Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca2+-permeable AMPARs (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc precedes and enables CP-AMPAR accumulation. Thus, restoring mGluR1 tone by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results demonstrate a strategy whereby recovering addicts could use a systemically active compound to protect against cue-induced relapse.
Determining the normal developmental trajectory of individual GABAergic components in the prefrontal cortex (PFC) during the adolescent transition period is critical because local GABAergic interneurons are thought to play an important role in the functional maturation of cognitive control that occurs in this developmental window. Based on the expression of calcium-binding proteins, 3 distinctive subtypes of interneurons have been identified in the PFC: parvalbumin (PV)-, calretinin (CR)-, and calbindin (CB)-positive cells. Using biochemical and histochemical measures, we found that the protein level of PV is lowest in juveniles (postnatal day -PD- 25–35) and increases during adolescence (PD45–55) to levels similar to those observed in adulthood (PD65–75). In contrast, the protein expression of CR is reduced in adults compared to juvenile and adolescent animals, whereas CB levels remain mostly unchanged across the developmental window studied here. Semi-quantitative immunostaining analyses revealed that the periadolescent upregulation of PV and the loss of the CR signal appear to be attributable to changes in PV- and CR-positive innervation, which are dissociable from the trajectory of PV- and CR-positive cell number. At the synaptic level, our electrophysiological data revealed that a developmental facilitation of spontaneous glutamatergic synaptic inputs onto PV-positive/fast-spiking interneurons parallels the increase in prefrontal PV signal during the periadolescent transition. In contrast, no age-dependent changes in glutamatergic transmission were observed in PV-negative/non fast-spiking interneurons. Together, these findings emphasize that GABAergic inhibitory interneurons in the PFC undergo a dynamic, cell-type specific remodeling during adolescence and provide a developmental framework for understanding alterations in GABAergic circuits that occur in psychiatric disorders.
Converging epidemiological studies indicate that cannabis abuse during adolescence increases the risk of developing psychosis and prefrontal cortex (PFC)-dependent cognitive impairments later in life. However, the mechanisms underlying the adolescent susceptibility to chronic cannabis exposure are poorly understood. Given that the psychoactive constituent of cannabis binds to the CB1 cannabinoid receptor, the present study was designed to determine the impact of a CB1 receptor agonist (WIN) during specific windows of adolescence on the functional maturation of the rat PFC. By means of local field potential (LFP) recordings and ventral hippocampal stimulation in vivo, we found that a history of WIN exposure during early (postnatal day -P-35-40) or mid-(P40-45) adolescence, but not in late adolescence (P50-55) or adulthood (P75-80), is sufficient to yield a state of frequency-dependent prefrontal disinhibition in adulthood comparable to that seen in the juvenile PFC. Remarkably, this prefrontal disinhibition could be normalized following a single acute local infusion of the GABA-Aα1 positive allosteric modulator Indiplon, suggesting that adolescent exposure to WIN causes a functional downregulation of GABAergic transmission in the PFC. Accordingly, in vitro recordings from adult rats exposed to WIN during adolescence demonstrate that local prefrontal GABAergic transmission onto layer V pyramidal neurons is markedly reduced to the level seen in the P30-35 PFC. Together, these results indicate that early and mid-adolescence constitute a critical period during which repeated CB1 receptor stimulation is sufficient to elicit an enduring state of PFC network disinhibition resulting from a developmental impairment of local prefrontal GABAergic transmission.
The striatum is the principal input structure of the basal ganglia. Major glutamatergic afferents to the striatum come from the cerebral cortex and make monosynaptic contacts with medium spiny projection neurons (MSNs) and interneurons. Also: glutamatergic afferents to the striatum come from the thalamus. Despite differences in axonal projections, dopamine (DA) receptors expression and differences in excitability between MSNs from “direct” and “indirect” basal ganglia pathways, these neuronal classes have been thought as electrophysiologically very similar. Based on work with bacterial artificial chromosome (BAC) transgenic mice, here it is shown that corticostriatal responses in D1- and D2-receptor expressing MSNs (D1- and D2-MSNs) are radically different so as to establish an electrophysiological footprint that readily differentiates between them. Experiments in BAC mice allowed us to predict, with high probability (P > 0.9), in rats or non-BAC mice, whether a recorded neuron, from rat or mouse, was going to be substance P or enkephalin (ENK) immunoreactive. Responses are more prolonged and evoke more action potentials in D1-MSNs, while they are briefer and exhibit intrinsic autoregenerative responses in D2-MSNs. A main cause for these differences was the interaction of intrinsic properties with the inhibitory contribution in each response. Inhibition always depressed corticostriatal depolarization in D2-MSNs, while it helped in sustaining prolonged depolarizations in D1-MSNs, in spite of depressing early discharge. Corticostriatal responses changed dramatically after striatal DA depletion in 6-hydroxy-dopamine (6-OHDA) lesioned animals: a response reduction was seen in substance P (SP)+ MSNs whereas an enhanced response was seen in ENK+ MSNs. The end result was that differences in the responses were greatly diminished after DA depletion.
The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels.
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