Dopaminergic activity and the discriminative stimulus effects of mu opioids in pigeons: importance of training dose and attenuation by the D 3 agonist (±)-7-OH-DPAT

Abstract

The present investigation examined the effects of several dopaminergic compounds in pigeons trained to discriminate either a 0.1 (low) or 5.6 (high) mg/kg dose of the mu opioid butorphanol from saline. Various dopamine (DA) re-uptake inhibitors, releasers, a D1 agonist, a D2 agonist and a D3 agonist engendered partial substitution (50-79% butorphanol responding) for the butorphanol stimulus in the low-dose group. In the high-dose group, with a few exceptions, these compounds produced predominately saline responding. In the low-dose group, the opioid antagonist naloxone antagonized the stimulus effects produced by butorphanol, but failed to attenuate the butorphanol-like discriminative stimulus effects produced by the DA re-uptake inhibitors mazindol and cocaine. The D1 antagonist (+)-SCH 23390 and the D2 antagonist raclopride failed to attenuate the stimulus effects produced by either the low or high training dose of butorphanol. Doses of mazindol and cocaine that engendered between 16% and 70% butorphanol responding failed to alter the butorphanol dose-effect curve in either the low- or high-dose group, indicating a less than additive interaction. In the high-dose group, the D3 agonist (+/-)-7-hydroxy-dipropylaminotetralin [(+/-)-7-OH-DPAT] attenuated butorphanol's stimulus effects in a dose-dependent manner along with the butorphanol-like stimulus effects produced by nalbuphine and morphine. The present findings indicate that direct and indirect DA agonists share similar stimulus effects with a low but not high training dose of butorphanol, and in the high-training dose group, activation of the D3 receptor by (+/-)-7-OHDPAT results in the attenuation of the discriminative stimulus effects of mu opioids.

Asymmetric Generalization and Interaction Profiles in Rhesus Monkeys Discriminating Intravenous Cocaine or Intravenous Heroin from Vehicle

“…With respect to DA substitution profiles, only cocaine, GBR 12909, and R-(Ϫ)-NPA engendered partial-to-full substitution for the training dose of cocaine, and none of the DA agonists engendered heroin-like DS effects regardless of dose. These findings differ from some studies (Cook and Picker, 1998;Lamas et al, 1998;Platt et al, 1999) in which cocaine and other stimulants substituted for heroin or morphine in rats, pigeons, and squirrel monkeys. It is interesting to note that in nondependent humans trained in a three-choice drug discrimination procedure with saline, hydromorphone, and pentazocine as the training stimuli, amphetamine did not generalize to hydromorphone but did partially generalize to both pentazocine and saline (Bickel et al, 1989).…”

“…These findings strongly implicate both D1-and D2-like receptor mechanisms in the ability of cocaine to attenuate the DS effects of heroin. Previous studies in rats have shown that D2-like agonists can attenuate the behavioral effects of heroin and other high efficacy opioid agonists (Cook and Picker, 1998;Cook and Beardsley, 2004). Both R-(Ϫ)-NPA and quinpirole, another D2-like agonist, have been shown to inhibit selfadministration of heroin under a progressive ratio schedule in rhesus monkeys (Rowlett et al, 2007).…”

“…The mechanisms underlying the DS effects of speedball combinations have not yet been elucidated fully but could reflect interactions mediated via subtypes of both dopamine (DA) and opioid receptors (Spealman and Bergman, 1994;Suzuki et al, 1997;Cook and Picker, 1998;Negus et al, 1998a;Rowlett and Spealman, 1998;Rowlett et al, 2001;Negus and Mello, 2002). Thus, the purpose of the present study was to investigate systematically the DS effects of cocaine-heroin combinations in rhesus monkeys trained to discriminate either cocaine or heroin from vehicle.…”

“…For example, in previous experiments using morphine or butorphanol as a DS, combined administration of cocaine and either opioid resulted in infra-additive interactions that depended at least in part on the species and the training dose (Suzuki et al, 1995;Cook and Picker, 1998;Platt et al, 1999). Likewise, coadministration of cocaine with heroin produced dose-dependent increases in the ED 50 value for the DS effects of heroin in rats (Lamas et al, 1998).…”

Cocaine-Like Discriminative Stimulus Effects of Heroin: Modulation by Selective Monoamine Transport Inhibitors

“…There remains a possibility, however, that interactions between the opioid and DA systems in heroin-trained subjects may be unique to a specific DA receptor subtype. For example, Cook and Picker (1998) demonstrated an attenuation of the DS effects of a agonist by the D 3 subtype-preferring agonist 7-OH-DPAT (7-hydroxy-2-dipropylaminotetralin).…”