Dopamine D2-like receptor agonists induce penile erection in male rats: differential role of D2, D3 and D4 receptors in the paraventricular nucleus of the hypothalamus

Pramipexole, a dopamine D3/D2 receptor agonist, induces penile erection when administered subcutaneously (s.c.) or into the paraventricular nucleus of the hypothalamus of male rats, like apomorphine, a mixed D1/D2 receptor agonist, and PD 168,077, a D4 receptor agonist. A U-inverted dose-response curve was found with pramipexole and apomorphine, but not with PD 168,077 (0.025-0.5 mg/kg s.c.). Pramipexole effect was abolished by L-741,626, a D2 receptor antagonist (2.5 and 5 mg/kg s.c.) and raclopride, a D2/D3 receptor antagonist (0.025 and 0.1 mg/kg s.c.), but not by SB277011A (2.5 and 10 mg/kg s.c.) or FAUC 365 (1 and 2 mg/kg s.c.), two D3 receptor antagonists, or L-745,870 (1 and 5 mg/kg i.p.), a D4 receptor antagonist. Similar results were found with apomorphine (0.08 mg/kg s.c.), although its effect was also partially reduced by L-745,870. In contrast, PD 168,077 effect was abolished by L-745,870, but not L-741,626, SB277011A, FAUC 365 or raclopride. Similar results were found when dopamine agonists (5-200 ng/rat) and antagonists (1-5 μg/rat) were injected into the paraventricular nucleus. However, no U-inverted dose-response curve was found with any of the three dopamine agonists injected into this nucleus. As pramipexole- and apomorphine-induced penile erection was reduced mainly by D2, but not D3 or D4 antagonists, D2 receptors are those that mediate the pro-erectile effect of these dopamine agonists. Although the selective stimulation of paraventricular D4 receptors induces penile erection, D4 receptors seem to play only a modest role in the pro-erectile effect of the above dopamine agonists.     

Dopamine agonist-induced penile erection and yawning: differential role of D₂-like receptor subtypes and correlation with nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats

The dopamine D? preferring agonist pramipexole (50 ng) induced penile erection and yawning when injected into the paraventricular nucleus of the hypothalamus of male rats, like the mixed D?/D?-like agonist apomorphine (50 ng), while the D? agonist PD 168,077 (100 ng), induced penile erection only. These responses lasted for 45-60 min and occurred with an increase of NO?- and NO?- concentrations in the dialysate obtained from the paraventricular nucleus by intracerebral microdialysis. Pramipexole and apomorphine responses were reduced by the D? preferring antagonist L-741,626 (5 μg), but not by the D? preferring antagonist SB-277011A (10 μg), or the D? preferring antagonist L-745,870 (5 μg), injected into the PVN before the dopamine agonist. In contrast, PD 168,077 responses were reduced by L-745,870, but not by L-741,626 or SB-277011A. Pramipexole, apomorphine and PD 168,077 effects were also reduced by the nitric oxide synthase inhibitor S-methyl-L-thiocitrulline (20 μg) and the N-type voltage-dependent Ca2? channels blocker ω-conotoxin (5 ng), given into the paraventricular nucleus, and by the oxytocin antagonist d(CH?)?Tyr(Me)2-Orn?-vasotocin (2 μg), given intracerebroventricularly but not into the paraventricular nucleus before dopamine agonists. These results suggest that stimulation of D?, but not D? or D? receptors, by pramipexole or apomorphine increases Ca2? influx in cell bodies of oxytocinergic neurons. This increases the production of nitric oxide, which activates oxytocinergic neurotransmission in extra-hypothalamic brain areas and spinal cord, leading to penile erection and yawning. However, the stimulation of D? receptors by PD 168,077 also increases Ca2? influx/nitric oxide production leading to penile erection, but not yawning.     

Dopamine D(4) receptor activation decreases the expression of mu-opioid receptors in the rat striatum

The dopaminergic and opioid peptide systems interact in many nuclei of the brain. In the striatum, dopamine/opioid peptide interactions modulate locomotor and motivated behaviors as well as reward, motivational, and tolerance processes in opiate dependence. Dopamine D(4) receptors (D(4) R) and mu-opioid receptors (MOR) are highly concentrated in the striosomes (islands) of the striatum, suggesting the existence of receptor-receptor interactions between them. In the present work we studied the role of D(4) R in modulating MOR expression in the islands by using immunohistochemistry and image analysis. The activation of D(4) R by the agonist PD168,077 (1 mg/kg) decreased MOR immunoreactivity (IR) in the striosomes 6 hours after drug treatment. MOR IR levels had recovered 12 hours later. Treatment with a D(4) R antagonist (L745,870, 1mg/kg) blocked downregulation of MOR IR, showing that the D(4) R agonist effects observed were specific. Furthermore, treatment with the D(2)/D(3) receptor agonist quinpirol (1 mg/kg) and D(2)/D(3) receptor antagonist raclopride (1 mg/kg) had no effect in MOR IR, suggesting that D(4) R is the only D2-like receptor producing an MOR downregulation in the islands. The decreases of MOR IR in the striosomes suggest that D(4) R activation may reduce MOR signaling. Increasing evidence has demonstrated that the islands in the striatum play a critical role in habit acquisition during drug addiction. D(4) R/MOR interactions could be crucial in such processes.     

Blockade of dopamine d4 receptors attenuates reinstatement of extinguished nicotine-seeking behavior in rats

Since cloning of the dopamine receptor D4 (DRD4), its role in the brain has remained unclear. It has been reported that polymorphism of the DRD4 gene in humans is associated with reactivity to cues related to tobacco smoking. However, the role of DRD4 in animal models of nicotine addiction has seldom been explored. In our study, male Long-Evans rats learned to intravenously self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Effects of the selective DRD4 antagonist L-745,870 were evaluated on nicotine self-administration behavior and on reinstatement of extinguished nicotine-seeking behavior induced by nicotine-associated cues or by priming injections of nicotine. L-745,870 was also tested on reinstatement of extinguished food-seeking behavior as a control. In addition, the selective DRD4 agonist PD 168,077 was tested for its ability to reinstate extinguished nicotine-seeking behavior. Finally, L-745,870 was tested in Sprague Dawley rats trained to discriminate administration of 0.4?mg/kg nicotine from vehicle under an FR schedule of food delivery. L-745,870 significantly attenuated reinstatement of nicotine-seeking induced by both nicotine-associated cues and nicotine priming. In contrast, L-745,870 did not affect established nicotine self-administration behavior or reinstatement of food-seeking behavior induced by food cues or food priming. L-745,870 did not produce nicotine-like discriminative-stimulus effects and did not alter discriminative-stimulus effects of nicotine. PD 168,077 did not reinstate extinguished nicotine-seeking behavior. As DRD4 blockade by L-745,870 selectively attenuated both cue- and nicotine-induced reinstatement of nicotine-seeking behavior, without affecting cue- or food-induced reinstatement of food-seeking behavior, DRD4 antagonists are potential therapeutic agents against tobacco smoking relapse.     

Targeting the dopamine D3 receptor cannot influence continuous reinforcement cocaine self-administration in rats

Recent studies point out the important role of dopamine D3 receptors in drug addiction. Therefore, D3 receptor ligands have been proposed as candidate medications for the treatment of cocaine dependence. The present study was designed to compare several dopamine D3 ligands of various selectivity in an animal model of drug-dependence, the cocaine self-administration paradigm. None of the doses of SB-277011 (5, 20 mg/kg), the most selective dopamine D3 antagonist to date, and the lower dose (12 mg/kg) of the moderately D3 selective antagonist U-99194A could influence the rate of self-administration. At the higher dose (24 mg/kg), U-99194A decreased the lever-pressing for cocaine. Both the dopamine D1 selective SCH-23390 (0.2, 0.1 mg/kg) and the dopamine D2 receptor preferring haloperidol (0.5, 0.2 mg/kg) increased the lever-pressing. Both the most dopamine D3 selective agonist PD-128907 (1.0 mg/kg) and the less selective 7-OH-DPAT (0.1, 0.5 mg/kg, s.c.) caused significant decrease in lever-pressing. At lower dose (0.2 mg/kg) PD-128907 was ineffective. The partial agonist BP-897 (1 mg/kg) evoked slight but significant increase in self-administration, while the lower dose (0.5 mg/kg) was ineffective. In all, in contrast to the dopamine D1 and D2 receptors acute inhibition or stimulation of the D3 receptor do not appear to exert considerable influence on the acute reinforcing effect of cocaine.     

The role of D2 and D3 dopamine receptors in the mediation of emesis in Cryptotis parva (the least shrew)

This study introduces Cryptotis parva (the least shrew) as a new dopaminergic animal model of emesis. The potential emetogenic effects of a nonselective dopamine agonist [apomorphine], two D1 agonists [SKF-38393 and SKF-82958], a D2 preferring agonist [quinpirole], and two D3-preferring agonists [7-(OH) DPAT and PD 128, 907] were investigated. Intraperitoneal administration of D1 agonists failed to induce emesis. However, other agonists caused a dose-dependent increase in the percentage of animals vomiting as well as potentiating the mean frequency of emesis with the following ED50, potency order: 7-(OH) DPAT < apomorphine < quinpirole < PD 128, 907. For antagonist studies a 2 mg/kg dose of these agonists were used to induce emesis. Thus, the inhibitory dose-response effects of a D2-preferring [sulpride], a D3-preferring [U 99194A] and combination of varying doses of these antagonists [sulpride + U 99194A] were evaluated on the ability of the cited agonists to produce vomiting. Sulpride decreased the number of shrews vomiting and the mean vomiting frequency produced by the cited agonists in a dose-dependent fashion with the following ID50 order [apomorphine < PD 128, 907 < 7-(OH) DPAT < quinpirole]. By itself, U 99194A failed to significantly alter the emesis produced by any of the cited agonists, however, it potentiated (3-8 times) the antiemetic effects of sulpride both in reducing the number of shrews vomiting as well as decreasing the mean vomiting frequency with the following ID50 order: PD 128, 907 < 7-(OH) DPAT < quinpirole. However, U 99194A attenuated the potent antiemetic effect of sulpride on the apomorphine-induced emesis. The results suggest that the tested agonists primarily activate dopamine D2 receptors to induce emesis in the least shrew whereas activation of D3 sites potentiate the vomiting action of D2 dopamine receptors.     

Strain-dependent involvement of D1 and D2 dopamine receptors in muscarinic cholinergic influences on memory storage

These experiments examined the interaction of muscarinic and dopaminergic systems in influencing memory for one-trial inhibitory avoidance training in mice of the C57BL/6 and DBA/2 strains. In both strains, immediate post-training systemic administration of the muscarinic cholinergic agonist oxotremorine enhanced retention and the cholinergic antagonist atropine impaired retention. No effects were seen with injections 2 h post-training. Furthermore, the drugs did not affect retention performance of animals that received no footshock on the training trial. These results confirm previous findings indicating that muscarinic cholinergic drugs affect memory by influencing memory consolidation. In C57 mice, pretreatment with selective D1 or D2 dopamine (DA) receptor agonists (SKF 38393 or LY 171555, respectively) in otherwise non-effective doses (5 and 0.25 mg/kg, respectively) potentiated the effects of oxotremorine (0.04 mg/kg). Furthermore, in C57 mice pretreatment with selective D1 or D2 receptor antagonists (SCH 23390 or (-)-sulpiride) in otherwise non-effective doses (0.025 and 6 mg/kg, respectively) blocked the memory enhancing effects of oxotremorine. The memory impairing effects of atropine (3 mg/kg) were blocked by the D1 and D2 selective agonists and potentiated by the selective D1 or D2 antagonists. In contrast, in DBA mice, the D1 and D2 selective agonists antagonised the memory enhancing effects of oxotremorine (0.02 mg/kg) and potentiated the effects of atropine (2 mg/kg). Furthermore, the D1 and D2 antagonists potentiated the effects of oxotremorine and antagonised those of atropine. These findings indicate that although muscarinic cholinergic influences on memory storage are comparable in mice of these two strains, the cholinergic-dopaminergic interactions are opposite in the two strains. These results have implications for hypotheses of cholinergic and dopaminergic regulation of memory storage.     

