Sandro Fenu

Drug Addiction as a Disorder of Associative Learning: Role of Nucleus Accumbens Shell/Extended Amygdala Dopamine

ABSTRACT: Conventional reinforcers phasically stimulate dopamine transmission in the nucleus accumbens shell. This property undergoes one‐trial habituation consistent with a role of nucleus accumbens shell dopamine in associative learning. Experimental studies with place‐ and taste‐conditioning paradigms confirm this role. Addictive drugs share with conventional reinforcers the property of stimulating dopamine transmission in the nucleus accumbens shell. This response, however, undergoes one‐trial habituation in the case of conventional reinforcers but not of drugs. Resistance to habituation allows drugs to repetitively activate dopamine transmission in the shell upon repeated self‐administration. This process abnormally facilitates associative learning, leading to the attribution of excessive motivational value to discrete stimuli or contexts predictive of drug availability. Addiction is therefore the expression of the excessive control over behavior acquired by drug‐related stimuli as a result of abnormal strenghtening of stimulus‐drug contingencies by nondecremental drug‐induced stimulation of dopamine transmission in the nucleus accumbens shell.

Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats

In order to investigate the role of adenosine A2A receptor blockade on dopamine-mediated motor responses, contralateral turning behaviour and expression of the early-gene c-fos was evaluated in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. SCH 58261, (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1 , 5-c]pyrimidine) a potent and selective antagonist of adenosine A2A receptors (5 mg/kg i.p.), induced a 70-fold increase in the contralateral turning behaviour induced by a low dose (2 mg/kg i.p.) of the dopamine precursor L-DOPA (L-3, 4-dihydroxyphenylalanine). Expression of c-fos as measured by Fos-like immunoreactivity after SCH 58261 plus L-DOPA was also potentiated as compared with L-DOPA alone, both in striatum and globus pallidus of the 6-hydroxydopamine-lesioned side of the brain. SCH 58261 induced a less marked potentiation (7-fold) of turning behaviour induced by dopamine D2 receptor stimulation with quinpirole, while Fos-like immunoreactivity in the striatum and globus pallidus was not affected. Previous studies have shown that SCH 58261 strongly potentiated dopamine D1 receptor-mediated responses. The results of the present study therefore indicate that the positive interaction between SCH 58261 and L-DOPA, in 6-hydroxydopamine-lesioned rats, is mainly due to an interaction with dopamine D1 receptors. The data also suggest that adenosine A2A receptor antagonists might be useful for potentiating the effects of L-DOPA in Parkinsons disease.

Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats.

Several evidences indicate that the selective blockade of adenosine A2A receptors counteracts the motor activity impairment in experimental models of Parkinsons disease. In the present study, the effects of the adenosine A2A receptor antagonist, SCH 58261 (5‐amino‐7‐(β‐phenylethyl)‐2‐(8‐furyl)pyrazolo(4,3‐e)‐1,2,4‐triazolo(1,5‐c)pyrimidine, were assessed following a repeated treatment schedule in the contralateral turning behavior rat model of Parkinsons disease. Unilateral lesions of the nigrostriatal pathway were induced by injecting 6‐hydroxydopamine (6‐OHDA) in medial forebrain bundle. Repeated administration of SCH 58261 was performed either alone (7 and 14 days repeated SCH 58261) or together with L‐dopa (19 days repeated SCH 58261 plus L‐dopa or L‐dopa alone). After a 7‐ and 14‐day repeated administration schedule, SCH 58261 (5 mg/kg) maintained its ability to potentiate the contralateral turning behavior induced by a subthreshold dose of L‐dopa (2 mg/kg i.p.), showing no tolerance to its stimulant effects. SCH 58261 (5 mg/kg) plus L‐dopa (3 mg/kg) or L‐dopa (6 mg/kg) alone induced, at these dosages, the same number of contralateral turnings after the first administration. While chronic intermittent SCH 58261 plus L‐dopa did not lead to a modified turning behavior during treatment, L‐dopa alone produced a progressive increase in turning behavior intensity and duration. These results provide evidence that SCH 58261 retains its ability to potentiate L‐dopa effects in a validated rat model of Parkinsons disease even after repeated treatments. Moreover, these results suggest that adenosine A2A blockade prevents the appearance of motor response alterations in L‐dopa‐treated rats, supporting the concept that A2A receptor antagonists have a therapeutic potential for the treatment of Parkinsons disease. Synapse 39:233–238, 2001.

Adenosine A2 receptors interact negatively with dopamine D1 and D2 receptors in unilaterally 6-hydroxydopamine-lesioned rats

In rats bearing a unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal pathway, stimulation of adenosine A2 receptors by CGS 21680 reduced the contralateral turning behavior induced by L-3,4-dihydroxyphenylalanine (L-DOPA). Administration of CGS 21680 completely blocked the contralateral turning induced by the dopamine D1 receptor agonist, SKF 38393, and reduced the turning induced by the dopamine D2 receptor agonist, LY 171555. Quinolinic acid lesion of the striatum or 6-hydroxydopamine lesion of the dopaminergic nigro-striatal neurons demonstrated that [3H]CGS 21680 binding sites are associated to striatal intrinsic neurons. This study provides evidence for a negative postsynaptic interaction of both dopamine D1 and D2 receptors with adenosine A2 receptors.

