C.11 - VENTROMEDIAL PREFRONTAL CORTEX PYRAMIDAL CELLS HAVE A TEMPORAL DYNAMIC ROLE IN RECALL AND EXTINCTION OF COCAINE-ASSOCIATED MEMORY

In addicts, associative memories related to the rewarding effects of drugs of abuse can evoke powerful craving and drug seeking urges, but effective treatment to suppress these memories is not available. Detailed insight into the neural circuitry that mediates expression of drug-associated memory is therefore of crucial importance. Substantial evidence from rodent models of addictive behavior points to the involvement of the ventromedial prefrontal cortex (vmPFC) in conditioned drug seeking, but specific knowledge of the temporal role of vmPFC pyramidal cells is lacking. To this end, we used an optogenetics approach to probe the involvement of vmPFC pyramidal cells in expression of a recent and remote conditioned cocaine memory. In mice, we expressed Channelrhodopsin-2 (ChR2) or Halorhodopsin (eNpHR3.0) in pyramidal cells of the vmPFC and studied the effect of activation or inhibition of these cells during expression of a cocaine-contextual memory on days 1–2 (recent) and ∼3 weeks (remote) after conditioning. Whereas optical activation of pyramidal cells facilitated extinction of remote memory, without affecting recent memory, inhibition of pyramidal cells acutely impaired recall of recent cocaine memory, without affecting recall of remote memory. In addition, we found that silencing pyramidal cells blocked extinction learning at the remote memory time-point. We provide causal evidence of a critical time-dependent switch in the contribution of vmPFC pyramidal cells to recall and extinction of cocaine-associated memory, indicating that the circuitry that controls expression of cocaine memories reorganizes over time

Ventral Striatopallidal Regulation of Cocaine Addiction

Addiction is characterized by a recurrent pattern of relapse to drug seeking and drug use. This behavior is driven by neuronal activity in the nucleus accumbens and ventral pallidum (VP). Nucleus accumbens dopamine D1 and D2 receptor expressing medium spiny neurons (D1-/D2-MSN) both project to the VP, and we investigated the effects of cocaine self administration on D1-VP and D2-VP projections (see: Chapter III). After cocaine self-administration, we observed a synaptic loss of function in the D2-VP projection, and further reducing D2-VP functioning augmented the motivation to seek cocaine. Activating D1-VP projections also increased reinstatement. These data indicate that cocaine induced weakening of D2-VP pathway predisposes animals to relapse. D2-MSN exclusively project to the VP, whereas D1-MSN also project to the ventral midbrain (VM). We investigated whether D1-MSN collateralize between the VP and VM, and tested the involvement of D1-VP and D1-VM projections during reinstatement of cocaine seeking (see: Chapter IV). Surprisingly, nucleus accumbens D1-MSN heavily collateralize between the VP and VM, but only D1-VP projections regulate cocaine seeking. These data further implicate the D1-VP pathway as a critical regulator of relapse to cocaine seeking. Besides a major population of GABAergic neurons (VP-GABA), the VP also contains a substantial number of glutamatergic neurons (VP-Glu). We used retrograde rabies tracing to investigate the innervation of VP-Glu and VPGABA neurons by D1- and D2-MSN, and used chemogenetics to see whether these cells differentially drive reinstatement. We also investigated whether cocaine alters the synaptic inputs onto these neurons (see: Chapter V). VP-Glu neurons inhibit reinstatement. Furthermore, VP-GABA neurons drive drug seeking and taking behavior, but do not mediate reinstatement. Instead, a small subset of VP-GABA neurons that co-express enkephalin (VP-Penk) drive reinstatement. Inhibitory inputs onto VP-GABA neurons originate from both D1- and D2-MSN and are reduced after cocaine self-administration. Meanwhile VP-Penk and VP-Glu neurons are preferentially innervated by D1-MSN, and inhibitory inputs onto VP-Penk neurons, but not VP-Glu neurons, are increased following cocaine self-administration. Combined these data indicate that cued reinstatement is driven by D1-VP projections onto VP-Glu and VP-Penk neurons, and they place the VP as a central component of basal ganglia circuits controlling addiction

Glutamatergic systems and memory mechanisms underlying opioid addiction

Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse, and glutamatergic neurotransmission is essential for the formation and maintenance of these memories. In this review, we discuss the mechanisms by which gluta-mate, dopamine, and opioid signaling interact to mediate the primary rewarding effects of opioids, and cover the glutamatergic systems and circuits that mediate the expression, extinc-tion, and reinstatement of opioid seeking over the course of opioid addiction

Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior.

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking

Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior.

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking