Apomorphine conditioning and sensitization: The paired/unpaired treatment order as a new major determinant of drug conditioned and sensitization effects

Abstract

Repeated treatments with psychostimulant drugs generate behavioral sensitization. In the present study we employed a paired/unpaired protocol to assess the effects of repeated apomorphine (2.0 mg/kg) treatments upon locomotion behavior. In the first experiment we assessed the effects of conditioning upon apomorphine sensitization. Neither the extinction of the conditioned response nor a counter-conditioning procedure in which we paired an inhibitory treatment (apomorphine 0.05 mg/kg) with the previously established conditioned stimulus modified the sensitization response. In the second experiment, we administered the paired/unpaired protocol in two phases. In the second phase, we reversed the paired/unpaired protocol. Following the first phase, the paired group alone exhibited conditioned locomotion in the vehicle test and a sensitization response. In the second phase, the initial unpaired group which received 5 paired apomorphine trials during the reversal phase did not develop a conditioned response but developed a potentiated sensitization response. This disassociation of the conditioned response from the sensitization response is attributed to an apomorphine anti-habituation effect that can generate a false positive Pavlovian conditioned response effect. The potentiated sensitization response induced by the treatment reversal protocol points to an important role for the sequential experience of the paired/unpaired protocol in behavioral sensitization.

Memory re-consolidation and drug conditioning: an apomorphine conditioned locomotor stimulant response can be enhanced or reversed by a single high versus low apomorphine post-trial treatment

“…In line with a number of prior studies (Mattingly and Gotsick 1989;Braga et al 2009a, b;Dias et al 2010;de Matos et al 2010), we found that the repeated pairing of a locomotor stimulant dose level of apomorphine with placement in an open-field generated a sensitized locomotor stimulant response. Following the induction of sensitization, we conducted a series on non-drug tests for conditioning.…”

“…This behavioral sensitization and conditioned drug effect has been repeatedly demonstrated (Borowsky and Kuhn 1991;Heidbreder and Shippenberg 1994;Mattingly et al 1994;Carey and Gui 1998;Bloise et al 2007;Braga et al 2009a, b;Dias et al 2010;Filip et al 2010;de Matos et al 2010). Sensitization is generally considered an important contributor to the addictive potency of psychostimulant drugs such as cocaine (e.g., Wise and Bozarth 1987;Robinson and Berridge 1993;Carey and Damianopoulos 2006) because of the effects of psychostimulant sensitization upon associated contextual stimuli.…”

“…These treatments were administered for five consecutive days, one trial per day, and served as the induction phase in which locomotion was recorded for 30 min. The induction phase was designed to establish an apomorphine conditioned response selectively in the paired apomorphine treatment groups (de Matos et al 2010). After a period of 2 days without injections or behavioral testing (withdrawal period), the first conditioning test was performed in which the animals received an injection of saline prior to being placed into the test environment, and locomotion was recorded for 30 min.…”

Serotonin and conditioning: Focus on Pavlovian psychostimulant drug conditioning

“…In our most recent studies, we have shown that repeated pairing of the D1/D2 agonist apomorphine, at dose levels that elicit hyper-locomotion with placement in an open-field, generates both context specific cue conditioned hyper-locomotion and context specific sensitized drug induced hyper-locomotion effects [47,49,51,85]. In line with the extant literature, extinction eliminates the conditioned apomorphine hyper-locomotion response but not the sensitized apomorphine hyper-locomotion response.…”

“…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.…”