The novel dopamine D4 receptor agonist (PD 168,077 maleate): doses with different effects on locomotor activity are without effect in classical conditioning

Conditioning is normally selective to the most likely predictors of motivationally significant events and some dopamine (DA) agonists produce dysfunction in this process. Moreover, the DA D(4) receptor is implicated in normal and abnormal functions that have some dopaminergic basis (e.g., in attention deficit hyperactivity disorder and schizophrenia). We therefore used locomotor activity to identify doses of a novel D(4) receptor agonist (PD 168,077) with contrasting behavioral effects (over the range 0.064-1 mg/kg). Doses that either did (0.064 mg/kg) or did not (0.5 mg/kg) significantly increase activity were then tested using aversive and appetitive procedures, in which conditioning was reflected in decreased and increased response rates, respectively. Associating a signal with food or foot shock is normally reduced in trace conditioning, when stimulus events are separated in time. Similarly, animals normally learn relatively little about background stimuli that do not well predict food delivery or the onset of shock. Both doses of PD 168,077 were without effect on conditioning, whether appetitive or aversive, and irrespective of how informative the predictive stimulus was. Thus, we find no evidence that the D(4) receptor has any likely effect on associative learning or its disorder. Furthermore, D(4)-mediated hyperactivity was dissociable from cognitive effects.     

D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine

D(3) dopamine receptor agonists inhibit locomotor activity in rodents and modulate the reinforcing effect of psychostimulants; however, their functional role during behavioral sensitization remains unclear. In the present study, we intend to investigate if D(3) dopamine receptors alter during the amphetamine sensitization and test if manipulation of D(3) receptors would affect the development of locomotor sensitization to amphetamine. We have found that D(3) dopamine receptors are down-regulated in the limbic forebrain in chronic amphetamine-treated (5 mg/kg x 7 days) animals. The levels of both D(3) receptor protein (B(max) value) and mRNA decreased significantly in the behaviorally sensitized rats compared to the saline-treated controls. When animals were co-administered a putative D(3) receptor antagonist (U99194A or GR103691; 20 microg x 7 days; intracerebroventricle) and amphetamine (5 mg/kg x 7 days, i.p.), the locomotor sensitization to amphetamine was significantly inhibited. However, when the putative D(3) receptor antagonist U99194A was administered during the amphetamine withdrawal period at day 10, it did not affect the development of locomotor sensitization. Furthermore, pretreatment with the preferential D(3) agonist 7-hydroxydipropylaminotetralin partially blocked the inhibitory effect of U99194A on locomotor sensitization. These data prove the participation of D(3) dopamine receptors in the development of amphetamine sensitization and, in addition, suggest a potential application for D(3) antagonists in the prevention of amphetamine addiction.     

An endogenous dopaminergic tone acting on dopamine D3 receptors may be involved in diurnal changes of tuberoinfundibular dopaminergic neuron activity and prolactin secretion in estrogen-primed ovariectomized rats

The diurnal rhythm of tuberoinfundibular dopaminergic (TIDA) neuron activity, i.e., high in the morning and low in the afternoon, is prerequisite for the afternoon prolactin (PRL) surge in proestrous and estrogen-primed ovariectomized (OVX) female rats. Whether dopamine acts via D(3) receptors in regulating the rhythmic TIDA neuron activity and PRL secretion in estrogen-primed OVX (OVX+E(2)) rats is the focus of this study. Intracerebroventricular (icv) injection of a D(3) receptor agonist, PD128907 (0.1-10 μg/3 μl), in the morning significantly reduced the basal activity of TIDA neurons and increased plasma PRL level. The effects of PD128907 were reversed by co-administration of U99194A, a D(3) receptor antagonist, but not by raclopride, a D(2) receptor antagonist. To determine whether endogenous dopamine acts on D(3) receptors involved in the diurnal changes of the activities, we used both U99194A, a D(3) receptor antagonist, and an antisense oligodeoxynucleotide (ODN) against D(3) receptor mRNA in the study. U99194A (0.1 μg/3 μl, icv) given at 1200 h significantly reversed the lowered TIDA neuron activity and the afternoon PRL surge at 1500 h. Moreover, OVX+E(2) rats pretreated with the antisense ODN (10 μg/3 μl, icv) for 2 days had the same effects as the D(3) receptor antagonist on TIDA neuron activity and the PRL surge. The same treatment with sense ODN had no effect. In conclusion, an endogenous DA tone may act on D(3) receptors to inhibit TIDA neuron activity and in turn stimulate the PRL surge in the afternoon of OVX+E(2) rats.     