Blockade of adenosine A2A receptors antagonizes parkinsonian tremor in the rat tacrine model by an action on specific striatal regions

Acute administration of the acetylcholinesterase inhibitor tacrine to rats induces tremulous jaw movements which can be used as a valuable model of parkinsonian tremor. In the present study, the number of tremor episodes and jaw movements were evaluated to assess the effects of the selective A2A antagonists SCH 58261 and SCH BT2 on tremorgenesis. SCH 58261 dose-dependently, and maximally at 5 mg/kg, reduced the number of both tremor episodes (-35%) and jaw movements (-50%), induced in rats by tacrine (2.5 mg/kg ip). Since adenosine A2A receptors are largely expressed throughout the striatum, chronic cannulae were implanted in the rat dorsomedial (DMS) and ventrolateral striatum (VLS) to investigate whether A2A antagonists could act at this level. Infusion of SCH BT2 (5 microg/microl), a water-soluble analogue of SCH 58261, in VLS antagonized both tremor episodes (-68%) and jaw movements (-76%) elicited by tacrine (2.5 mg/kg ip), whereas SCH BT2 infusion in DMS was less effective in blocking jaw movements (-50%) and did not significantly affect the number of tremor episodes. Taken together, the results of this study indicate that A2A antagonists effectively reduce the magnitude of tremulous jaw movements induced in rats by acute tacrine, mainly by an action in VLS and suggest that A2A antagonists might be used as specific agents against parkinsonian tremor.

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.

Blockade of muscarinic receptors potentiates D1 dependent turning behavior and c-fos expression in 6-hydroxydopamine-lesioned rats but does not influence D2 mediated responses

In rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway, blockade of muscarinic receptors by scopolamine potentiates the contralateral turning induced by selective dopaminergic D1 agonists (SKF 38393, A 68930), but does not influence the contralateral turning induced by the D2 agonist LY 171555. Studies on the expression of the early gene c-fos as reflected by the immunohistochemical demonstration of the Fos protein, show that administration of scopolamine (5 mg/kg, i.p.) potentiates c-fos expression elicited by SKF 38393 (1.5 mg/kg, s.c.) in the caudate-putamen of the lesioned side. The results indicate that cholinergic transmission is differentially involved in the behavioral expression of D1 versus D2 receptor stimulation in a denervated condition and suggest that blockade of central cholinergic transmission might be useful in improving the antiparkinsonian efficacy of D1 receptor agonists.

l-Dopa stimulates c-fos expression in dopamine denervated striatum by combined activation of D-1 and D-2 receptors

Administration of L-dopa to unilaterally 6-hydroxydopamine-lesioned rats, activates the early gene c-fos in the lesioned caudate-putamen. D-1 receptor blockade by SCH 23390, prevented L-dopa-induced Fos-like immunoreactivity in the whole caudate-putamen, while D-2 receptor blockade by raclopride reduced Fos-like immunoreactivity only in the dorso-lateral portion. The results suggest that L-dopa induces c-fos primarily through an activation of D-1 receptors, while D-2 receptor stimulation plays a facilitatory influence on D-1-mediated c-fos expression.

Substantia nigra as a site of origin of dopamine-dependent motor syndromes induced by stimulation of μ and δ opioid receptors

Abstract Opioid agonists having different affinity for δ and μ receptors were injected bilaterally in the substantia nigra (SN) of rats. The selective agonist of μ receptors N -MePhe 3 ,- d -Pro 4 morphiceptin (PLO 17) produced a stereotyped behavior characterized by stereotyped sniffing and gnawing antagonized by the irreversible antagonist of μ receptors β-funaltrexamine. In contrast, bilateral intranigral injection of the selective δ agonist d -Pen 2 , d -Pen 5 enkephalin (DPDPE) elicited dose-dependent exploratory behavior and rearing but failed to produce gnawing. The behavioral syndrome induced by DPDPE was significantly reduced by the selective δ antagonist ICI 174,864. Naloxone, a non-selective opioid antagonist, antagonized the effects of both compounds. SCH 23390 and haloperidol, two antagonists of dopaminergic D 1 and D 2 receptors, respectively, blocked the effects of PLO 17 and DPDPE. The results indicate that stimulation of specific opioid receptor types in the SN elicits specific behavioral syndromes and suggest that the SN might be the site of origin of certain items of the behavioral syndrome evoked by systemic opiates. These items might be mediated by activation of dopaminergic neurons of the ventral mesencephalon.

Behavioural expression of D-1 receptor supersensitivity depends on previous stimulation of D-2 receptors

SKF 38393 (2 mg/kg s.c.), a reportedly selective D-1 agonist, failed to induce contralateral turning behaviour in naive rats bearing 12 days old unilateral 6-hydroxydopamine lesions. On the other hand strong contraversive turning in response to SKF 38393 was obtained if rats had been tested 2 or 7 days before with apomorphine (0.1 mg/kg s.c.) or with LY 171555 (0.2 mg/kg s.c.), a selective D-2 receptor agonist. Contraversive turning in response to SKF 38393 was blocked by a low dose (0.05 mg/kg s.c.) of the specific D-1 antagonist SCH 23390. The results indicate that the behavioural expression of D-1 receptor supersensitivity following lesion of dopaminergic neurons depends on previous exposure to a stimulation of D-2 receptors.