ABSTRACT
Dopamine (DA) and N-methyl-D-aspartate (NMDA) receptors seem to be critically involved in working memory processing in the medial prefrontal cortex (mPFC). Effects of NMDA receptors blockade on dopamine D1 receptors activation in the mPFC on spatial working memory was investigated. Adult male Wistar rats, well trained in an eight-arm radial maze and bilaterally cannulated in the mPFC, received intracortical administrations of saline (SAL) or SKF-38393 (DA D1 receptor agonist) followed, 10 min later, by MK-801 (non-competitive NMDA receptor antagonist). They were tested in 1 h delayed tasks after 5 min of the second administration. SKF-38393 (0.56 and 1.8 microg) was disruptive to working memory, increasing significantly the number of errors in the 1 h post-delay performance when administered into the mPFC. MK-801, at doses with no significant effects alone (0.32 or 1.0 microg), reduced significantly the disruptive effect of 0.56 microg SKF-38393. These results showed that the disruptive effect of DA D(1) receptors activation in the mPFC on working memory was significantly reduced by an open-channel NMDA receptor blockade, suggesting that the processing of working memory in the mPFC involving DA D1 receptors depend, at least in part, of NMDA receptors activity in this cortical area.
Subject(s)
Memory, Short-Term/physiology , Prefrontal Cortex/physiology , Receptors, Dopamine D1/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Space Perception/physiology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Catheterization , Dizocilpine Maleate/administration & dosage , Dizocilpine Maleate/pharmacology , Dopamine Agonists/administration & dosage , Dopamine Agonists/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacology , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory, Short-Term/drug effects , Prefrontal Cortex/drug effects , Rats , Rats, Wistar , Receptors, Dopamine D1/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Space Perception/drug effects , Time FactorsABSTRACT
RATIONALE: Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) disrupts working memory. The prefrontal cortex (PFC) is involved in the processing of working memory, and its medial portion (mPFC) is part of a brain reward circuit as constituted by the mesocorticolimbic dopaminergic system. OBJECTIVE: This study examined the involvement of the mPFC in the effects of Delta(9)-THC on spatial working memory. METHODS: Ten male Wistar rats well-trained in a radial arm maze and with bilateral cannula implanted in the mPFC received Delta(9)-THC intra-cortically (Delta(9)-THC IC) at doses of 0 (VEH), 32, 100 or 180 microg, 5 min before a 5-s or a 1-h delayed task in order to measure a short- or long-term spatial working memory, respectively. By contrast, 11 other animals received Delta(9)-THC intraperitoneally (Delta(9)-THC IP) at doses of 0 (VEH), 0.32, 1 or 1.8 mg/kg, 30 min before a 5-s or a 1-h delayed task. Additionally, after a 15-day washout, the effect of an IP or IC pre-exposure of Delta(9)-THC was examined by repeating both dose-effect curves in a crossover order for the routes of administration. RESULTS: Delta(9)-THC IP produced significantly larger number of errors at doses of 0.32 or 1 mg/kg as compared to VEH in the 1-h post-delay performance. Delta(9)-THC 100 microg IC also produced significantly larger number of errors as compared to VEH and also to the other doses (32 or 180 microg) IC in the 1-h post-delay performance. Previous exposure to Delta(9)-THC IP or IC did not significantly affect the disruptive effect of this cannabinoid. CONCLUSIONS: Delta(9)-THC administered directly in the mPFC impaired 1-h delayed task in the radial arm maze in a manner similar to that observed for its systemic administration, suggesting that the mPFC is involved in the disruptive effects of Delta(9)-THC on spatial working memory.