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 D(1) 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 D(1) receptors stimulation in acetaldehyde-elicited ERK phosphorylation, we studied the effect of the D(1) receptor antagonist, SCH 39166. Pretreatment with the D(1) 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.

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.

Role of dopamine D(1) receptors in caffeine-mediated ERK phosphorylation in the rat brain.

The aim of this research was to study the role of dopamine D(1) receptors in caffeine elicited ERK phosphorylation in the prefrontal and other cortical (cingulate and motor) and subcortical (shell and core of the nucleus accumbens) regions. To this end, caffeine (3 and 10 mg/kg) was administered before phosphoERK immunohistochemistry. Caffeine dose-dependently increased the number of phosphoERK-positive neurons in the prefrontal and cingulate cortices but not in the secondary motor cortex and in the nucleus accumbens shell and core. The dopamine D(1) receptor antagonist, SCH 39166 (50 microg/kg), fully prevented phosphoERK activation by caffeine (10 mg/kg) in the superficial and deep layers of the prefrontal cortex but failed to prevent it in the cingulate cortex. Given that phosphoERK can be regarded as a postsynaptic marker of neuronal activation, the present results indicate that psychotropic properties of caffeine may result from the activation of prefrontal, via dopamine D(1) receptors, and cingulate cortices. Failure of caffeine to activate ERK in the nucleus accumbens further supports, indirectly, the observation that caffeine fails to activate dopamine transmission in this structure and is consistent with the tenet that caffeine lacks of true addictive properties.

Withania somnifera prevents morphine withdrawal-induced decrease in spine density in nucleus accumbens shell of rats: a confocal laser scanning microscopy study.

Opiate withdrawal is associated with morphological changes of dopamine neurons in the ventral tegmental area and with reduction of spine density of second-order dendrites of medium size spiny neurons in the nucleus accumbens shell but not core. Withania somnifera has long been used in the Middle East, Africa, and India as a remedy for different conditions and diseases and a growing body of evidence points to its beneficial effects on a number of experimental models of neurological disorders. Recently, many studies focused on the potential neuritic regeneration and synaptic reconstruction properties of its methanolic extract and its constituents (withanolides). This study investigates whether morphine withdrawal-induced spine reduction in the nucleus accumbens is affected by the administration of a Withania somnifera extract. To this end, rats were chronically treated with Withania somnifera extract along with morphine or saline and, upon spontaneous (1 and 3 days) or pharmacologically precipitated withdrawal, their brains were fixed in Golgi-Cox stain for confocal microscopic examination. In a separate group of animals, Withania somnifera extract was administered during three days of spontaneous withdrawal. Withania somnifera extract treatment reduced the severity of the withdrawal syndrome when given during chronic morphine but not during withdrawal. In addition, treatment with Withania somnifera extract during chronic morphine, but not during withdrawal, fully prevented the reduction of spine density in the nucleus accumbens shell in spontaneous and pharmacologically precipitated morphine withdrawal. These results indicate that pretreatment with Withania somnifera extract protects from the structural changes induced by morphine withdrawal potentially providing beneficial effects on the consequences related to this condition.

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.