tacrine and that the striatum is deeply involved in the observed effect. Moreover, the ineffectiveness of SCH 58261 in blocking pilocarpine-stimulated perioral tremor suggests that the antitremorigenic effects of A(2A) antagonists described here are not related to a direct action on muscarinic receptor. The prospective of providing additional antitremor benefits considerably enhances the therapeutic potential of A(2A) antagonists.

Morphine-conditioned single-trial place preference: role of nucleus accumbens shell dopamine receptors in acquisition, but not expression.

RATIONALE: A large body of evidence indicates an involvement of the mesolimbic dopamine (DA) pathway innervating the ventral striatum in the motivational effects of drug abuse. OBJECTIVE: The goal of the study is to clarify the role of DA D1 and D2 receptors of the rat nucleus accumbens (NAc) shell and core in the motivational effects of morphine as studied by conditioned place preference (CPP). METHODS: The effect of the intracerebral infusion of DA antagonists specific for DA D1 (SCH 39166) and D2 receptors (L-sulpiride) was studied in a single-trial place conditioning paradigm with fixed assignment of the drug to the unpreferred compartment. RESULTS: Morphine induced significant CPP at all the doses tested (0.5, 1.0, and 2.0 mg/kg, subcutaneously). A dose of 1.0 mg/kg was selected for further studies. Intra-NAc shell infusion of SCH 39166 and L-sulpiride at doses of 25 and 50 ng/1 microl per side impaired the acquisition of CPP by morphine. No effect was observed at 12.5 ng/1 microl per side. Intra-NAc core infusion of SCH 39166 (12.5, 25, and 50 ng/1 microl per side) did not affect the acquisition of morphine-induced CPP, while L-sulpiride (12.5, 25, and 50 ng/1 microl per side) impaired CPP acquisition only at the dose of 50 ng/1 microl per side. No effect on morphine-induced CPP was observed when the DA antagonists were infused into the NAc shell or core 10 min before the test session. CONCLUSION: These results indicate that DA D1 and D2 receptors in the NAc shell are involved in the acquisition of morphine-induced CPP.

Nicotine-conditioned single-trial place preference: selective role of nucleus accumbens shell dopamine D1 receptors in acquisition.

RATIONALE: Experimental evidence indicates that the mesolimbic dopamine (DA) pathway innervating the ventral striatum is critically involved in the motivational effects of drug abuse. However, the role of DA transmission of the two main subdivisions of the nucleus accumbens (NAc), the shell and the core, in the motivational properties of nicotine is unknown. OBJECTIVES: The aim of this study was to investigate the role of DA D1 and D2 receptors of the rat NAc shell and core in the motivational effects of nicotine using a conditioned place preference (CPP) paradigm. METHODS: The effect of the intracerebral infusion of DA antagonists specific for DA D1 (SCH 39166) and D2 receptors (L-sulpiride) was studied in a single-trial place-conditioning paradigm with fixed assignment of the drug to the unpreferred compartment. RESULTS: Nicotine induced significant CPP at the dose of 0.4 and 0.6 mg/kg subcutaneously (s.c.). Intra-NAc shell infusion of SCH 39166 (6.25, 12.5, 25 and 50 ng bilaterally, 10 min before nicotine administration), impaired in a dose-dependent manner the acquisition of CPP by nicotine (0.4 mg/kg s.c.). SCH 39166 failed to affect nicotine CPP when infused into the NAc core. L-sulpiride (25 and 50 ng bilaterally) had no effect on acquisition after intra-Nac shell infusion. SCH 39166 and L-sulpiride were ineffective after infusion in the NAc shell and core 10 min before the test session. CONCLUSIONS: The results indicate that dopamine D1 but not D2 receptors of the NAc shell are specifically involved in the acquisition of nicotine-induced CPP.