Contextual response time adaptation in the countermanding performance of rats.

Humans and non-human primates are known to lengthen their response time (RT) to a go signal when they occasionally must cancel their responses following a stop signal in a countermanding task as well as to adjust their RT adaptively on a trial-by-trial basis. Less is clear regarding the adaptive RT adjustments in the countermanding performance of rodents. To investigate this question, male Wistar rats (N=12) were trained with food reward to press a lever directly below an illuminated light (go signal), but to countermand the lever press subsequent to a tone (stop signal) presented infrequently (25% of trials) at variable delays. Rats were then tested in a standard responding task (0% stop trials) or a countermanding task with a 10-s or 1-s TO interval following errors. Rats exhibited significant RT lengthening in the countermanding task, compared with the standard responding task, and RT shortening following consecutive correct go trials. They also show RT lengthening following both error trials in the standard responding task and unrewarded, non-canceled stop trials in the countermanding task. RT lengthening following erroneous stop trials was observed in sessions with a 10-s TO interval, but not with a 1-s TO interval. Analyses of RT distributions suggest that RT lengthening results largely from reduced sensitivity to the go signal, but also from reduced readiness. These findings indicate that rats exert control in the countermanding task by lengthening RT in anticipation of stop trials to avoid long, unrewarded TO intervals.

GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.

Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA-mediated potentiation of AMPA receptors in this region may be part of the neural circuits of drug relapse.