Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations

Abstract

This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0-250 micrograms/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.

Long-term haloperidol administration enhances and short-term administration attenuates the behavioral effects of cocaine in a place conditioning procedure

“…In support of this notion are data showing that long-term haloperidol administration predominately enhances horizontal locomotor to cocaine with little effect seen in stereotypy (LeDuc and Mittleman 1993). Cocaine is thought to exert many of its behavioral effects through its ability to inhibit DA uptake in the mesolimbic DA system (see Introduction).…”

“…More rapid locomotor sensitization to cocaine, an indirect DA agonist, occurs after long-term haloperidol administration (LeDuc and Mittleman 1993). After cessation of long-term administration of D 2 -like antagonists (raclopride or spiperone), an enhanced sensitivity to the effects of cocaine on schedule-controlled behavior occurs (Howell and Byrd 1992).…”

The Safety, Tolerability, and Subject-Rated Effects of Acute Intranasal Cocaine Administration During Aripiprazole Maintenance II: Increased Aripipirazole Dose and Maintenance Period

“…Consistent with this hypothesis, a large body of literature has demonstrated increased sensitivity of dopamine systems following chronic D 2 antagonist administration. In one study, for example, treatment with haloperidol increased the locomotor response to cocaine in rats (19).…”

Continuous, but not Intermittent, Antipsychotic Drug Delivery Intensifies the Pursuit of Reward Cues

“…Thus, although acute exposure to antipsychotics/D2 antagonists generally reduces the incentive motivational properties of primary and conditioned rewards (Beninger et al, 1989;Le Moal and Simon, 1991), chronic antipsychotic treatment can enhance reward function. For example, chronic antipsychotic treatment augments operant responding for intravenous injections of cocaine (Howell and Byrd, 1992;Roberts and Vickers, 1987), facilitates the acquisition of heroin self-administration (Stinus et al, 1989), enhances cocaine-induced psychomotor sensitization (Fukushiro et al, 2008;LeDuc and Mittleman, 1993), and facilitates conditioned place preference to cocaine (Fukushiro et al, 2007;Kosten et al, 1996) and heroin (Stinus et al, 1989).…”