Anaplasticity and changes in synaptic transmission

Activity-dependent long-term depression (LTD) and long-term potentiation (LTP) of synaptic-transmission are the two principal forms of synaptic plasticity that permit strengthening (LTP) or weakening (LTD) of synapses in a dynamic that allows the adaptation of neuronal circuits necessary to respond to an ever-changing environment. Drugs of abuse modify LTP and LTD in different areas of the mesocorticolimbic system.

In a study published by Kazanetsz et al it is shown that during the acquisition phase synaptic plasticity in the nucleus accumbens is not impaired by cocaine, supporting a role for NMDAR-LTP in de the NAC in learning new reward-response associations. Once the learning has been consolidated, LTD is suppressed in all subjects. However, subsequently, a normal NMDAR-LTD is progressively recovered in animals that maintain a controlled drug intake, whereas it is persistently lost in animals undergoing the transition to addiction. This persistent impairment in LTD could explain the loss of control on drug intake observed in Addict rats. LTD in the NAC is considered important in rescaling synapses that were enhanced during acquisition of motor responses and cue-reward associations, allowing those synapses to encode furute associations and restore flexibility to neural circuits. The persistent inability to rescale synapsis in Addict animals may render drug-seekling behavior consistently resistant to modulation by environmental contingencies, finally resulting in loss of control over drug intake. 

Our results also provide unanticipated insight into the type of homeostatic alterations that characterize Addicts. We expected, as largely assumed in the field, to discover specific pathological adaptation –a particular phenotype- characterizing synaptic plasticity in Addicts. In contrast, the transition to addiction as associated, at least in the NAC, with a form of anaplasticity, i.e., the incapacity of Addicts to counteract initial drug-induced impairments. 

The anaplasticity of Addict rats is relevant to  revising conceptualizations of the transition to addiction, currently seen as the progressive development of specific brain adaptations that lead to loss of control over drug intake. Our data suggest that instead, the transition to addiction could be mediated by the incapacity to engage the active processes that allow control of drug intake. After a prolonged exposure to drugs, all the subjects are probably at the point of losing control over drug-intake behavior, as shown by the loss of LTD in all rats. This probably corresponds to the situation when an individual engaged in sustained drug use experiences the sensation that “it is becoming too much”and that “a line is being crossed”. Fortunately, for most individuals, the brain adapts to recover a normal plasticity and allows learning to control drug intake. In contrast, the anaplasticity that characterizes addicts makes them enter a downward spiral in which drug-associated stimuli, which can no longer be over-ridden by other associations, gain more and more power in controlling behavior, finally leading to the compulsive drug intake that characterizes addiction.

 All drugs of abuse have in common that they cause surges in dopamine concentration in the mesolimbic reward system and elicit synaptic plasticity in dopaminergic (DA) neurons of the ventral tegmental area (VTA). Plasticity is defined as the activity-dependent modifications of synapses and/or neural circuits at the central nervous system level. Previous work has shown that plasticity at excitatory glutamatergic synapses plays a critical role in memory acquisition and consolidation. Several signal transduction cascades, initiated by Ca2+ influx through NMDA receptors, mediate a rapid and sustained enhancement of glutamatergic synapses by regulating local synaptic strength through the modulation of AMPA receptors number and function, in a process known as long-term potentiation (LTP).

It is of our interest to note that drug-evoked synaptic plasticity in the VTA appears at excitatory afferents onto DA neurons of the VTA already 24 h after a single injection of addictive drugs (Ungless et al., 2001; Saal et al., 2003). In particular, acute exposure to cocaine in vivo induces NMDAR-dependent delayed AMPA receptor potentiation of dopaminergic neurons in the VTA (Argilli et al., 2008). Moreover, Brown et al., 2010 showed that in mice where the effect of cocaine on DAT was genetically blocked, there was no AMPAR redistribution following administration of cocaine. Furthermore, the researchers observed that other addictive drugs, such as morphine and nicotine, also cause a similar AMPAR redistribution. Taken together, these results suggest that 1) DA signaling within the VTA drives AMPA receptor distribution; and 2) posits glutamate signaling and synaptic plasticity in the mesolimbic DA circuit as an underlying mechanism for drug addiction.

References: 

Ungless MA, Whistler JL, Malenka RC, Bonci A. (2001). Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583-587.

Saal D., Dong Y., Bonci A., Malenka RC. (2003). Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37: 577-582.

Malinow R and Malenka RC. (2002). AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25: 103-26.

Kasanetz F, Deroche-Gamonet V, Berson N, et al. (2012). Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science, 2012:328:1709-1712.