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.

Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial. A critical component in DA actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA-glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA-D1 synergism required postsynaptic intracellular Ca 2ϩ and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2-NMDA interaction was also blocked by the GABA A antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons. In contrast, the D2-AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C-IP 3 and intracellular Ca 2ϩ at a postsynaptic level. Thus, the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability are mediated by multiple intracellular mechanisms and by activation of GABA A receptors, depending on the glutamate receptor subtypes involved.

Traditionally, animal models of schizophrenia were predominantly pharmacological constructs focused on phenomena linked to dopamine and glutamate neurotransmitter systems, and were created by direct perturbations of these systems. A number of developmental models were subsequently generated that allowed testing of hypotheses about the origin of the disease, mimicked a wider array of clinical and neurobiological features of schizophrenia, and opened new avenues for developing novel treatment strategies. The most thoroughly characterized (~100 primary research articles) is the neonatal ventral hippocampal lesion (NVHL) model, which is the subject of this review. We highlight its advantages and limitations, and how it may offer clues about the extent to which positive, negative, cognitive, and other aspects of schizophrenia, including addiction vulnerability, represent interrelated pathophysiological mechanisms.

Neurons in the basal ganglia output nuclei display rhythmic burst firing after chronic nigrostriatal lesions. The thalamocortical network is a strong endogenous generator of oscillatory activity, and the striatum receives a massive projection from the cerebral cortex. Actually, the membrane potential of striatal projection neurons displays periodic shifts between a very negative resting potential (down state) and depolarizing plateaus (up states) during which they can fire action potentials. We hypothesized that an increased excitability of striatal neurons may allow transmission of cortical slow rhythms through the striatum to the remaining basal ganglia in experimental parkinsonism. In vivo intracellular recordings revealed that striatal projection neurons from rats with chronic nigrostriatal lesions had a more depolarized membrane potential during both the down and up states and an increased firing probability during the up events. Furthermore, lesioned rats had significantly fewer silent neurons than control rats. Simultaneous recordings of the frontal electrocorticogram and membrane potential of striatal projection neurons revealed that the signals were oscillating synchronously in the frequency range 0.4-2 Hz, both in control rats and rats with chronic nigrostriatal lesions. Spreading of the slow cortical rhythm is limited by the very low firing probability of control rat neurons, but a slow oscillation is well reflected in spike trains of ϳ60% of lesioned rat neurons. These findings provide in vivo evidence for a role of dopamine in controlling the flow of cortical activity through the striatum and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.

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.