Low dose apomorphine induces context-specific sensitization of hypolocomotion without conditioning: Support for a new state dependent retrieval hypothesis of drug conditioning and sensitization

Abstract

High doses of apomorphine induce sensitization to locomotor stimulant effects whereas low doses induce locomotor inhibition. We examined whether repeated low dose apomorphine induced sensitization and conditioning to the locomotor inhibitory effect. Three doses of the D1/D2 agonist, apomorphine, were used in a Pavlovian conditioning protocol: 0.05 mg/kg (autoreceptor level), 0.5 and 2.0 mg/kg (post-synaptic level). Rats received 5 daily apomorphine treatments paired or unpaired to an open-field environment (conditioning phase) followed by a saline test (conditioning test) and an apomorphine challenge test (sensitization test). Locomotion was measured for 30 min. During the acquisition phase, the 0.05 mg/kg paired treatment decreased locomotion while the high dose paired treatments increased locomotion. The 0.05 mg/kg paired treatment did not induce conditioning but induced inhibitory locomotor sensitization. The post-synaptic paired treatments produced conditioned and sensitized locomotor stimulation. For the low dose results, we propose an expanded contextual stimulus, which includes interoceptive drug cues. In the sensitization test, the same interoceptive drug cues and test environment cues are present as those during acquisition. In the conditioning test, normative dopaminergic activity is present which generates internal cues that may or may not generalize to the drug-induced cues and, permit or prevent retrieval of conditioning.

Time-dependent effects of prazosin on the development of methamphetamine conditioned hyperactivity and context-specific sensitization in mice

“…Recently, authors have suggested that state-dependent learning mechanisms may contribute to drug conditioning and context-specific sensitization [36]. Braga, Dias, Carey and Carrera (2009) suggested that drug USs, particularly dopamine agonists, produce conditioned hyperactive responses that reflect the presence of both internal (drug effects) and external (e.g., smell of the chamber) cues at the time of testing.…”

“…While this retrieval hypothesis may explain the results of Experiment 1, the results of Experiment 2 seem incapable with this account. Namely, because prazosin was administered immediately after the conditioning session, there would not be a mismatch between internal and external cues from the Conditioning-to-Testing Phases and should not weaken conditioned hyperactivity or context-specific sensitization according to the retrieval hypothesis [36]. However, such a weakening was observed in mice treated with prazosin immediately after the conditioning session.…”

Apomorphine-induced context-specific behavioural sensitization is prevented by the D1 antagonist SCH-23390 but potentiated and uncoupled from contextual cues by the D2 antagonist sulpiride

“…It is also the case that these agonist-induced behavioural sensitization effects are typically contextspecific which indicates a contributory learning mechanism in this process. Behavioural sensitization to apomorphine is not only context specific but it can also develop even if the dose level used does not initially elicit behavioural hyperactivity (Braga et al 2009a) or when a dose is used which remains activity neutral even with repeated treatments (Mattingly et al 1988). The fact that a dose level of apomorphine can be used with an acute treatment that is initially activity neutral but nonetheless elicits hyperactivity with repeated treatment (Braga et al 2009a) provides a useful methodological feature for tracking the development of behavioural sensitization to repeated apomorphine treatment and for assessing the influence of a dopamine antagonist on the emergence of this sensitization.…”

Serotonin and conditioning: Focus on Pavlovian psychostimulant drug conditioning

“…In contrast to many drugs that induce tolerance effects, the repeated use of psychostimulants induce sensitization and conditioned drug effects that enhance the drug effects [42][43][44][45][46][47][48][49][50][51]. In terms of Pavlovian conditioning, psychostimulant drugs are administered to animals by an experimenter independent of the animal's behavior and therefore serve as unconditioned stimuli that elicit unconditioned drug responses.…”