Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.
Cannabis use during adolescence is associated with an increased risk for schizophrenia and other disorders. The neuronal basis is unclear, but prefrontal cortical mechanisms have been implicated. Here, we investigated developmental changes in the endocannabinoid system by assessing expression and function of the CB1 cannabinoid receptor in prefrontal and other cortical areas in juvenile (postnatal day 25, P25), adolescent (P40) and adult (P70) rats. Overall, the expression of CB1 receptors in the cortex is highest in juveniles and drops thereafter towards adult levels. However, CB1 receptor expression follows distinct developmental trajectories in different cortical areas. The most pronounced and progressive decrease in CB1 expression was observed in medial prefrontal and other limbic/associative regions. In contrast, major changes in sensorimotor cortices occurred only after P40. We also assessed electrophysiological measures of CB1 receptor function and found that CB1-dependent inhibition of synaptic transmission in the prefrontal cortex follows the same developmental trajectory as observed for receptor expression. Together, these findings indicate that CB1 receptor-mediated signaling decreases during development, but is differentially regulated in limbic/associative vs. sensorimotor systems. Therefore, cannabis use during adolescence likely differentially affects limbic/associative and sensorimotor cortical circuits.
Background Refinement of mature cognitive functions such as working memory and decision-making typically take place during adolescence. The acquisition of these functions is linked to the protracted development of the prefrontal cortex (PFC) and dopamine facilitation of glutamatergic transmission. However, the mechanisms that support these changes during adolescence remain elusive. Methods Electrophysiological recordings (in vitro and in vivo) combined with pharmacological manipulations were employed to determine how NMDA transmission in the medial PFC changes during the adolescent transition to adulthood. The relative contribution of GluN2B transmission and its modulation by postsynaptic PKA and D1 receptor signaling were determined in two distinct age groups of rats: postnatal days (P) 25–40 and P50–80. Results We found that only NMDA receptor transmission onto the apical dendrite of layer V pyramidal neurons undergoes late adolescent remodeling due to a functional emergence of GluN2B function after P40. Both PKA and dopamine D1 receptor signaling are required for the functional expression of GluN2B transmission and to sustain PFC plasticity in response to ventral hippocampal, but not basolateral amygdala inputs. Conclusion Thus, the late adolescent acquisition of GluN2B function provides a mechanism for dopamine D1-mediated regulation of PFC responses in an input-specific manner.
Further understanding of how prefrontal cortex (PFC) circuit change during postnatal development is of great interest due to its role in working memory and decision-making, two cognitive abilities that are refined late in adolescence and become altered in schizophrenia. While it is evident that dopamine facilitation of glutamate responses occurs during adolescence in the PFC, little is known about the cellular mechanisms that support these changes. Among them, a developmental facilitation of postsynaptic Ca 2+ function is of particular interest given its role in coordinating neuronal ensembles, a process thought to contribute to maturation of PFC function. Here we conducted whole-cell patch clamp recordings of deep-layer pyramidal neurons in PFC brain slices and determined how somatic-evoked Ca 2+ -mediated plateau depolarizations change throughout postnatal day (PD) 25 (juvenile) to adulthood (PD 80). Postsynaptic Ca 2+ potentials in the PFC increase in duration throughout postnatal development. A remarkable shift from short to prolonged depolarizations was observed after PD 40. This change is reflected by an enhancement of L-type Ca 2+ channel function and postsynaptic PKA signaling. We speculate that such a protracted developmental facilitation of Ca 2+ response in the PFC may contribute to improvement of working memory performance through adolescence.
Black hairy tongue (BHT) is characterized by a discolored, hairy tongue. We herein report two cases of BHT associated with antibacterial agents and review previous cases. In Case 1, a 17-year-old girl with a central neurocytoma was administered intravenous piperacillin–tazobactam for postoperative infection, and BHT developed 12 days later. Her symptoms resolved 8 days after she discontinued the piperacillin–tazobactam and brushed her tongue three times daily. In Case 2, a 65-year-old man was administered intravenous piperacillin–tazobactam and levofloxacin to treat multidrug-resistant Pseudomonas aeruginosa, and BHT developed 15 days later. The piperacillin–tazobactam was discontinued and the patient brushed his tongue, and the discoloration gradually subsided thereafter. However, the BHT reappeared after linezolid treatment. The patient had adverse drug reactions to both the piperacillin–tazobactam and linezolid treatments. The BHT might have been related to antibiotic use in both cases. We identified 19 cases of antibiotic-related BHT in a literature search, but none were related to piperacillin–tazobactam use. In all cases, symptoms resolved after discontinuation of the drug and brushing of the tongue. BHT may be a rare adverse effect of antibiotics. Treatment strategies include removal of the causative agents, mechanical debridement, and good oral hygiene.
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