Potentiation Of Glutamatergic Transmission Research Articles

Cell-type specific synaptic plasticity in dorsal striatum is associated with punishment-resistance compulsive-like cocaine self-administration in mice

Addiction-related compulsion-like behavior can be modeled in rodents with drug self-administration (SA) despite harmful consequences. Recent studies suggest that the potentiation of glutamatergic transmission at the orbitofrontal cortex (OFC) to dorsal striatum (DS) synapses drives the transition from controlled to compulsion-like SA. However, the timing of the induction of this synaptic plasticity remains elusive. Here, mice were first allowed to intravenously self-administer cocaine. When mice had to endure a risk of electrical foot shock, only a fraction persevered in cocaine SA. In these persevering mice, we recorded high A/N ratios (AMPA-R/NMDA-R: α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor) in both types of spiny projection neurons (i.e., D1 and D2 dopamine receptor-expressing SPNs). By contrast, when we prepared slices at the end of the acquisition period, in all mice, the A/N was high in D1R- but not D2R-SPNs. These results indicate that the transition to compulsion-like cocaine SA emerges during the punishment sessions, where synapses onto D2R-SPNs are strengthened. In renouncing individuals, the cocaine-evoked strengthening in D1R-SPNs is lost. Our study thus reveals the cell-type specific sequence of the induction of plasticity that eventually may cause compulsion-like SA.

Experience of defeat in the social conflict induces potentiation of glutamatergic transmission in the ventral interpeduncular nucleus

Experience of defeat in the social conflict induces potentiation of glutamatergic transmission in the ventral interpeduncular nucleus

Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex

The prefrontal cortex (PFC), a region responsible for high-order cognitive functions, such as decision-making, attention and working memory, is highly influenced by stress and corticosteroid stress hormones. Recently it has been shown that acute stress affects PFC functions by potentiating glutamatergic transmission via a mechanism dependent on glucocorticoid receptor (GR) and its downstream target, serum and glucocorticoid-inducible kinase (SGK). To identify the key regulators of stress responses, we examined the role of histone deacetylase 6 (HDAC6), a unique member of the HDAC family that could regulate the GR chaperone protein heat shock protein 90 (HSP90), in the synaptic action of acute stress in PFC. We found that HDAC6 inhibition or knockdown blocked the enhancement of glutamatergic transmission and glutamate receptor trafficking by acute stress in vivo or corticosterone treatment in vitro. In addition, HDAC6 inhibition blocked the up-regulation of SGK in animals exposed to acute stress. HSP90 inhibition or knockdown produced a similar blockade of the acute stress-induced enhancement of glutamatergic signalling. These findings have identified HDAC6 as a key molecule gating the effects of acute stress on synaptic functions in the PFC.

The Mglur5 Positive Allosteric Modulator CDPPB Does not Alter Extinction or Contextual Reinstatement of Methamphetamine-Seeking Behavior in Rats

Extinction of drug-seeking behavior is a form of new and active learning. Facilitation of extinction learning is of clinical interest since cue exposure therapies for the treatment of addiction have largely been unsuccessful in preventing relapse, primarily due to the context specificity of extinction learning. Recently, several studies have shown that potentiation of glutamatergic transmission can facilitate extinction learning in rodent models of cocaine addiction. In this study we investigated the effects of the type 5 metabotropic glutamate receptor (mGluR5) positive allosteric modulator (PAM) 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction and contextual reinstatement of methamphetamine-seeking behavior. Rats were trained and allowed to self-administer methamphetamine (0.1 mg/kg/infusion) in 2 hr daily sessions in Context A where self-administration chambers had distinct tactile, visual, auditory, and olfactory cues. Next, CDPPB (60 mg/kg) or vehicle was administered prior to subsequent extinction training sessions that were conducted in modified self-administration chambers (Context B) that were Context A. Following 16 days of extinction training in Context B, animals were placed back in Context A for assessment of contextual reinstatement of methamphetamine-seeking behavior. CDPPB failed to produce significant reductions in extinction responding or in the magnitude of contextual reinstatement of methamphetamine-seeking compared to vehicle treated controls. We postulate that numerous factors, including methamphetamine-induced changes in mGluR5 receptor expression or function, may have contributed to the observed lack of effects. Although these findings initially suggest that mGluR5 PAMs may be ineffective in facilitating extinction learning or preventing context-induced relapse in methamphetamine addiction, additional studies are warranted examining effects of other mGluR5 PAMs, particularly those with improved pharmacological properties and devoid of potential side effects at higher doses.

Glutamatergic substrates of drug addiction and alcoholism

The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior. In addition, glutamatergic agents that are currently in use or are undergoing testing in clinical trials for the treatment of addiction are discussed, including acamprosate, N-acetylcysteine, modafinil, topiramate, lamotrigine, gabapentin and memantine. All drugs of abuse appear to modulate glutamatergic transmission, albeit by different mechanisms, and this modulation of glutamate transmission is believed to result in long-lasting neuroplastic changes in the brain that may contribute to the perseveration of drug-seeking behavior and drug-associated memories. In general, attenuation of glutamatergic transmission reduces drug reward, reinforcement, and relapse-like behavior. On the other hand, potentiation of glutamatergic transmission appears to facilitate the extinction of drug-seeking behavior. However, attempts at identifying genetic polymorphisms in components of glutamate transmission in humans have yielded only a limited number of candidate genes that may serve as risk factors for the development of addiction. Nonetheless, manipulation of glutamatergic neurotransmission appears to be a promising avenue of research in developing improved therapeutic agents for the treatment of drug addiction and alcoholism.

Stress and Drugs and Midbrain Synapses

Different drugs of abuse act on different molecular targets and mediate distinct effects on physiology and behavior. All of the classes of addictive substances, however, have a common effect of increasing dopamine release from a group of neurons whose cell bodies are in a region of the midbrain called the ventral tegmental area. This suggests that activation of these neurons may be involved in the mechanisms underlying addiction. Cocaine produces long-term potentiation (LTP)-like increases in excitatory synaptic transmission to midbrain dopaminergic neurons. Saal et al. examined the effects of different classes of addictive drugs with distinct molecular mechanisms, as well as the effects of stress, which can facilitate addiction and elicit relapse, to see if they produced similar changes. The authors measured the ratio of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated synaptic currents to N -methyl-D-aspartate (NMDA)-receptor mediated currents as a marker of LTP, using whole-cell recording from dopaminergic neurons in slices of mouse midbrain 24 hours after in vivo drug exposure. Cocaine, amphetamine, morphine, nicotine, and ethanol all increased the AMPA receptor to NMDA receptor excitatory post-synaptic potential (EPSP) ratio, whereas fluoxetine and carbemazepine, psychoactive drugs that are not addictive, did not. Acute stress, caused by a swim in cold water, elicited an even greater increase in the AMPA receptor to NMDA receptor EPSP ratio than did the drugs of abuse. The effects of stress on potentiation of glutamatergic transmission, but not those of cocaine, were blocked by a glucocorticoid antagonist, indicating that cocaine's effects were not mediated through a stress response. See the Perspective by Kauer. D. Saal, Y. Dong, A. Bonci, R. C. Malenka, Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37 , 577-582 (2003). [Online Journal] J. A. Kauer, Addictive drugs and stress trigger a common change at VTA synapses, Neuron 37 , 449-450 (2003). [Online Journal]

Long-term potentiation of glutamatergic transmission and epileptiform activity induced by transient episodes of anoxia in slices of rats hippocampus field CA1.

Long-term potentiation of glutamatergic transmission and epileptiform activity induced by transient episodes of anoxia in slices of rats hippocampus field CA1.