Liliana Spina

Permissive role of D-1 receptor stimulation for the expression of D-2 mediated behavioral responses: a quantitative phenomenological study in rats

The syndrome of behavioral stimulation induced in male Sprague-Dawley rats by two dopaminergic agents was studied by distinguishing specific behavioral items and quantifying them in terms of their incidence. The specific D-2 agonist LY 171555 elicited yawning, genital grooming, exploratory behavior, downward sniffing and licking but failed to induce gnawing even at high doses. On the other hand, the D-1/D-2 agonist apomorphine elicited the full stereotyped syndrome including gnawing. Depletion of endogenous dopamine (DA) by alpha-methyltyrosine (alpha-MT) prevented the ability of LY 171555 to elicit all the items of behavioral stimulation including the stereotyped ones (sniffing and licking). In contrast, the ability of apomorphine to induce stereotypies was not reduced by depletion of endogenous DA by alpha-MT pretreatment. Blockade of D-1 receptors with SCH 23390 abolished the capacity of both LY 171555 and apomorphine to elicit all the items of behavioral stimulation. In alpha-MT pretreated rats, administration of low doses of the D-1 agonist SKF 38393 (2.5 mg/kg s.c.) reinstated the ability of LY 171555 to elicit behavioral stimulation and eventually conferred the ability of inducing gnawing. The results support the hypothesis that stimulation of D-1 receptors exerts a permissive role for the expression of behavioral stimulation following D-2 receptor stimulation. Endogenous DA appears to provide sufficient D-1 input to permit full expression of yawning, genital grooming, exploratory behavior, downward sniffing and licking following D-2 stimulation; pharmacological stimulation of D-1 in addition to D-2 receptors seems however necessary for full expression of the highest rank stereotypy item, gnawing.

Permissive role of D-1 receptor stimulation by endogenous dopamine for the expression of postsynaptic D-2-mediated behavioural responses. Yawning in rats

Low doses of BHT 920, LY 171555 and (+)3PPP, three dopamine agonists selective for D-2 receptors, induced yawning in rats. This effect was reduced by the selective D-1 antagonist SCH 23390 but the antagonism did not exceed a 50% reduction from the control values. In contrast, the selective D-2 antagonist (-)sulpiride completely abolished agonist-induced yawning. A 6 h reserpine pretreatment (5 mg/kg i.p.), which depletes brain dopamine (DA) by about 95%, reduced agonist-induced yawning by an extent similar to SCH 23390; in the reserpinized rats, SCH 23390 completely lost the property of blocking agonist-induced yawning while (-)sulpiride retained it. Two 5HT receptor antagonist, ketanserin and metergoline failed to influence agonist-induced yawning. The reportedly selective D-1 agonist, SKF 38393, failed to induce yawning in normal rats as well as in rats pretreated with reserpine 6 or 16 h earlier. If one excludes that SCH 23390 and the D-2 agonists interact with the same DA-receptors, the data are consistent with the possibility that stimulation of D-1 receptors by endogenous DA plays a permissive-facilitatory role for the behavioural expression of D-2 receptor activation.

Piecing together the puzzle of acetaldehyde as a neuroactive agent.

Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehydes psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanols central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol.

Antagonism of apomorphine-induced yawning by SCH 23390: evidence against the autoreceptor hypothesis

The ability of apomorphine to induce yawning (YWG) in normal and reserpinized rats and its interaction with SCH 23390, a potent and specific D-1 receptor antagonist, was studied. Apomorphine was more potent in inducing YWG in reserpine-pretreated as compared to control rats. SCH 23390, in low doses (0.05 mg/kg SC), was able to significantly reduce the YWG evoked by apomorphine both in control and in reserpine-pretreated rats. The results indicate that D-1 receptors contribute to YWG elicited by apomorphine and contradict the idea that this effect is mediated by DA autoreceptors.

Dopaminergic D-1 receptors: essential role in morphine-induced hypermotility

Administration of morphine HCl (20 mg/kg SC) to male C57B1/6 mice evoked hypermotility. Pretreatment with low doses of the specific D-1 antagonist SCH 23390 (0.006, 0.012, 0.025 mg/kg SC) dose-dependently inhibited morphine-evoked hypermotility. The results suggest that dopamine is the essential mediator of opiate hypermotility and indicate that D-1 receptors play an important role in this effect.

Ethanol-induced extracellular signal regulated kinase: role of dopamine D1 receptors.

BACKGROUND Addictive drugs activate extracellular signal regulated kinase (ERK) in brain regions critically involved in their affective and motivational properties. The aim of this study was to demonstrate the ethanol-induced activation of ERK in the nucleus accumbens (Acb) and in the extended amygdala [bed nucleus of the stria terminalis lateralis (BSTL) and central nucleus of the amygdala (CeA)] and to highlight the role of dopamine (DA) D(1) receptors in these effects. METHODS Ethanol (0.5, 1, and 2 g/kg) was administered by gavage and ERK phosphorylation was determined in the nucleus Acb (shell and core), BSTL, and CeA by immunohistochemistry. The DA D(1) receptor antagonist, SCH 39166 (SCH) (50 microg/kg), was administered 10 minutes before ethanol (1 g/kg). RESULTS Quantitative microscopic examination showed that ethanol, dose-dependently increased phospho-ERK immunoreactivity (optical and neuronal densities) in the shell and core of nucleus Acb, BSTL, and CeA. Pretreatment with SCH fully prevented the increases elicited by ethanol (1 g/kg) in all brain regions studied. CONCLUSIONS The results of this study indicate that ethanol, similar to other addictive drugs, activates ERK in nucleus Acb and extended amygdala via a DA D(1) receptor-mediated mechanism. Overall, these results suggest that the D(1) receptors/ERK pathway may play a critical role in the motivational properties of ethanol.

