Amphetamine-induced changes in dendritic morphology in rat forebrain correspond to associative drug conditioning rather than nonassociative drug sensitization.

BACKGROUND: Systemic exposure to amphetamine (AMPH) leads to a number of long-lasting neuroadaptations including changes in dendritic morphology in rat forebrain. It remains unknown whether these changes relate to associative drug conditioning or to nonassociative drug sensitization, two forms of plasticity produced by systemic exposure to AMPH. METHODS: We compared the behavioral, neuronal, and morphologic consequences of exposing rats to intraperitoneal (IP) AMPH to those of exposure to AMPH applied to the ventral tegmental area (VTA), infusions that sensitize AMPH-induced locomotion and nucleus accumbens (NAcc) DA overflow but do not produce drug conditioning. RESULTS: Both IP and VTA AMPH exposure sensitized locomotion and NAcc DA overflow, but only IP AMPH exposure produced conditioned locomotion. Importantly, whereas IP AMPH exposure increased spine density and dendritic length and branching in the NAcc, exposure to VTA AMPH produced the opposite effects. A similar differentiation of effects was observed in cortical areas. CONCLUSIONS: Together these findings suggest that the morphological changes seen following IP AMPH exposure reflect associative drug conditioning rather than nonassociative drug sensitization. The decreases observed in the NAcc of VTA AMPH exposed rats may reflect the inability of these infusions to support conditioning.

Chronic treatment with Delta-9-tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats.

The potential of repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) to produce long-lasting changes in synaptic connections in a manner similar to other drugs of abuse was evaluated in Sprague-Dawley rats. For 12 days, rats received two i.p. injections per day (8 h apart) of vehicle, a low dose of Delta(9)-THC (0.5 mg/kg), or escalating doses of Delta(9)-THC (0.5-4.0 mg/kg). Thirty days later, they were evaluated for sensitized locomotor activity (during the night cycle) for 60 min on each of three trials. Using a within-groups design, rats were tested following an injection of vehicle, 0.5 mg/kg Delta(9)-THC or 2.0 mg/kg Delta(9)-THC. The rats showed no evidence of sensitized locomotor activity in any group. Twenty-four hours after the final sensitization test, their brains were removed and then processed for Golgi-Cox staining. Prior exposure to Delta(9)-THC (both the low dose and the escalating doses) increased the length of the dendrites as well as the number of dendritic branches in the shell of the nucleus accumbens and in the medial prefrontal cortex, but not in the hippocampus, striatum, orbital frontal cortex, parietal cortex, or occipital cortex. These results are similar to those evident in brains of rats sensitized to amphetamine, and support previous findings that cannabinoids promote DA activity in the mesolimbic DA system.

Neural and behavioral plasticity associated with the transition from controlled to escalated cocaine use.

BACKGROUND: Rats given extended access to cocaine develop several symptoms of addiction, including a gradual escalation of drug intake, whereas rats given limited access do not. We asked here whether extended access to cocaine also produces drug-induced sensitization, a form of neurobehavioral plasticity implicated in addiction. METHODS: Rats were given limited (1 hour/session) or extended access (6 hours/session) to self-administered cocaine. Following a period of abstinence, rats were selected at random for assessment of their psychomotor response to cocaine or drug-seeking during extinction or for anatomic studies. RESULTS: When re-exposed to cocaine, rats allowed extended drug access showed greater drug-seeking behavior and were hypersensitive (sensitized) to the psychomotor activating effects of cocaine compared with rats given limited access. Extended access to cocaine was also associated with a greater increase in the density of dendritic spines on neurons specifically in the core of the nucleus accumbens (and not in the shell or medial or orbital frontal cortex). CONCLUSIONS: The transition from stable to escalated cocaine use, a hallmark of addiction, is associated with especially robust behavioral sensitization and synaptic reorganization in the core of the nucleus accumbens.

Opposite effects of amphetamine self-administration experience on dendritic spines in the medial and orbital prefrontal cortex.

We studied the long-term effects of amphetamine self-administration experience (or sucrose reward training) on dendritic morphology (spine density) in nucleus accumbens (Nacc), medial (MPC) and orbital prefrontal cortex (OFC), and hippocampus (CA1 and dentate). Independent groups of rats were trained under a continuous schedule of reinforcement to nose-poke for infusions of amphetamine (0.125 mg/kg/inf) or to receive sucrose pellets during 2 h daily test sessions for 14-20 days. One month after the last training session, the brains were collected and processed for Golgi-Cox staining. We found that: (i) amphetamine self-administration experience selectively increased spine density on medium spiny neurons in the Nacc and on pyramidal neurons in the MPC; (ii) in contrast, amphetamine self-administration decreased spine density in the OFC, whereas sucrose-reward training increased spine density; and (iii) both amphetamine self-administration and sucrose-reward experience increased spines in the CA1, but had no effect in the dentate gyrus. Thus, amphetamine self-administration experience produces long-lasting and regionally-selective morphological alterations in rat forebrain--alterations that may underlie some of the persistent psychomotor, cognitive and motivational consequences of chronic drug exposure.

Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens.

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.

Environmental complexity has different effects on the structure of neurons in the prefrontal cortex versus the parietal cortex or nucleus accumbens.

Complex housing has been used widely as a model of experience-dependent change. Animals housed in complex environments typically show synaptogenesis throughout the sensory and motor cortex as well as the striatum and hippocampus, and thus it is generally assumed that such changes are likely to be found throughout the cerebrum. The purpose of the present study was to determine whether persistent alterations of dendritic morphology would be found in two regions that had previously not been examined, namely, the medial prefrontal region (Cg3) and nucleus accumbens (NAcc). The results show that housing female rats in complex environments for 3.5 months increased dendritic arborization on medium spiny neurons in the NAcc and on pyramidal cells in the somatosensory cortex (Par 1), but not in Cg3. Environmental complexity increased spine density in all three areas, however. The failure to find increased dendritic length or branching in Cg3 was unexpected. Thus, the data suggest that complex housing may not engage prefrontal neurons in the same manner as neurons in sensory or motor areas. It appears that complex housing may not produce generalized changes in cerebral morphology. The data further suggest that it is prudent to measure both dendritic length and spine density in studies of experience-dependent effects on synaptic plasticity.

Experience-dependent changes in dendritic arbor and spine density in neocortex vary qualitatively with age and sex.

Male and female Long-Evans hooded rats were placed in the complex environments for 3 months either at weaning (22 days), in young adulthood (120 days), or in senescence (24 months). The dendritic morphology of both the apical and basilar fields of layer III pyramidal cells was analyzed in both parietal and visual cortex. There were two novel results. First, although spine density was increased significantly with complex-housing in adulthood, it was decreased significantly by the same housing during development. Second, dendritic length was increased in both parietal and occipital cortex at all ages in males and was increased in adult females as well, but juvenile females showed no change in dendritic length in the occipital cortex and only a small effect on the apical field in parietal cortex. Thus, there are qualitative differences in the changes in spine density at different ages and the dendritic changes in response to complex versus isolated housing vary with sex, and in females, the changes vary with age as well. These results may explain some of the apparent inconsistencies in reports of spine and dendrite changes in the literature.

Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats.

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.