L-745,870 suppresses the nighttime serotonin N-acetyltransferase activity in chick retina: in vivo evidence for agonist activity at D<Subscript>4</Subscript>-dopamine receptors

Summary. This study examined the in vivo activity of L-745,870 at dopamine (DA) D₄ receptors, using the chick retina as a model system. In dark-adapted retinas of various vertebrates, including hen, DA acting via D₄ receptors suppresses melatonin content and activity of serotonin N-acetyltransferase (AA-NAT, a key regulatory enzyme in melatonin synthesis). Systemic administration to chicks of quinpirole (0.1 mg/kg), a high affinity agonist of D₃/D₄-DA receptors, potently decreased the nighttime AA-NAT activity of the retina. The quinpirole-evoked decline in the enzyme activity was attenuated by L-745,870 (0.1–10 nmol/eye). In addition to this action, L-745,870 given to chicks either directly into the eye (0.03–10 nmol/eye) or intraperitoneally (0.5–5 mg/kg) decreased the nighttime AA-NAT activity of the retina in a dose-dependent manner. The suppressive effect of L-745,870 on retinal AA-NAT activity was blocked by 2-chloro-11-(4-methylpiperazino)dibenz[b,f]oxepin, an antagonist of D₄-DA receptors, but was not affected by raclopride, an antagonist of D₂/D₃-DA receptors. Altogether these results indicate that in chicks L-745,870, the potent putative D₄-DA receptor antagonist, behaves in vivo as a partial D₄ agonist. Received May 5, 2002; accepted September 16, 2002 Published online December 9, 2002 Authors' address: Dr. J. B. Zawilska, Department of Biogenic Amines, Polish Academy of Sciences, POB-225 Lodz-1, 90-950 Poland, e-mail: jolantaz@amina1.zabpan.lodz.pl     

Stimulation of D1-like or D2 dopamine receptors in the shell, but not the core, of the nucleus accumbens reinstates cocaine-seeking behaviour in the rat

Although increases in dopamine transmission in the brain are clearly involved in the reinstatement of cocaine seeking, the role of nucleus accumbens dopamine in cocaine priming-induced reinstatement remains controversial. The goal of these experiments was to evaluate the relative contributions of D1-like and D2-like dopamine receptors in the nucleus accumbens core and shell in the reinstatement of cocaine-seeking behaviour. Initially, rats were trained to press a lever for cocaine (0.25 mg, i.v.) using a fixed-ratio 5 (FR5) schedule of reinforcement. Responding was then extinguished by substituting saline for cocaine. During the reinstatement phase, subtype-specific dopamine receptor agonists were microinjected into the nucleus accumbens core or medial shell in order to assess their ability to induce cocaine seeking. Administration of the D1/D5 dopamine receptor agonist SKF-81297 (1.0 microg) into the nucleus accumbens shell, but not core, reinstated drug-seeking behaviour. Similarly, microinjection of quinpirole (3.0 microg), a D2/D3 dopamine receptor agonist, into the nucleus accumbens shell and not core reinstated drug-seeking behaviour. In contrast, administration of the D3- or D4-preferring dopamine receptor agonists PD 128,907 (1.5 and 3.0 microg) and PD 168,077 (0.3 and 3.0 microg), respectively, did not promote reinstatement when administered into either the core or the shell. Taken together, these results indicate that activation of D1/D5 or D2 dopamine receptors, in the limbic shell subregion of the nucleus accumbens but not the basal ganglia-orientated accumbens core, promotes the reinstatement of cocaine-seeking behaviour.     

Role of NMDA and AMPA glutamate receptors in the induction and the expression of dopamine-mediated sensitization in 6-hydroxydopamine-lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization following repeated treatment with dopamine agonists, a phenomenon called "priming." Priming has two distinct phases: induction and expression. Priming induction using three injections with D1/D2 agonist apomorphine (0.5 mg/kg) or D1 agonist SKF38393 (10 mg/kg) allows priming expression, robust contralateral rotational behavior and striatal Fos expression, following a challenge with the D2 agonist quinpirole (0.25 mg/kg). We examined the roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors on dopamine agonist priming. Administration of the NMDA antagonist (+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) (0.5 mg/kg) blocked apomorphine-priming of quinpirole-mediated responses, while MK801 dose-dependently attenuated SKF38393-priming of quinpirole-mediated striatal Fos expression and had no effect on SKF38393-priming of quinpirole-mediated rotational behavior. In contrast, administration of the AMPA antagonist 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo[f]quinoxaline (NBQX) (5 or 10 mg/kg) potentiated apomorphine- and SKF38393-priming of quinpirole-mediated striatal Fos expression, but had no effect on their priming of quinpirole-mediated rotational behavior. In SKF38393-primed 6-OHDA rats, administration of MK801 (0.5 mg/kg) blocked the expression of quinpirole-mediated responses, while administration of NBQX (10 mg/kg) or the noncompetitive AMPA antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine dihydrochloride (GYKI52466) (5 or 15 mg/kg) had no effect. These results suggest that NMDA and AMPA glutamate receptors have differing roles in dopamine agonist priming-with NMDA receptors required for D1/D2 priming induction and D2-mediated priming expression, and AMPA receptors inhibiting priming induction of D2-mediated immediate early gene expression in the striatum, but not affecting priming induction of D2-mediated rotational behavior or the expression of D2-mediated responses.     