Role of Dopamine D1 Receptors and Extracellular Signal Regulated Kinase in the Motivational Properties of Acetaldehyde as Assessed by Place Preference Conditioning

BACKGROUND The role of dopamine D1 receptors and Extracellular signal Regulated Kinase (ERK) in the motivational properties of drugs can be studied by place-conditioning. Recent advances have shown that the motivational properties of ethanol, determined by place-conditioning, are mediated by its metabolic conversion into acetaldehyde. To date, the role of D1 receptors and ERK activation in acetaldehyde-elicited place preference has not been determined. The aim of this study was to assess the role of D1 receptors blockade and MEK inhibition in the acquisition of acetaldehyde-elicited conditioned place preference. METHODS Male Sprague-Dawley rats were subjected to repeated pairings with 1 compartment of the conditioning apparatus immediately following acetaldehyde (20 mg/kg i.g.) or ethanol (1 g/kg i.g.) administration. The D1 receptor antagonist, SCH 39166 (50 microg/kg s.c.), was administered 10 minutes before acetaldehyde or ethanol administration. In order to study the role of activated ERK in the acetaldehyde-elicited place preference, rats were administered the MEK inhibitor, PD98059 (1, 30, and 90 microg i.c.v.), 10 or 30 minutes before acetaldehyde. To verify the specificity of these effects, we also studied whether PD98059 pretreatment could affect morphine (1 mg/kg s.c.)-elicited place preference. RESULTS Both acetaldehyde and ethanol elicited significant place preferences and these were prevented by pretreatment with SCH 39166. In addition, pretreatment with PD98059, dose (30 and 90 but not 1 microg i.c.v.) and time (10 but not 30 minutes before) dependently, prevented the acquisition of acetaldehyde- and significantly reduced the acquisition of morphine-elicited conditioned place preference. CONCLUSIONS These results confirm that acetaldehyde and ethanol elicit conditioned place preference and demonstrate that D1 receptors are critically involved in these effects. Furthermore, the finding that PD98059 prevents the acquisition of acetaldehyde-elicited conditioned place preference highlights the importance of the D1 receptor-ERK pathway in its motivational effects.

Ipsiversive turning behaviour after discrete unilateral lesions of the dorsal mesencephalic reticular formation by kainic acid

Discrete axon-sparing lesions were placed unilaterally in the mesencephalon by the local injection of kainic acid. Unilateral lesions of the dorsal reticular formation just beneath the superior colliculus and lateral to the periacqueductal grey resulted in consistent ipsiversive apomorphine-induced circling. Only weak motor asymmetries were observed after unilateral lesions restricted to the superior colliculus or to the periacqueductal grey. The results indicate that the dorsal mesencephalic reticular formation plays an essential role as an output station for striatal postural functions.

Acetaldehyde elicits ERK phosphorylation in the rat nucleus accumbens and extended amygdala.

Recent advances suggest that acetaldehyde mediates some of the neurobiological properties of ethanol. In a recent study, we have shown that ethanol elicits the phosphorylation of extracellular signal‐regulated kinase (pERK) in the nucleus accumbens and extended amygdala, via a dopamine D1 receptor‐mediated mechanism. The aim of this study was to determine whether acetaldehyde and ethanol‐derived acetaldehyde elicit the activation of ERK in the nucleus accumbens and extended amygdala. The effects of acetaldehyde (10 and 20 mg/kg) and ethanol (1 g/kg), administered to rats intragastrically, were assessed by pERK peroxidase immunohistochemistry. To establish the role of ethanol‐derived acetaldehyde, the alcohol dehydrogenase inhibitor, 4‐methylpyrazole (90 mg/kg), and the acetaldehyde‐sequestering agent, D‐penicillamine (50 mg/kg), were administered before ethanol. Acetaldehyde increased pERK immunoreactivity in the nucleus accumbens and extended amygdala. Inhibition of ethanol metabolism and sequestration of newly synthesized acetaldehyde completely prevented ERK activation by ethanol. In addition, to establish the role of D1 receptors stimulation in acetaldehyde‐elicited ERK phosphorylation, we studied the effect of the D1 receptor antagonist, SCH 39166. Pretreatment with the D1 receptor antagonist (50 μg/kg) fully prevented acetaldehyde‐elicited ERK activation. Overall, these results indicate that ethanol activates ERK by means of its metabolic conversion into acetaldehyde and strengthen the view that acetaldehyde is a centrally acting compound with a pharmacological profile similar to ethanol. Synapse 64:916–927, 2010.

Withania somnifera prevents acquisition and expression of morphine-elicited conditioned place preference.

Previous studies have reported that some of the central effects of morphine are counteracted by the administration of the methanolic extract of the root of Indian ginseng, Withania somnifera Dunal (WSE). The present study sought to determine whether WSE affects acquisition and expression of morphine-elicited conditioned place preference (CPP) in CD-1 mice. In CPP acquisition experiments, WSE (0, 25, 50, and 100 mg/kg) was administered, during conditioning, 30 min before morphine (10 mg/kg), whereas in expression experiments, WSE (0, 25, 50, and 100 mg/kg) was administered 30 min before the postconditioning test. The results demonstrate (i) that WSE was devoid of motivational properties; (ii) that WSE (100 mg/kg) was devoid of effects on spontaneous and morphine-stimulated motor activity and on spatial memory; and (iii) that WSE (50 and 100 mg/kg) significantly prevented the acquisition and expression of CPP. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for µ-opioid and &ggr;-aminobutyric acid B receptors. These experiments revealed a higher affinity of WSE for &ggr;-aminobutyric acid B than for µ-opioid receptors. Overall, these results point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction.