It could be habit forming: drugs of abuse and striatal synaptic plasticity

doi:10.1016/S0166-2236(03)00065-1

Trends in Neurosciences

Volume 26, Issue 4, April 2003, Pages 184-192

https://doi.org/10.1016/S0166-2236(03)00065-1 Get rights and content

Abstract

Drug addiction can take control of the brain and behavior, activating behavioral patterns that are directed excessively and compulsively toward drug usage. Such patterns often involve the development of repetitive and nearly automatic behaviors that we call habits. The striatum, a subcortical brain region important for proper motor function as well as for the formation of behavioral habits, is a major target for drugs of abuse. Here, we review recent studies of long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse can exert pronounced influences on these processes, both in the striatum and in the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears to play a prominent role in early stages of drug use, whereas dopamine- and endocannabinoid-dependent synaptic plasticity in the dorsal striatum could contribute to the formation of persistent drug-related habits when casual drug use progresses towards compulsive drug use and addiction.

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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Published by Elsevier Ltd.

Trends in Neurosciences

It could be habit forming: drugs of abuse and striatal synaptic plasticity

Abstract

Section snippets

Functional organization of the striatum

Striatal physiology, drugs of abuse and dopamine

Long-term synaptic plasticity: mechanisms and involvement of dopamine and other targets for drugs of abuse

An endocannabinoid retrograde messenger in striatal LTD

Nicotinic ACh receptors activate dopamine release and facilitate LTD

Further implications: striatal LTP

Drugs of abuse and synaptic plasticity in the VTA

Concluding remarks

Neuron

Neuropsychopharmacology

Trends Neurosci.

Trends Neurosci.

Trends Neurosci.

Prog. Neurobiol.

Neuropsychopharmacology

Neuroscience

Neuroscience

Neural Netw.

Neuron

Neuroscience

Trends Neurosci.

Eur. J. Pharmacol.

Trends Neurosci.

Neuron

Neuron

Neuropharmacology

Neuron

Neuron

Neurosci. Lett.

Neuroscience

Neuropharmacology

Neurobiol. Learn. Mem.

Trends Neurosci.

Brain Res.

Molecular basis of long-term plasticity underlying addiction

Nat. Rev. Neurosci.

Addiction and the brain: the neurobiology of compulsion and its persistence

Nat. Rev. Neurosci.

Psychomotor stimulant addiction: a neural systems perspective

J. Neurosci.

Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens

Annu. Rev. Neurosci.

Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum

J. Neurosci.

Inhibitory control of the GABAergic transmission in the rat neostriatum by D2 dopamine receptors

Neuroscience

Activation of D2-like dopamine receptors reduces synaptic inputs to striatal cholinergic interneurons

J. Neurosci.

Modulation of synaptic transmission by dopamine and norepinephrine in ventral but not dorsal striatum

J. Neurophysiol.

A postsynaptic interaction between dopamine D1 and NMDA receptors promotes presynaptic inhibition in the rat nucleus accumbens via adenosine release

J. Neurosci.

Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex

J. Neurosci.

Direct actions of cannabinoids on synaptic transmission in the nucleus accumbens: a comparison with opioids

J. Neurophysiol.

Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure

Eur. J. Neurosci.

The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior

J. Neurosci.

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies

Psychopharmacology (Berl.)

Long-term synaptic depression in the striatum: physiological and pharmacological characterization

J. Neurosci.

A cellular mechanism of reward-related learning

Nature

Bi-directional changes in synaptic plasticity induced at corticostriatal synapses in vitro

Exp. Brain Res.

Dopamine-dependent synaptic plasticity in striatum during in vivo development

Proc. Natl. Acad. Sci. U. S. A.

Inhibitory control of the GABAergic transmission in the rat neostriatum by D₂ dopamine receptors

Activation of D₂-like dopamine receptors reduces synaptic inputs to striatal cholinergic interneurons

A postsynaptic interaction between dopamine D₁ and NMDA receptors promotes presynaptic inhibition in the rat nucleus accumbens via adenosine release