Edward Castañeda

Long-term monoamine depletion, differential recovery, and subtle behavioral impairment following methamphetamine-Induced neurotoxicity

Squads of rats were assayed at three intervals following MA-induced neurotoxicity to investigate the persistence of monoamine deficits, the potential for monoamine recovery, and spatial task abilities. At 48, 139, and 237 days postinjection, MA animals showed significant monoamine depletions compared with controls. Investigating percent depletions (MA/control) across time showed monoamine recovery in some structures. Initially, 5-HT within medial prefrontal cortex (MPFC), caudate (CdN), and hippocampus (HPC) was reduced to 30% of control levels. By 237 days, MPFC and CdN levels were elevated to 70%. Similarly, initial CdN DA reductions (30% of control levels) showed recovery to 80% by 237 days. These findings support neurochemical recovery following MA neurotoxicity. However, the persistent depression of HPC 5-HT suggests that not all structures recover equally. The HPC did show elevated turnover (metabolite/neurotransmitter) over time, suggesting a unique compensatory response. MA treatment also produced an impairment in the Morris water-maze place task at 65 days postinjection. No impairments were observed in water-maze moving platform or place task at 79 and 165 days postinjection, respectively, or in T-maze alternation. The possibility that partial recovery in tissue monamine levels underlies the sparing of function and behavioral improvement is discussed.

Dopamine Overflow in the Nucleus Accumbens during Extinction and Reinstatement of Cocaine Self-Administration Behavior

Both cocaine and cocaine-associated stimuli can reinstate extinguished self-administration behavior in animals. It has been suggested that reinstatement of drug-seeking behavior may be mediated by enhanced dopamine (DA) neurotransmission. To examine this hypothesis, DA overflow was measured in the nucleus accumbens (NAc) of rats during both extinction and cocaine-induced reinstatement of self-administration behavior. Rats were either allowed to self-administer cocaine for 3 hours daily for 14 days, or they received yoked administration of saline. A stimulus light above the lever was illuminated during drug delivery. Baseline DA overflow was measured in the NAc, using in vivo microdialysis 7 to 8 days after the last self-administration session. The rats were then placed into the operant chambers and allowed to respond in extinction for 90 minutes, during which responses resulted in presentation of the stimulus light. The rats then received a cocaine injection that reinstated self-administration behavior. Contrary to our hypothesis, cocaine-experienced animals exhibited less DA overflow in the NAc relative to controls during both extinction and reinstatement.

Dopamine depletion in neonatal rats: effects on behavior and striatal dopamine release assessed by intracerebral microdialysis during adulthood.

Rats depleted of dopamine (DA) by intraventricular 6-hydroxydopamine (6-OHDA) in infancy show behavioral impairments as adults, but their basic sensory-motor functions and feeding abilities are intact; at least relative to the pronounced deficits seen in rats given similar treatment in adulthood. Here we investigate whether presynaptic changes culminating in enhanced DA release are present in adult rats that received neonatal damage, and whether these are of a sufficient magnitude to contribute to the sparing of function. We used microdialysis in rats during the resting state, walking on a treadmill, and after a systemic injection of amphetamine. It was found that neonatal 6-OHDA produced a nearly complete (less than 1% of control) depletion of DA in postmortem tissue, but this was not accompanied by a comparable decline in the basal extracellular concentrations of DA, which were only reduced by 12-54% of control values. In contrast, the extracellular concentrations of DA metabolites were greatly reduced, reflecting the post-mortem tissue concentrations of DA. Nevertheless, neonatally depleted animals were markedly deficient in their ability to respond to an amphetamine challenge, both behaviorally and in their ability to further increase DA release. Thus, following neonatal DA depletion there appear to be extensive changes in the few remaining DA terminals that are sufficient to maintain relatively high extracellular (and presumably synaptic) concentrations of DA during the resting state, but the capacity of the remaining DA neurons to respond to increased demand is very limited. This presynaptic compensatory response may play a role in the sparing of behavioral function seen following neonatal damage.

Beta frequency synchronization in basal ganglia output during rest and walk in a hemiparkinsonian rat

Synchronized oscillatory neuronal activity in the beta frequency range has been observed in the basal ganglia of Parkinsons disease patients and hypothesized to be antikinetic. The unilaterally lesioned rat model of Parkinsons disease allows examination of this hypothesis by direct comparison of beta activity in basal ganglia output in non-lesioned and dopamine cell lesioned hemispheres during motor activity. Bilateral substantia nigra pars reticulata (SNpr) recordings of units and local field potentials (LFP) were obtained with EMG activity from the scapularis muscle in control and unilaterally nigrostriatal lesioned rats trained to walk on a rotary treadmill. After left hemispheric lesion, rats had difficulty walking contraversive on the treadmill but could walk in the ipsiversive direction. During inattentive rest, SNpr LFP power in the 12-25 Hz range (low beta) was significantly greater in the dopamine-depleted hemisphere than in non-lesioned and control hemispheres. During walking, low beta power was reduced in all hemispheres, while 25-40 Hz (high beta) activity was selectively increased in the lesioned hemisphere. High beta power increases were reduced by l-DOPA administration. SNpr spiking was significantly more synchronized with SNpr low beta LFP oscillations during rest and high beta LFP oscillations during walking in the dopamine-depleted hemispheres compared with non-lesioned hemispheres. Data show that dopamine loss is associated with opposing changes in low and high beta range SNpr activity during rest and walk and suggest that increased synchronization of high beta activity in SNpr output from the lesioned hemisphere during walking may contribute to gait impairment in the hemiparkinsonian rat.

