Larry Kokkinidis

Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes

Rates of responding for intracranial self-stimulation from the medial forebrain bundle, nucleus accumbens and substantia nigra were evaluated in mice that had been exposed to either escapable shock, yoked inescapable shock or no shock treatment. Whereas performance was unaffected by escapable shock, marked reductions of responding from the medial forebrain bundle and nucleus accumbens were evident following the uncontrollable shock treatment. Responding from the substantia nigra was unaffected by the stress treatment. Uncontrollable shock is thought to reduce the rewarding value of responding for electrical brain stimulation from those brain regions in which stressors are known to influence dopamine activity.

Interaction between cholinergic and catecholaminergic agents in a spontaneous alternation task.

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 (perseveration). 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.

Effects of scopolamine, d-amphetamine and other drugs affecting catecholamines on spontaneous alternation and locomotor activity in mice

Locomotor activity and Y-maze spontaneous alternation were examined in three strains of inbred mice (A/J, DBA/2J and C57BL/6J) following various drug treatments. Although the strains exhibited different levels of locomotor activity, the level of spontaneous alternation was comparable among the strains. Scopolamine produced dose dependent increases in locomotor activity in the A and DBA/2 strains, but produced a transient inhibitory effect upon locomotor activity in C57BL/6. Nevertheless, spontaneous alternation was eliminated equally, regardless of strain. d-Amphetamine increased locomotor activity and reduced alternation significantly below chance levels (perseveration). α-Methyl-p-tyrosine (α-MpT) and FLA-63 reduced the locomotor stimulating effects of d-amphetamine; however, the effectiveness of these agents was found to be strain dependent. Neither α-MpT nor FLA-63 reduced the perseverative behavior. A subsequent study employing Swiss-Webster mice revealed that with pretreatment of reserpine, both α-MpT and FLA-63 eliminated the amphetamine-induced perseverative behavior. Results were interpreted in terms of (a) the role of cholinergic and catecholaminergic systems in modulating alternation behavior, (b) qualitative differences in the behavioral effects elicited by scopolamine and d-amphetamine, (c) strain-specificity regarding pharmacological effects, and (d) role of newly synthesized norepinephrine and dopamine in subserving amphetamine-induced locomotor activity and perseveration.

Amphetamine withdrawal a behavioral evaluation

The effects of withdrawal from long-term amphetamine treatment of intracranial self-stimulation, forced swim-induced immobility, shuttle escape performance, acoustic startle and locomotor activity were evaluated. Mice implanted with stimulating electrodes in the lateral hypothalamus demonstrated stable and reliable rates of self-stimulation responding. After exposure to a chronic schedule of amphetamine treatment response rates were severely depressed. In addition to modifying intracranial self-stimulation responding, amphetamine withdrawal increased the duration of immobility in a forced-swim situation. Although chronic amphetamine exposure induced pronounced behavioral changes in the intracranial self-stimulation and forced swim tasks, drug withdrawal had little effect on shuttle escape performance, acoustic startle and locomotor activity. Based on these findings it was suggested that the development of post-amphetamine depression in the self-stimulation and forced swim paradigms was not related to variations in motoric or arousal mechanisms resulting from amphetamine withdrawal, but rather involved drug-induced changes in motivational processes.

Dissociation of the effects of scopolamine and d-amphetamine on a spontaneous alternation task.

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.

Involvement of norepinephrine in startle arousal after acute and chronic d-amphetamine administration

Treatment with d-amphetamine produced a dose-dependent increase in startle amplitude in response to a buzzer. This increase appeared to be a reflection of a sensitization effect, i.e., enhanced responsivity as a function of repeated stimulus presentations. Treatment with α-methyl-p-tyrosine, which reduced whole brain concentrations of dopamine (DA) and norepinephrine (NE), or treatment with FLA-63, which reduced only NE, antagonized the effects of d-amphetamine on the startle reflex, suggesting a role of NE in this behavior. Startle amplitude was also reduced following chronic d-amphetamine treatment. The effect of d-amphetamine on startle was found to be independent of changes in drug-induced locomotor excitation. The data of the present investigation, together with earlier reports, suggests that tolerance occurs to those behaviors that involve a noradrenergic component.

Perseveration and rotational behavior elicited by d-amphetamine in a Y-maze exploratory task: differential effects of intraperitoneal and unilateral intraventricular administration.

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 μg) or 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.

Tolerance to d-amphetamine: behavioral specificity.

Abstract In a Y-maze exploratory task mice tend to enter that compartment which was least recently visited (spontaneous alternation). Low doses of d-amphetamine (1.0 mg/kg) reduce alternation to chance levels, while high doses (10.0 mg/kg) result in animals successively visiting only two compartments of the Y-maze (perseveration). Following daily d-amphetamine injection (1.0 or 10.0 mg/kg) over a 30 day period tolerance to the d-amphetamine induced perseveration was observed; however, chronic amphetamine treatment did not modify the locomotor stimulating effects of d-amphetamine or the reduction of alternation to chance levels produced by low doses of the drug. It was hypothesized that tolerance to d-amphetamine occurs exclusively to behaviors mediated by norepinephrine.

Behavioural specific tolerance following chronic d- or l-amphetamine treatment: Lack of involvement of p-hydroxynorephedrine

Abstract In a free-running Y-maze exploratory task mice tend to enter the least recently visited compartment (spontaneous alternation). Treatment with d- or l-amphetamine produced a dose-dependent increase in locomotor activity and resulted in animals successively exploring two compartments of the Y-maze only (perseveration). Whereas five daily injections of d-amphetamine (10 mg/kg) or /-amphetamine (45 mg/kg) did not result in tolerance to the locomotor-stimulating properties of the drug, a dose-dependent attenuation of the perseverative tendency was observed. Moreover, symmetrical cross-tolerance between the isomers was apparent. Since formation of p-hydroxynorephedrine is stereo-specific to the d-isomer, these data suggest that this possible false transmitter does not play a primary role in the development of the tolerance. Alternative explanations which may account for the behaviour-specific tolerance were considered.

Abatement of stimulus perseveration following repeated d-amphetamine treatment: absence of behaviorally augmented tolerance.

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.