Trends in Neurosciences
It could be habit forming: drugs of abuse and striatal synaptic plasticity
Section snippets
Functional organization of the striatum
The striatum is the major entry into the basal ganglia, receiving inputs from all areas of cortex, as well as afferents from the thalamus and limbic structures such as the hippocampus and amygdala [7]. The glutamate-mediated excitatory drive from these afferents activates striatal neurons that, in turn, alter the activity of neurons throughout the entire basal ganglia circuitry (Fig. 1a). Control of cortical input to the striatum is, thus, crucial for influencing basal ganglia physiology and
Striatal physiology, drugs of abuse and dopamine
Glutamatergic synaptic input to striatal neurons is modulated by several neurotransmitters and neuropeptides, many of the receptors for which are targeted by drugs of abuse (Table 1). Of particular significance to drug addiction is dopamine. Acute exposure to almost all known drugs of abuse increases striatal extracellular levels of dopamine, either by acting directly on dopaminergic terminals or by increasing the activity of VTA neurons 2, 5. Yet, the molecular and cellular mechanisms by which
Long-term synaptic plasticity: mechanisms and involvement of dopamine and other targets for drugs of abuse
Persistent changes in striatal function during the progression of addiction might be brought about by mechanisms of long-lasting synaptic plasticity. Recent studies have revealed that in the striatum, such mechanisms are strongly regulated by dopamine signaling and are also influenced by other signaling systems that are targets for drugs of abuse.
High-frequency activation of cortical inputs to striatal neurons can produce either long-term depression (LTD) or long-term potentiation (LTP) of
An endocannabinoid retrograde messenger in striatal LTD
It has been shown that dopamine-dependent striatal LTD is expressed as a long-lasting decrease in the probability of glutamate release onto MSNs 27, 28, 39, a finding which led to the postulation that a retrograde messenger translates the known postsynaptic mechanisms of LTD induction 39, 40 into persistent changes in presynaptic function. Recent studies have indicated that a postsynaptically released endocannabinoid acts as such a retrograde messenger, and that the subsequent activation of CB1
Nicotinic ACh receptors activate dopamine release and facilitate LTD
Nicotinic ACh receptors appear to play a permissive role in LTD induction. We have observed that blockade of nicotinic ACh receptors prevents LTD in striatal slices, but this effect can be overcome by application of dopamine-transport inhibitors, which would have the effect of increasing synaptic dopamine during high-frequency stimulation [51]. This finding indicates that nicotinic ACh receptors are not absolutely required for LTD induction but demonstrates an important interaction between ACh
Further implications: striatal LTP
In the foregoing discussion, we have emphasized the impact that drugs of abuse might have on striatal LTD. However, glutamatergic synapses in the striatum are also capable of expressing LTP that is dependent on NMDA-receptor activation 9, 37, 56. It is known that dopamine, acting through D1-like receptors, plays a prominent role in this form of plasticity. Thus, drugs that alter release of dopamine and glutamate in the striatum might alter LTP as well as LTD, and it could indeed be a
Drugs of abuse and synaptic plasticity in the VTA
Other recent studies have focused on influences by drugs of abuse on synaptic function and/or plasticity in the VTA. Interestingly, the effects of psychostimulants on long-term synaptic plasticity in the VTA seem to favor enhanced dopamine signaling in the striatum. Application of amphetamine to VTA slices was found to block LTD of glutamate inputs [57] and to enhance AMPA-receptor sensitivity [58]. By contrast, nicotine appears to induce LTP of glutamatergic synaptic input, thereby enhancing
Concluding remarks
There is growing evidence that processes of long-lasting synaptic plasticity in the striatum and dopaminergic midbrain can be significantly influenced by the molecular actions of many abused drugs. Thus, synaptic plasticity in these circuits could represent a substrate upon which drugs of abuse act to induce the persistent alterations in behavior that are typical of addictive states 2, 3, 4. By highlighting the role of the striatum in learning and memory of habitual behaviors, this review
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