Enduring enhancement in frontal cortex dopamine utilization in an animal model of amphetamine psychosis

It is reported that in rats the repeated intermittent administration of amphetamine produces a long-lasting enhancement in medial frontal cortex dopamine utilization. This change in mesocortical dopamine activity may be involved in the behavioral sensitization produced by psychomotor stimulant drugs, and some of the cognitive abnormalities (e.g. amphetamine psychosis) associated with stimulant drug abuse in humans.

Conditioned increases in behavioral activity and accumbens dopamine levels produced by intravenous cocaine

In vivo microdialysis, behavioral activity assessments, and a conditioned place preference (CPP) test were used to investigate dopaminergic correlates of cocaine-conditioned behaviors. Over 12 days, rats were given either intravenous cocaine (4.2 mg/kg) or saline (6 cocaine and 6 saline infusions) daily in distinctively different environments. The following day, rats were tested in the cocaine- and saline-paired environments; 48 hr later, CPP was determined. The cocaine-associated environment elicited greater nucleus accumbens dopamine (NAcc DA) levels, hyperactivity, and place preference, though the emergence of DA increases was not in synchrony with peak behavioral activation. Although conditioned behavioral effects after repeated cocaine are well documented, direct evidence of increased NAcc DA in response to a cocaine-paired environment has not been previously reported. Discrepancies with previous work are attributed to a number of methodological differences.

The Propensity for Nonregulatory Ingestive Behavior Is Related to Differences in Dopamine Systems. Behavioral and Biochemical Evidence

Previous research has shown that animals predisposed to eat and drink in response to electrical stimulation of the lateral hypothalamus (ESLH) are similarly predisposed to drink excessively when tested for schedule-induced polydipsia. The eating and drinking elicited by both experimental paradigms appears to be unrelated to homeostatic need and has been called nonregulatory ingestive behavior. In this study, the relation between properties of dopaminergic neural systems and the predisposition to exhibit nonregulatory ingestive behavior was investigated. It was found that rats that eat and drink during ESLH show greater behavioral sensitization to a series of amphetamine injections that those that do not exhibit ingestive behavior during ESLH. In addition, footshock stress produced a greater increase in forebrain dopamine utilization in rats that engaged in nonregulatory ingestive behavior. This evidence is consistent with the hypothesis that there are individual differences in the responsiveness of forebrain dopamine systems that are related to the behavioral predisposition to exhibit nonregulatory ingestive behavior.

The role of the striatum in organizing sequences of play fighting in neonatally dopamine-depleted rats

Juvenile rats sustaining dopamine depletions by intraventricular injections of 6-hydroxydopamine (6-OHDA) as neonates were used to study the role of the striatum in controlling play fighting. As juveniles, the rats exhibited all the behavior elements typical of play fighting. However, they were more likely to use defensive tactics that shortened the playful contact between partners; and when contacting the partner, they were more likely to switch to other behaviors, such as allogrooming and sexual mounting, rather than continue with the play sequence. It is suggested here that the striatum is important for maintaining sequential organization of play fighting.

Dose-dependent differences in the development of reserpine-induced oral dyskinesia in rats: support for a model of tardive dyskinesia.

Rats treated with reserpine develop spontaneous orofacial dyskinesia that has features similar to tardive dyskinesia (TD) in humans. In contrast to TD, however, reserpine-induced oral dyskinesia develops rapidly reaching a maximal level within 3 days at a dose of 1 mg/kg per day. The present study examined whether rats administered lower doses of reserpine would develop the oral dyskinesia at a slower rate, similar to the protracted development of TD. Rats were administered 0, 0.01, 0.05, 0.1, or 1.0 mg/kg reserpine subcutaneously every other day for 100 days. Oral dyskinesia was measured by recording the incidence of tongue protrusions for 30 min on days 1, 4, 10, 20, 40, 60, and 100. The time course of the development of reserpine-induced oral dyskinesia varied dose-dependently. The response was evident within 4 days at 1 mg/kg, within 20 days at 0.1 mg/kg, within 60 days at 0.05 mg/kg, and was not evident at 0.01 mg/kg at any time during the 100 days of treatment. The protracted development of reserpine-induced oral dyskinesia at the lower doses is consistent with TD. Doses of reserpine that produced an increase in tongue protrusions also produced a 90–95% depletion of dopamine and an increase in the ratio of dopamine metabolites to dopamine in the caudate-putamen. The disruption of dopamine neurotransmission may be involved in development of the oral dyskinesia. Furthermore, it is suggested that the 1 mg/kg dose of reserpine may induce neurochemical changes similar to that produced by long-term neuroleptic treatment, but at an accelerated rate, thereby providing a new efficient model of TD.

THC does not affect striatal dopamine release: Microdialysis in freely moving rats

The hypothesis that cannabinoids potentiate the motor effects of neuroleptics and produce their abuse potential by stimulating dopaminergic activity was tested by measuring the ability of THC to increase extracellular dopamine concentrations. Male Long-Evans rats were implanted with guide cannulae for the striatum or nucleus accumbens. Fifteen hours prior to testing, removable microdialysis probes were inserted through the guide cannulae. Dialysis samples were collected during resting baseline, after 1.0 mg/kg, 10 mg/kg THC, or vehicle of olive oil with 5% ETOH (by gavage) followed by amphetamine (1.5 mg/kg) or fluphenazine (0.3 mg/kg). THC produced no change in the extracellular concentrations of DA, DOPAC, and HVA, nor in 5-HIAA. THC also had no effect on the enhancement of extracellular DA produced by amphetamine nor on the transient increase in DA, DOPAC, and HVA produced by fluphenazine. There were also no behavioral differences between groups during any of these treatments.