Persistent Structural Modifications in Nucleus Accumbens and Prefrontal Cortex Neurons Produced by Previous Experience with Amphetamine

Abstract

Experience-dependent changes in behavior are thought to involve structural modifications in the nervous system, especially alterations in patterns of synaptic connectivity. Repeated experience with drugs of abuse can result in very long-lasting changes in behavior, including a persistent hypersensitivity (sensitization) to their psychomotor activating and rewarding effects. It was hypothesized, therefore, that repeated treatment with the psychomotor stimulant drug amphetamine, which produces robust sensitization, would produce structural adaptations in brain regions that mediate its psychomotor activating and rewarding effects. Consistent with this hypothesis, it was found that amphetamine treatment altered the morphology of neurons in the nucleus accumbens and prefrontal cortex. Exposure to amphetamine produced a long-lasting (Ͼ1 month) increase in the length of dendrites, in the density of dendritic spines, and in the number of branched spines on the major output cells of the nucleus accumbens, the medium spiny neurons, as indicated by analysis of Golgi-stained material. Amphetamine treatment produced similar effects on the apical (but not basilar) dendrites of layer III pyramidal neurons in the prefrontal cortex. The ability of amphetamine to alter patterns of synaptic connectivity in these structures may contribute to some of the long-term behavioral consequences of repeated amphetamine use, including amphetamine psychosis and addiction.

Richter and sodium appetite: From adrenalectomy to molecular biology

“…Such changes in morphology are similar to those that occur in the nucleus accumbens after repeated use of amphetamines (Robinson and Kolb 1997). Interestingly, repeated use of amphetamines increases or sensitizes locomotor responses (Robinson and Kolb 1997), similar to the way that prior treatments with furosemide increases or sensitizes the salt intake that follows sodium depletion (Sakai et al 1987(Sakai et al , 1989. The similar morphological and behavioral changes caused by furosemide and amphetamines led to subsequent studies examining cross-sensitization.…”

“…Specifically, it was found that furosemide administration increased dendritic branching and spines of neurons within the shell of nucleus accumbens (Roitman et al, 2002). Such changes in morphology are similar to those that occur in the nucleus accumbens after repeated use of amphetamines (Robinson and Kolb 1997). Interestingly, repeated use of amphetamines increases or sensitizes locomotor responses (Robinson and Kolb 1997), similar to the way that prior treatments with furosemide increases or sensitizes the salt intake that follows sodium depletion (Sakai et al 1987(Sakai et al , 1989.…”

Impairments of Reversal Learning and Response Perseveration after Repeated, Intermittent Cocaine Administrations to Monkeys

“…Repetitive administrations of cocaine to monkeys produced impairments of reversal learning that persist even after cessation of drug administration. Additional studies may indicate how drug-induced changes in cortical neuron morphology (Robinson and Kolb 1997;Robinson et al 2001), signal transduction mechanisms (Nestler and Aghajanian 1997), cortical-subcortical physiological interactions (Onn and Grace 2000) or excitatory amino acid and monoaminergic neurotransmission (Wolf 1998;Robbins and Everitt 1999;Berke and Hyman 2000;Vanderschuren and Kalivas 2000) contribute to this form of addiction-related psychopathology.…”

“…Volkow and Fowler 2000;London et al 2000). Second, chronic drug administration affects the neurochemistry and anatomy of these brain regions in animal models (Nestler and Aghajanian 1997;Robinson and Kolb 1997;Wolf 1998;Berke and Hyman 2000; Vandershuren and Kalivas 2000;Robinson et al 2001 (Post et al 1976), altered incentive motivation (Shippenberg and Heidbreder 1995;Taylor and Horger 1999;Robbins and Everitt 1999) and impaired cognitive and executive function (Jentsch et al 1997(Jentsch et al , 2000Rogers et al 1999;Robbins and Everitt 1999;Grant et al 2000;Ornstein et al 2000) after chronic stimulant drug administration.Because of its important role in decision-making (Bechara et al 2000) and inhibitory control over pre-potent behavior (Roberts and Wallis 2000), an involvement of ventromedial regions of the frontal cortex in drug abuse has been proposed. In essence, impairments of frontal lobe function are thought to effectively 'un-gate' subcortically-mediated, conditioned tendencies (such as established instrumental responses to obtain and consume drugs), resulting in the compulsive drug seeking and taking that characterize addiction (Jentsch and Taylor 1999).…”

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…In all studies to date, both non-contingent and contingent cocaine or amphetamine administration were found to increase spine density, as well as dendritic branching on medium spiny GABAergic neurons within both the shell and core subregions of the NAC [198][199][200][201][202][203][204][205][206][207]. Similarly, repeated treatment with both psychomotor stimulants increase spine density and branching of the apical, and to a lesser extent the basalar, dendrites of glutamatergic pyramidal neurons within the PFC [198][199][200][201]204,205]. These structural data are consistent with greater levels of filamentous actin (Factin) within the NAC following both acute exposure to and withdrawal from repeated cocaine exposure [129].…”