No abstract

We studied the influence of cocaine use on the structure of neurons in brain regions that contribute to its rewarding effects by allowing rats to self-administer cocaine (0.33 mg/infusion) for 1 h a day for 1 month. Control animals were left undisturbed or allowed to work for food for the same period of time. After an additional 1 month drug-free period the brains were processed for Golgi-Cox staining. In rats that self-administered cocaine, but not rats that worked for food, there was a significant increase in dendritic branching and in the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal (but not occipital) cortex. There was also a 2.6-fold increase in the incidence of spines with multiple heads (branched spines) on medium spiny neurons. Finally, in the prefrontal cortex some of the apical dendrites of pyramidal cells appeared misshaped, having large bulbous structures on their terminal tips. We speculate that cocaine self-administration experience alters patterns of synaptic connectivity within limbocortical circuitry that is thought to contribute to cocaine's incentive motivational effects and may have neuropathological effects in frontal areas involved in decision making and judgment. Together, these two classes of drug-induced neuroadaptations may contribute to the development of addiction.

We studied the effects of self‐administered (SA) vs. experimenter‐administered (EA) morphine on dendritic spines in the hippocampal formation (CA1 and dentate), nucleus accumbens shell (NAcc‐s), sensory cortex (Par1 and Oc1), medial frontal cortex (Cg3), and orbital frontal cortex (AID) of rats. Animals in the SA group self‐administered morphine in 2‐h sessions (0.5 mg/kg/infusion, i.v.) for an average of 22 sessions and animals in the EA group were given daily i.v. injections of doses that approximated the total session dose for matched rats in Group SA (average cumulative dose/session of 7.7 mg/kg). Control rats were given daily i.v. infusions of saline. One month after the last treatment the brains were processed for Golgi‐Cox staining. In most brain regions (Cg3, Oc1, NAcc‐s) morphine decreased the density of dendritic spines, regardless of mode of administration (although to a significantly greater extent in Group SA). However, only SA morphine decreased spine density in the hippocampal formation and only EA morphine decreased spine density in Par1. Interestingly, in the orbital frontal cortex morphine significantly increased spine density in both Groups SA and EA, although to a much greater extent in Group SA. We conclude: 1) Morphine has persistent (at least 1 month) effects on the density of dendritic spines in many brain regions, and on many different types of cells (medium spiny neurons, pyramidal cells, and granule cells); 2) The effect of morphine on spine density (and presumably synaptic organization) varies as a function of both brain region and mode of drug administration; and 3) The ability of morphine to remodel synaptic inputs in a regionally specific manner may account for the many different long‐term sequelae associated with opioid use. Synapse 46:271–279, 2002. © 2002 Wiley‐Liss, Inc.

Drugs of abuse and many other kinds of experiences share the ability to alter the morphology of neuronal dendrites and spines, the primary site of excitatory synapses in the brain. We hypothesized, therefore, that exposure to psychostimulant drugs might influence later experience-dependent structural plasticity. We tested this hypothesis by treating rats repeatedly with amphetamine or cocaine and then housing them in either a complex environment or standard laboratory cages for 3-3.5 mo. The brains were processed for Golgi-Cox staining, and the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the nucleus accumbens and pyramidal cells in the parietal cortex were quantified. On most measures, prior treatment with amphetamine or cocaine interfered with the ability of experience in a complex environment to increase dendritic arborization and spine density. We conclude that in some brain regions, repeated exposure to psychomotor-stimulant drugs limits the ability of later experience to produce this form of synaptic plasticity, which may contribute to the persistent behavioral and cognitive deficits associated with drug abuse.complex environment ͉ behavioral sensitization ͉ dendrites ͉ dendritic spines T he idea that experience-dependent changes in behavior are due to alterations in the physical structure of neurons can be traced to Ramon y Cajal (1), and Hebb (2) made this a central tenet of his inf luential neuropsychological theory. The first direct experimental evidence for experience-dependent changes in brain structure came from studies by Rosenzweig and colleagues in the 1960s (3), who compared the brains of animals housed in a relatively complex environment with those housed in standard laboratory cages. Since that time, there have been many demonstrations that experience in complex environments and learning experiences can increase the length of dendrites and the density of dendritic spines on cells throughout the neocortical mantle, in the hippocampus and striatum, and can produce associated changes in patterns of synaptic connectivity (4 -8).The ability of experience to alter dendritic structure is generally considered advantageous and is thought to be the primary mechanism by which past experience inf luences subsequent behavior (for reviews, see refs. 5-7 and 9). However, alterations in dendritic structure are also associated with pathological states (10, 11). In particular, we have shown that repeated treatment with psychostimulant drugs, such as amphetamine, cocaine, or nicotine, produces long-lasting increases in dendritic branching and spine density in some brain regions, changes that may be related to the development of behavioral sensitization and compulsive patterns of drugseeking behavior (12-15).That environmental manipulations and drugs of abuse can have apparently similar effects on neuronal morphology raises questions regarding the extent to which these two kinds of experiences may interact. Indeed, given that there likely are limits on this form of n...