Through its complex role in cognition, memory, and emotion, the mammalian prefrontal cortex is thought to contribute to the organization of adaptive behavioral actions. In the present studies we examined the role of dopaminergic D1 and glutamatergic NMDA receptors within the prefrontal cortex of the rat during the development of adaptive instrumental learning. Hungry rats with bilateral indwelling cannulas aimed at the medial prefrontal cortex were trained to lever-press for food. Infusion of the selective D1 antagonist SCH-23390 (0.15, 0.3, 3.0 nmol) dosedependently impaired acquisition of this behavior. Higher doses also impaired expression of this task. Co-infusion of the lowest dose of SCH 23390 with a low dose of the NMDA antagonist AP-5 (0.5 nmol), each of which had no effect on learning when infused alone, potently reduced the ability to acquire the response. Inhibition of intracellular protein kinase A with the selective PKA inhibitor Rp-cAMPS also disrupted acquisition, suggesting that PKA is an intracellular substrate for a D1-NMDA receptor interaction. In control experiments, drug infusions that impaired learning did not affect food intake or locomotion, suggesting a specific effect on learning. We hypothesize that coincident detection of D1-NMDA receptor activation and its transcriptional consequences, within multiple sites of a distributed corticostriatal network, may represent a conserved molecular mechanism for instrumental learning.

The effect of microinfusion of the W-methyl-D-aspartate (NMDA) antagonist 2-amino-5phosphonopentanoic acid (AP-5) into the amygdala, medial prefrontal cortex, and dorsal and ventral subiculum on acquisition of a lever-pressing task for food in rats was examined. Serial transmission between the basolateral amygdala and nucleus accumbens core was also examined in an asymmetric infusion design. AP-5 administered bilaterally into either the amygdala or medial prefrontal cortex markedly impaired learning, whereas administration into the dorsal or ventral subiculum had no effect. Unilateral infusion of AP-5 into either the nucleus accumbens core or amygdala was also sufficient to impair learning. These data provide novel evidence for NMDA receptor-dependent plasticity within corticostriatal networks in the acquisition of appetitive instrumental learning.

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Rats suppress intake of a normally preferred 0.15% saccharin conditioned stimulus (CS) when it is paired with an aversive agent like lithium chloride (LiCl) or a preferred substances such as sucrose or a drug of abuse. The reward comparison hypothesis suggests that rats avoid intake of a saccharin cue following pairings with a drug of abuse because the rats are anticipating the availability of the rewarding properties of the drug. The present study used bilateral ibotenic acid lesions to examine the role of the gustatory cortex in the suppression of CS intake induced by cocaine, morphine, and LiCl. The results show that bilateral lesions of the insular gustatory cortex (1) fully prevent the suppressive effects of both a 15- and a 30-mg/kg dose of morphine, (2) attenuate the suppressive effect of a 10 mg/kg dose of cocaine, but (3) are overridden by a 20 mg/kg dose of the drug. Finally, these same cortical lesions had no impact on LiCl-induced conditioned taste aversion. The current data show that the insular taste cortex plays an integral role in drug-induced avoidance of a gustatory CS.