PubMed · 4623587
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A N Patel. 1972. Self-inflicted strokes.. https://doi.org/10.7326/0003-4819-76-5-823
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We examined the role of the dopamine projection to the medial prefrontal cortex in amphetamine-induced sensitization of meso-nucleus accumbens dopamine function. In the first experiment, male rats received bilateral microinfusions either of 6-hydroxydopamine or of vehicle (sham) into prefrontal cortex. Six weeks later animals from both groups were injected once daily for 5 consecutive days with either amphetamine or saline. Two days after the last daily injection, all the animals were each implanted with a voltammetric electrode into nucleus accumbens. Increases in dopamine-dependent electrochemical signals elicited by amphetamine were monitored 3-4 days later using chronoamperometry. The results showed that amphetamine stimulates dopamine efflux to a greater extent in the nucleus accumbens of lesioned than of sham-lesioned animals. Furthermore, of the animals with prefrontal cortical lesions, amphetamine-induced dopamine efflux was greater in animals previously treated with the drug than in animals with no prior drug experience. In a second experiment, sensitization to the acute locomotor-stimulant effect of amphetamine was examined in prefrontal cortex-lesioned and sham-lesioned animals. The locomotor response of all animals to a test dose of amphetamine was first monitored and then on each of the subsequent 5 days, lesioned and sham-lesioned animals received an injection either of amphetamine or of saline. Five and then 13 days later, the locomotor response of all animals to the test dose of amphetamine was again measured. The results of this study showed that prefrontal cortex-lesioned animals were less responsive to the first amphetamine injection than sham-lesioned animals. However, after repeated daily administration, the acute locomotor response of lesioned animals to amphetamine was significantly greater than that of sham-lesioned animals with the same drug history. These findings are generally consistent with evidence from other sources suggesting that the dopamine input to medial prefrontal cortex exerts an indirect, inhibitory influence on mesolimbic dopamine transmission. They also suggest that long-term changes to a dopamine-sensitive mechanism in prefrontal cortex may contribute to the development of stimulant-induced sensitization of mesolimbic dopamine function.
CB1 receptors and their putative natural ligand anandamide, have been tentatively involved in the control of midbrain extrapyramidal function. Electrophysiological activity of dopamine neurones was measured after acute and repeated administration of the CB1 receptor antagonist SR 141716A (0.3-3 mg kg-1) in rats. Acute SR 141716A increased A9, but not A10 cell population response without affecting either their spontaneous firing rate or apomorphine-induced rate inhibition and prevented amphetamine-induced inhibition of A9, but not of A10 cell firing. After repeated administration SR 141716A (1 or 5 mg kg-1) decreased population response of A9 cells, which was reversed by apomorphine. These results suggest that CB1 receptor blockade by SR 141716A interrupts a cannabinoid-like endogenous tone controlling extrapyramidal function.
Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.