Synchronized oscillatory neuronal activity in the beta frequency range has been observed in the basal ganglia of Parkinson’s disease patients and hypothesized to be antikinetic. The unilaterally lesioned rat model of Parkinson’s 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.

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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.

lntracerebral microdialysis was used to measure the extracellular concentration of striatal dopamine (DA) and its metabolites in freely moving rats depleted of DA by the bilateral infusion of 6-hydroxydopamine into the substantia nigra approximately 1 month earlier. It was found that the basal extracellular concentration of DA remained within the same range as seen in control animals until the size of the lesion exceeded 60% (estimated by the postmortem tissue concentration of DA). In animals with an 60-95% lesion there was only a modest decrease in basal extracellular DA, but as lesion size exceeded 95% there was a marked drop in the basal extracellular concentration of DA. In contrast, the basal extracellular concentration of the DA metabolites showed a more steady decline as a function of lesion size. To determine the ability of the residual population of DA terminals to further increase DA release upon increased demand, animals were given a challenge injection of 1.5 mg/ kg of d-amphetamine.Amphetamine-evoked DA release remained within the control range until lesion size exceeded 95%. These results provide direct confirmation for the hypothesis that following recovery from partial bilateral damage to the nigrostriatal DA system in adulthood, there are presynaptic compensatory changes in the remaining population of DA neurons sufficient to "normalize" the extracellular concentration of striatal DA. It is suggested that this normalization of extracellular DA is responsible for the sparing of function seen following the loss of up to 60% of the DA innervation to the striatum and contributes to the recovery of function seen after even more extensive damage (60-95%). However, at least 5% of the usual dopaminergic innervation to the striatum is required to maintain a relatively normal extracellular concentration of DA, and it appears that this 5% is necessary for any significant recovery of function.The bilateral destruction of dopamine (DA)-containing neurons in the substantia nigra with a neurotoxin such as 6-hydroxydopamine (6-OHDA) or 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a widespread depletion of DA throughout the primary projection field of these cells in the neostriatum Received Oct. 19, 1989; revised Jan. 18, 1990; accepted Jan. 25, 1990. (Ungerstedt, 1968;Heikkila et al., 1984). The depletion of striatal DA in animals results in the appearance of a behavioral syndrome that is considered an animal analog of Parkinson's disease in humans (Schultz, 1982). In rats this is characterized by bradykinesia, sensorimotor neglect, aphagia, adipsia, akathisia, short-step locomotion, postural abnormalities, and cognitive dysfunction (Ungerstedt, 1971;Zigmond and Stricker, 1972; Stricker and Zigmond, 1974;Zis et al., 1974;Schallert and Whishaw, 1978;Schallert et al., 1978;Whishaw et al., 1978Whishaw et al., , 1986Whishaw and Dunnett, 1985). The severity of behavioral deficits following DA depletion is not related to lesion size in a simple way. If essentially the entire DA input to the striatum i...

The repeated intermittent administration of amphetamine (AMP) produces an enduring enhancement in the response of dopamine (DA) systems in the brain to a subsequent "challenge" with amphetamine. However, former amphetamine addicts are not only hypersensitive to amphetamine, but also to "physical or psychological stress". This suggests that sensitization to amphetamine may change the response of DA neurons in brain to subsequent stress. To explore this idea, the effects of footshock stress on regional metabolism of DA in brain, and on the concentrations of plasma beta-endorphin and N-acetylated beta-endorphin, were studied in rats previously exposed to amphetamine or saline. It was found that: Prior treatment with amphetamine produced enduring (at least 7 days) changes in the dopaminergic response to footshock in the medial frontal cortex, hypothalamus, dorsolateral striatum and nucleus accumbens. Generally, rats pretreated with amphetamine showed a greater initial reduction in concentrations of DA in response to footshock, and a greater elevation in concentrations of metabolites of DA and/or metabolite/transmitter ratios, compared to nonhandled control rats. In some regions of the brain repeated injections of saline produced changes in the response to subsequent footshock that were comparable to those produced by amphetamine. Prior treatment with amphetamine enhanced the release of beta-endorphin and N-acetylated beta-endorphin from the pituitary elicited by footshock stress. It is concluded that repeated intermittent treatment with amphetamine or stress (injections of saline) produce enduring changes in the response of DA neurons and the pituitary to subsequent stress. These changes may be responsible for the hypersensitivity to stress reported in former amphetamine addicts, and in rats previously sensitized to amphetamine.