Behavioural specific tolerance following chronic d- or l-amphetamine treatment: lack of involvement of p-hydroxynorephedrine.
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Biomedical subjects
Publications and source records attributed to L Kokkinidis.
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Acute administration of d-amphetamine results in animals perseverating between two compartments when placed in a free running Y-maze exploratory situation. Experiment 1 indicated that perseverative behavior was attenuated by making the arms of the maze distinctively different. Experiments 2 and 3 demonstrated that repeated amphetamine treatment reduced arms of the maze distinctively different. Exeriment 2 and 3 demonstrated that repeated amphetamine treatment reduced stimulus perseveration. Drug-induced locomotor activity and stereotypy were not affected by chronic drug administration. The course of the tolerance effect was not altered by pairing the repeated drug experience with Y-maze exposure. It was concluded that although stimulus factors are involved in the perseverative response, conditioning factors are not of primary relevance in determining the tolerance. It was also suggested that the mechanisms which subserve stimulus perseveration are different from those which mediate locomotor activity and stereotypy.
Mice received either intraperitoneal (1.0, 3.0, 5.0, or 15.0 mg/kg) or unilateral intraventricular injection (50.0, 100.0 or 200.0 microgram) of d-amphetamine. Both routes of injection produced circling behavior in a dose-related fashion when animals were tested in a circular alley-way. In contrast, performance in a free running Y-maze alternation task was differentially affected by the route of administration. Whereas intraperitoneal injection induced perseveration (i.e., animals consecutively visited only two arms of the maze), intraventricular injection augmented alternation behavior normally seen in saline-treated mice. It was suggested that Y-maze performance following intraventricular d-amphetamine injection reflects response perseveration, whereas systemic d-amphetamine treatment produced stimulus perseveration (repetition of location rather than direction). Moreover d-amphetamine-induced circling produced by intraperitoneal administration probably is an artifact of drug-induced stimulus perseveration as opposed to motor biases observed following intraventricular injections.
A small and simple device is described for applying substances to the brain of freely moving mice. The effectiveness of the technique was evaluated by intraventricular injections of d-amphetamine sulfate. It was observed that intraventricular injections of d-amphetamine (50-200 microgram) produced a dose dependent increase in activity.
Spontaneous alternation was examined in a free running Y-maze task after various pharmacological manipulations. Whereas scopolamine reduced alternation to chance levels, d-amphetamine in some doses resulted in alternation significantly below chance (perservation). Physostigmine treatment increased levels of alternation whereas reserpine was without effect. Concurrent administration of drugs revealed that reserpine effectively reversed the effects of scopolamine, while the perseveration induced by d-amphetamine was antagonized by physostigmine. When animals were pre-exposed to the Y-maze the effects of d-amphetamine were enhanced, but effects of scopolamine were not modified. Finally, scopolamine treatment augmented the perseverative effects of d-amphetamine. It was suggested that cholinergic agents modify alternation by effects on habituation. On the other hand d-amphetamine produces genuine perseveration without effects on habituation per se. Alternation performance and perseveration were suggested to be mediated by the interaction between the distinct behavioral effects of cholinergic and catecholaminergic activity.
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The immediate and carry-over effects of scopolamine and d-amphetamine were evaluated in a free running Y-maze spontaneous alternation task. The immediate effect of scopolamine (1.0 mg/kg) or d-amphetamine (5.0 mg/kg) was to reduce alternation to chance or to levels significantly below chance (perseveration), respectively. On a second, non-drug test day alteration decreased in saline treated animals, but increased among mice which received scopolamine on Day 1. In contrast, upon retesting in the non-drug state, the performance of animals initially treated with d-amphetamine resembled that of saline treated mice. Subsequent experiments revealed that these effects could not be attributed to drug effects on peripheral mechanisms, consolidation, residual drug action or drug dissociated learning. It was concluded that the behavioral effects of scopolamine and d-amphetamine are qualitatively different. Whereas scopolamine disrupts habituation, d-amphetamine induces perseveration independently of any effects on habituation.
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Muscle correlates of reflex telson movement were recorded in intact Limulus (horseshoe crab) preparations with chronically implanted microelectrodes. Muscle activity habituated during repetitive tactile stimulation of the gills with puffs of air. Dishabituation was also observed, as were inverse relationships between the frequency and intensity of stimulation and the rate of response decrement. These findings closely paralleled those obtained during central recordings in acute dissected preparations, as did the demonstration under certain stimulation conditions of an initial incremental phase of responsivity. Although initial levels of responsivity recovered after 1 hr without stimulation, potentiation of habituation was observable after 2 hr. Both of these times greatly exceeded those previously observed in acute preparations. No generalization to a spatial displacement of the stimulus was obtained, although a visually elicited telson reflex had been shown to demonstrate a cross-optic generalization. Aspects of the comparative strategy and the adaptive value of telson reflex habituation in Limulus were briefly considered.
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In three experiments the following results were obtained: (a) Activity was greater both prior to and following exposure to shock among C57BL/6J mice than in DBA/2J mice, which in turn was greater than that of A/J mice. (b) Scopolamine hydrobromide increased general activity in DBA/2 and A mice, but had either no effect or decreased activity in the C57BL/6 strain. Following exposure to shock, however, the disinhibitory effects of scopolamine were apparent in all three strains. (c) d-amphetamine increased activity in all three strains. Moreover, following the single shock d-amphetamine had excitatory effects among both A and DBA/2 mice such that activity exceeded the level observed with d-amphetamine alone. Following several shock presentations a small but significant excitation was observed in C57BL/6 mice as well. Data were interpreted in terms of disinhibitory and excitatory effects of scopolamine and d-amphetamine, respectively, as well as possible interactions between the catecholaminergic and cholinergic systems. In addition, implications for sources of strain differences in avoidance behavior are discussed.