NEURONAL ADAPTATIONS AND COUNTERADAPTATIONS
Susan Volman, Ph.D.
National Institute on Drug Abuse
Long-lasting alterations in neuron excitability and synaptic
function observed after exposure to drugs or alcohol may result
(1) directly from pharmacological effects, (2) indirectly by engaging brain
systems involved in learning, or (3) by compensatory, homeostatic
responses. This symposium presents research on cellular
mechanisms that regulate neural circuit function and evaluates their
relevance to addiction.
Synaptic Plasticity in the Striatum
Robert C. Malenka, M.D., Ph.D.
The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. In the dorsal striatum, neural information flows through the basal ganglia in two distinct parallel circuits, termed the direct and indirect pathways. Imbalances in neural activity between these two pathways have been proposed to underlie the profound motor deficits observed in Parkinsonís and Huntingtonís diseases. Similar direct and indirect pathways also exist in the core of the nucleus accumbens. Despite their importance, little is known about the cellular and synaptic properties of neurons in these circuits, and current hypotheses suggest that these cells may share similar forms of synaptic plasticity.
Surprisingly, we find major differences between synapses onto direct and indirect pathway striatal medium spiny neurons (MSNs). Excitatory synapses onto indirect pathway MSNs exhibit higher release probability and larger N–methyl–D–asparate (NMDA) receptor currents than direct pathway synapses. Moreover, we find that indirect pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires D2 receptor activation. In a Parkinsonís disease model, indirect pathway eCB-LTD is absent, but is rescued by a D2 receptor agonist or an inhibitor of endocannabinoid degradation. Co-administration of these drugs in vivo reduces Parkinsonian motor deficits, which suggests that the indirect pathway eCB-LTD may play a critical role in the control of movement. We discuss the implication of these findings for the adaptations in neural circuitry that occur during addiction.
The Thorny Side of Addiction: Adaptive Plasticity and Dendritic Spines
L. Judson Chandler, Ph.D.
Dendritic spines are morphologically specialized structures that receive the vast majority of central excitatory synaptic inputs. Studies have implicated changes in the size, shape, and number of dendritic spines in activity-dependent plasticity, and have further demonstrated that spine morphology is highly dependent upon the dynamic organizational and scaffolding properties of its postsynaptic density (PSD). In vitro and in vivo models of experience-dependent plasticity have linked changes in the localization of glutamate receptors at the PSD with a molecular reorganization of the PSD and alterations in spine morphology. Chronic ethanol consumption results in adaptive changes in neuronal function that manifest as tolerance, physical dependence, and addiction. A potential mechanism supporting these adaptive changes that we recently identified is the homeostatic targeting of N–methyl–D–asparate (NMDA) receptors that contains NMDA receptor 2B (NR2B) to the synapse. Prolonged ethanol exposure results in the enchancement of NR2B-containing NMDA receptors selectively at the synapse. This increase is associated with, and dependent upon, a corresponding increase in the localization of the scaffolding protein PSD-95 at the PSD, and with an actin-dependent increase in the size of dendritic spines. These observations led us to propose a molecular model for ethanol-induced plasticity at excitatory synapses in which increases in NR2B-containing NMDA receptors and PSD-95 at the PSD provide an expanded scaffolding platform for the recruitment and activation of signaling molecules that regulate spine actin dynamics, protein translation, and synaptic plasticity. This model is consistent with accumulating evidence that glutamatergic modulation of spine actin by the PSD plays a role in the aberrant plasticity of addiction.
Neuregulin Regulation of Nicotinic Acetylcholine Receptors: Links Between Smoking and Schizophrenia
Lorna W. Role, Ph.D.
[Slides not available]
The heaviest smoking populations in the world include patients with schizophrenia and depressive disorders. Research indicates that nicotine may constitute an important form of self-medication for such patients, particularly in its effects on the pathognomonic deficits of sensorimotor gating. Genetic variations in the alpha7 nicotinic acetylcholine receptor (alpha7*-nAChR) are linked with the sensory-gating deficits associated with schizophrenia. These observations have prompted speculation for comorbidity of nicotine abuse with schizophrenia. Likewise, genetic variants of Neuregulin 1 (Nrg1), which is a key regulator of alpha7*-nAChRs, have recently been associated with heritable forms of schizophrenia. These observations suggest that alpha7 and Nrg1 variants may also predispose to nicotine dependence, and prompt our proposal to test for convergent effects on Nrg1 and alpha7* expression in the comorbidity of nicotine abuse and susceptibility to neuropsychiatric disorders, such as schizophrenia. Initial tests of this hypothesis have yielded intriguing leads as to the mechanisms of nicotinic regulation of corticolimbic circuits related to attention and motivational behaviors in studies of single and compound genetically modified mice.
Behavioral studies reveal deficits in working memory and in attention gating that worsen with age and are ameliorated by nicotine administration in Nrg1tm1Lwr (+/-) mice. Likewise, initial in vivo recordings in both anesthetized and in awake-behaving animals reveal distinct patterns of baseline and nicotine-induced cortico-striatal activity in Nrg1tm1Lwr (+/-) mice compared with wild-type littermates.
If genetic epistasis of Nrg1 and alpha7*-nAChR contributes to the high comorbidity of schizophrenia and nicotine dependence, then we predict that compound heterozygotes of Nrg1 and alpha7 would provide a strong model of schizophrenia-related cognitive deficits. To date, both our electrophysiological studies of corticolimbic circuits and our behavioral analyses (open field, PPI, and T-maze) of "single hit" Nrg1/alpha7 mice affirm this idea.