Deficits in ventromedial prefrontal cortex group 1 metabotropic glutamate receptor function mediate resistance to extinction during protracted withdrawal from an extensive history of cocaine self-administration.

Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. Because group 1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) on the PFC expression of group 1 mGluRs and the relevance of observed changes for cocaine seeking. After protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects on cue-induced cocaine-seeking behavior but produced residual effects on a subsequent test for cocaine seeking. At 3 d withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine seeking, persisted in their cocaine seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 d withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC group 1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior that may aid drug abstinence.

Rewarding and incentive motivational effects of excitatory amino acid receptor antagonists into the median raphe and adjacent regions of the rat.

RATIONALE: The motivational process that regulates approach behavior toward salient distal stimuli (i.e., incentive motivation) plays a key role in voluntary behavior and motivational disorders such as addiction. This process may be mediated by many neurotransmitter systems and a network of many brain structures, including the median and dorsal raphe regions (MR and DR, respectively). OBJECTIVE: We sought to examine whether the blockade of excitatory amino acid receptors in the MR and DR is rewarding, using intracranial self-administration, and whether the self-administration effect can be explained by drug's effectiveness to enhance incentive motivation, using a visual sensation seeking procedure. RESULTS: Rats learned to self-administer the AMPA receptor antagonist ZK 200775 into the vicinity of the MR, DR, or medial oral pontine reticular regions, but not the ventral tegmental area. The NMDA receptor antagonist AP5 was also self-administered into the MR, while it was not readily self-administered into other regions. When ZK 200775 was noncontingently administered into the MR, rats markedly increased approach responses rewarded by brief illumination of a light stimulus. In addition, contingent administration of ZK 200775 into the MR induced a conditioning effect on approach responses. CONCLUSIONS: Rats self-administer excitatory amino acid receptor antagonists into the MR and adjacent regions. Self-administration effect of AMPA receptor antagonists into the MR can be largely explained by the manipulation's properties to invigorate ongoing approach behavior and induces conditioned approach. Glutamatergic afferents to the median raphe and adjacent regions appear to tonically suppress incentive-motivational processes.

Amphetamine administration into the ventral striatum facilitates behavioral interaction with unconditioned visual signals in rats.

BACKGROUND: Administration of psychomotor stimulants like amphetamine facilitates behavior in the presence of incentive distal stimuli, which have acquired the motivational properties of primary rewards through associative learning. This facilitation appears to be mediated by the mesolimbic dopamine system, which may also be involved in facilitating behavior in the presence of distal stimuli that have not been previously paired with primary rewards. However, it is unclear whether psychomotor stimulants facilitate behavioral interaction with unconditioned distal stimuli. PRINCIPAL FINDINGS: We found that noncontingent administration of amphetamine into subregions of the rat ventral striatum, particularly in the vicinity of the medial olfactory tubercle, facilitates lever pressing followed by visual signals that had not been paired with primary rewards. Noncontingent administration of amphetamine failed to facilitate lever pressing when it was followed by either tones or delayed presentation or absence of visual signals, suggesting that visual signals are key for enhanced behavioral interaction. Systemic administration of amphetamine markedly increased locomotor activity, but did not necessarily increase lever pressing rewarded by visual signals, suggesting that lever pressing is not a byproduct of heightened locomotor activity. Lever pressing facilitated by amphetamine was reduced by co-administration of the dopamine receptor antagonists SCH 23390 (D1 selective) or sulpiride (D2 selective). CONCLUSIONS: Our results suggest that amphetamine administration into the ventral striatum, particularly in the vicinity of the medial olfactory tubercle, activates dopaminergic mechanisms that strongly enhance behavioral interaction with unconditioned visual stimuli.