Pentazocine-like discriminative stimulus effects of morphine are blocked by the dopamine D-1 antagonist SCH23390, but not by the dopamine D-2 antagonist sulpiride.

The effects of selective dopamine antagonists on the pentazocine-like discriminative stimulus effects of morphine were investigated in the rat trained to discriminate 3.0 mg/kg of pentazocine from vehicle. Morphine (3.0 mg/kg), a mu-selective agonist, produced stimulus effects in common with pentazocine (3.0 mg/kg), indicating that the stimulus effects are mediated through mu opioid receptors. The pentazocine-like stimulus effects of morphine (3.0 mg/kg) were clearly inhibited by the dopamine D-1 antagonist SCH23390 (0.03-0.56 mg/kg) but not by the dopamine D-2 antagonist sulpiride (20.0-80.0 mg/kg). The results suggest that the pentazocine-like discriminative stimulus effects of morphine are mediated via dopamine D-1 receptors.     

Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt

Recent research on genetically modified mice has attributed the amnesic effect of benzodiazepines mainly to the alpha1-containing GABA(A) receptor subtypes. The pharmacological approach, using subtype selective ligands, is needed to complement genetic studies. We tested the effects of the non-selective antagonist flumazenil (0-20.0 mg/kg), the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) (0-30.0 mg/kg), the non-selective agonist midazolam (0-2.0 mg/kg), the preferential alpha1-subunit selective agonist zolpidem (0-3.0 mg/kg), and the non-selective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0-2.0 mg/kg) in the one-trial step-through passive avoidance task in rats. The compounds were administered intraperitoneally, before the acquisition test. Flumazenil and beta-CCt did not affect retention performance. Midazolam and zolpidem induced amnesia in a dose-dependent manner. The complete reversal of amnesia was unattainable. The effects of zolpidem were significantly attenuated by the both, flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg); by contrast, only flumazenil was considerably effective when combined with midazolam. DMCM exerted promnesic effects at 0.2mg/kg, in an inverted U-shape manner. Both antagonists tended to abolish this action. The results indicate that some other alpha-subunit(s), in addition to the alpha1-subunit, contribute to the amnesic actions of non-selective benzodiazepine site agonists in the passive avoidance task. On the other hand, a significant part of the DMCM-induced promnesic effect could involve the alpha1-subunit and/or other putative beta-CCt-sensitive binding site(s).     

Place preference conditioning reveals the involvement of D1-dopamine receptors in the motivational properties of mu- and kappa-opioid agonists

The role of D1 dopamine receptors in mediating the motivational properties of opioid agonists was investigated by use of place preference conditioning. Administration of the D1 receptor antagonist SCH 23390 (0.001-0.5 mg/kg) or the kappa-opioid receptor agonist U-69593 (0.16 mg/kg) produced conditioned place aversions. In contrast, the mu-opioid agonist, morphine (3.0 mg/kg) was appetitively reinforcing. Chronic infusion of SCH 23390 (1.0 mg/kg/day) during conditioning abolished the effects of both opioid agonists. These data demonstrate the specific involvement of D1 receptors in the motivational properties of mu- and kappa-opioid agonists and suggest that dopaminergic systems are crucial for the expression of both reinforcing and aversive motivational states.     

