PubMed · 164972
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1975-03-01. Editorial: Narcolepsy.. https://pubmed.ncbi.nlm.nih.gov/164972/
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Although hyperkinesis is expressed in several neurological disorders, the biological basis of this phenotype is unknown. The mouse mutant coloboma (Cml+) exhibits profound spontaneous locomotor hyperactivity resulting from a deletion mutation. This deletion encompasses several genes including Snap, which encodes SNAP-25, a nerve terminal protein involved in neurotransmitter release. Administration of amphetamine, a drug that acts presynaptically, markedly reduced the locomotor activity in coloboma mice but increased the activity of control mice implicating presynaptic function in the behavioral abnormality. In contrast, the psychostimulant methylphenidate increased locomotor activity in both coloboma and control mice. When a transgene encoding SNAP-25 was bred into the coloboma strain to complement the Snap deletion, the hyperactivity expressed by these mice was rescued, returning these corrected mice to normal levels of locomotor activity. These results demonstrate that the hyperactivity exhibited by these mice is the result of abnormalities in presynaptic function specifically attributable to deficits in SNAP-25 expression.
Three drugs that affect the neuroendocrine system (amphetamine, methylphenidate, and codeine) caused decreases in body weights and in the incidence of spontaneously occurring mammary gland neoplasms in the female F344/N rat in 2-year carcinogenicity studies. Using a mathematical model that relates body weight changes to the incidence of mammary gland neoplasms, we find that the decrease in mammary gland tumours seen in female rats cannot be fully explained by body weight decreases relative to control animals. Further, the observed decreases in body weight in treated female rats were not a function of differences in feed consumption between treated and control groups. These pharmaceuticals are thought to affect the biologic system through interaction with membrane receptors. This interaction and/or subsequent cell signaling events may play a role in the observed decrease in spontaneously occurring mammary gland neoplasms in the female rat treated with amphetamine, methylphenidate, or codeine.
Single-unit activity was recorded from the amygdaloid complex in freely moving rats during an infusion of amphetamine directly into the recording site. Relative to the quiet resting period prior to the infusion, amphetamine routinely increased neuronal activity within 5-15 min after infusion onset, and this response continued for at least another 30 min. It was generally accompanied by marked increases in sniffing, rearing, locomotion, and grooming as well as by a tendency to turn to the ipsilateral side. Haloperidol and clozapine, typical and atypical antipsychotic drugs, respectively, were then tested in their ability to reverse these neuronal and behavioral effects. Both antipsychotics were administered subcutaneously at behaviorally effective doses within 10 min after termination of the amphetamine infusion. Haloperidol (1.0 mg/kg) failed to reverse the amphetamine-induced increase in amygdaloid neuronal activity and required more than 20 min to exert a partial blockade of the accompanying behavioral activation. Clozapine (10.0 mg/kg), in contrast, blocked the excitatory effects of amphetamine on all tested neurons and also blocked most amphetamine-induced behaviors within 10 min. Taken together, these results, which support other lines of electrophysiological evidence, point to the amygdala as a critical site in the differential behavioral effects of typical and atypical antipsychotic drugs.