Oral administration of levo-tetrahydropalmatine attenuates reinstatement of extinguished cocaine seeking by cocaine, stress or drug-associated cues in rats.

Cocaine addiction is characterized by a persistently heightened susceptibility to drug relapse. For this reason, the identification of medications that prevent drug relapse is a critical goal of drug abuse research. Drug re-exposure, the onset of stressful life events, and exposure to cues previously associated with drug use have been identified as determinants of relapse in humans and have been found to reinstate extinguished cocaine seeking in rats. This study examined the effects of acute oral (gavage) administration of levo-tetrahydropalmatine (l-THP), a tetrahydroprotoberberine isoquinoline with a pharmacological profile that includes antagonism of D1, D2 and D3 dopamine receptors, on the reinstatement of extinguished cocaine seeking by a cocaine challenge (10mg/kg, ip), a stressor (uncontrollable electric footshock [EFS]) or response-contingent exposure to a stimulus (tone and light complex) previously associated with drug delivery in male Sprague-Dawley rats. Extinguished drug seeking was reinstated by ip cocaine, EFS, or response-contingent presentation of drug-associated cues in vehicle-pretreated rats following extinction of iv cocaine self-adminisration. Oral administration of either 3.0 or 10.0mg/kg l-THP 1h prior to reinstatement testing significantly attenuated reinstatement by each of the stimuli. Food-reinforced responding and baseline post-extinction responding were significantly attenuated at the 10.0, but not the 3.0mg/kg, l-THP dose, indicating that the effects of 3mg/kg l-THP on reinstatement were likely independent of non-specific motor impairment. These findings further suggest that l-THP may have utility for the treatment of cocaine addiction.

NMDA receptors in the basolateral amygdala and gustatory neophobia.

The attenuation of gustatory neophobia occurs during repeated exposures to an initially novel taste solution that is increasingly perceived as safe and familiar. The present study examined whether NMDA receptors in the basolateral region of the amygdala (BLA) are involved in this important behavioral phenomenon. The results, which show that the attenuation, but not initial occurrence, of gustatory neophobia is dependent upon NMDA receptors in the BLA, are discussed with reference to a similar finding involving NMDA receptors in the insular cortex.

NMDA receptor antagonist MK-801 infused into the insular cortex prevents the attenuation of gustatory neophobia in rats.

Gustatory neophobia dissipates with repeated exposures to an initially novel taste solution. The aim of the present study was to determine whether NMDA receptors in the insular cortex are involved in this experience-dependent process. Results showed that acute microinfusion of MK-801 into the insular cortex prevented the attenuation of gustatory neophobia indicating that this process is an NMDA receptor-dependent phenomenon.

Brain-derived neurotrophic factor enhances conditioned taste aversion retention.

Brain-derived neurotrophic factor (BDNF) has recently emerged as one of the most potent molecular mediators of not only central synaptic plasticity, but also behavioral interactions between an organism and its environment. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the IC, previous to CTA training, enhances the retention of this task. Recently, we found that intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the Bla-IC projection of adult rats in vivo. In this work, we present experimental data showing that intracortical microinfusion of BDNF previous to CTA training enhances the retention of this task. These findings support the concept that BDNF may contribute to memory-related functions performed by a neocortical area, playing a critical role in long-term synaptic plasticity.

In vivo insular cortex LTP induced by brain-derived neurotrophic factor.

Recent studies suggest that brain-derived neurotrophic factor (BDNF) plays a critical role in long-term synaptic plasticity in the adult brain. Previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of different aversive learning tasks, have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induces an N-methyl-D-aspartate (NMDA)-dependent form of long-term potentiation (LTP) in the IC of adult rats in vivo. Here, we show that acute intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the Bla-IC projection of anesthetized adult rats. This constitutes an in vivo demonstration of neurotrophin-induced potentiation of synaptic transmission in the neocortex. These findings support the concept that BDNF could be a synaptic messenger involved in activity-dependent synaptic plasticity.