Involvement of dopamine D1 receptors of the central amygdala on the acquisition and expression of morphine-induced place preference in rat

In the present study, the effects of intra-central amygdala (CeA) injection of dopamine D1 receptor agonist and antagonist on morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-CeA administration of the dopamine D1 receptor agonist, SKF 38393 (2 and 4 micro g/rat) with an ineffective dose of morphine (0.5 mg/kg), elicited a significant conditioned place preference. On the other hand, a single dose of SKF 38393 (2 micro g/rat, intra-CeA) in combination with the lower doses (0.5 and 2.5 mg/kg), but not with the higher doses of morphine potentiated morphine-induced CPP. Furthermore, intra-CeA administration of the dopamine D1 receptor antagonist, SCH 23390 (0.5-1 micro g/rat) decreased the acquisition of conditioned place preference induced by morphine (7.5 mg/kg). The response of SKF 38393 was decreased by SCH 23390 (0.75 micro g/rat). SKF 38393 or SCH 23390 by themselves did not elicit any effect on place conditioning. On the other hand, intra-CeA administration of SKF 38393 or SCH 23390 significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. SKF 38393 or SCH 23390 injections into the CeA had no effects on the locomotor activity on the test sessions. The results indicate that the dopamine D1 receptors in the CeA may be involved in the acquisition and expression of morphine-induced place preference.     

Could the 5-HT1B receptor inverse agonism affect learning consolidation?

Diverse evidence indicates that, the 5-HT system might play a role in learning and memory, since it occurs in brain areas mediating such processes and 5-HT drugs modulate them. Hence in this work, in order to explore further 5-HT involvement on learning and memory 5-HT1B receptors' role is investigated. Evidence indicates that SB-224289 (a 5-HT1B receptor inverse agonist) post-training injection facilitated learning consolidation in an associative autoshaping learning task, this effect was partially reversed by GR 127935 (a 5-HT1B/1D receptor antagonist), but unaffected by MDL 100907 (a 5-HT2A receptor antagonist) or ketanserin (a 5-HT1D/2A/7 receptor antagonist) at low doses. Moreover, SB-224289 antagonized the learning deficit produced by TFMPP (a 5-HT1A/1B/1D/2A/2C receptor agonist), GR 46611 (a 5-HT1A/1B/1D receptor agonist), mCPP (a 5-HT2A/2C/3/7 receptor agonist/antagonist) or GR 127935 (at low dose). SB-224289 did not alter the 8-OH-DPAT (a 5-HT1A/7 receptor agonist) learning facilitatory effect. SB-224289 eliminated the deficit learning produced by the anticholinergic muscarinic scopolamine or the glutamatergic antagonist dizocilpine. Administration of both, GR 127935 (5mg/kg) plus ketanserin (0.01 mg/kg) did not modify learning consolidation; nevertheless, when ketanserin dose was increased (0.1-1.0mg/kg) and SB-224289 dose was maintained constant, a learning facilitation effect was observed. Notably, SB-224289 at 1.0mg/kg potentiated a subeffective dose of the 5-HT1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose. Collectively, the data confirm and extend the earlier findings with GR 127935 and the effects of non-selective 5-HT(1B) receptor agonists. Clearly 5-HT1B agonists induced a learning deficit which can be reversed with SB-224289. Perhaps more importantly, SB-224289 enhances learning consolidation when given alone and can reverse the deficits induced by both cholinergic and glutamatergic antagonist. Hence, 5-HT1B receptor inverse agonists or antagonists could represent drugs for the treatment of learning and memory dysfunctions.     

Adenosine A2A receptor knockout mice are partially protected against drug-induced catalepsy

Catalepsy assessed using the bar test was measured in both adenosine A2A receptor knockout (A2AR KO) and wild-type (A2AR WT) mice submitted to acute administration of the dopamine D2 receptor antagonist haloperidol (0.5, 2, 4, 6 mg/kg i.p.), the dopamine D1 antagonist SCH 23390 (0.3-3 mg/kg, s.c.), the vesicular monoamine transporter blocker reserpine (3-5 mg/kg, s.c.) or the acetylcholine muscarinic receptor agonist pilocarpine (25-50 mg/kg, i.p.). Except for reserpine, catalepsy scores were significantly lower in A2AR KO mice than in A2AR WT mice following low doses of these cataleptogenic agents. These results suggest that adenosine A2A receptors influence not only dopamine D2 and D1 receptor-mediated neurotransmission but also acetylcholine muscarinic receptor-mediated neurotransmission.