Observing responses maintained by stimuli associated with cocaine or remifentanil reinforcement in rhesus monkeys.

RATIONALE: The stimuli associated with drug reinforcement may be particularly relevant to drug abuse and relapse. OBJECTIVES: The study measured behavior maintained by conditioned reinforcing stimuli in an observing response procedure. METHODS: The experiment was conducted with rhesus monkeys in three stages: 1) discriminative control was established by reinforcing responding on one lever with either intravenous cocaine or remifentanil in the presence of one stimulus and extinguishing the response in the presence of another stimulus, 2) discriminative control was suspended by not presenting the stimuli, and 3) a final stage was implemented wherein the stimuli from the first stage were presented only when one or more responses were made on a second (observing) lever. RESULTS: Under FR1 conditions, observing responses were maintained at low rates, but increased markedly when the response requirement was increased. CONCLUSIONS: The procedure maintained observing responses quite well and may be useful to an analysis of conditioned reinforcement based on drug reinforcement.

Behavioral effects and receptor binding affinities of fentanyl derivatives in rhesus monkeys.

These studies examined the opioid receptor binding affinities and behavioral effects of several fentanyl derivatives in rhesus monkeys. OHM3295, OHM3296, OHM3326 and OHM3463 displayed high affinity for mu (IC50 = 7-66 nM) as compared to kappa (IC50 = 263-3255 nM) or delta (IC50 = 480-4500 nM) receptors as measured by their ability to displace [3H](D-Ala2-Me-Phe4,Glyol5)enkephalin, [3H](5,7,8[beta])-N-[2- (1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]benzeneacetamide and [3H](D-Pen2-D-Pen5)enkephalin, respectively. All four compounds maintained i.v. self-administration responding at rates above those maintained by the mu agonist alfentanil. In drug discrimination studies, OHM3463, OHM3326 and OHM3296 substituted completely for nalbuphine whereas OHM3295, and a related compound, mirfentanil, substituted partially for nalbuphine. In morphine-treated monkeys, OHM3295 substituted for naltrexone; in monkeys acutely deprived of morphine, only OHM3463 reversed naltrexone-lever responding. All four compounds had antinociceptive effects, although the extent to which these effects were accompanied by respiratory depression or modified by naltrexone, as well as the interactions between antinociceptive effects of fentanyl derivatives and alfentanil, varied markedly among compounds. Thus, OHM3463 shared effects with mu agonists (e.g., alfentanil) under all conditions; the other three compounds had opioid agonist effects under only a subset of conditions. Moreover, one of these compounds (OHM3295) antagonized the discriminative stimulus and antinociceptive effects of other mu agonists. Collectively, these compounds appear to vary on two dimensions: opioid efficacy and the contribution of nonopioid actions to their antinociceptive effects. Together with results obtained with other fentanyl derivatives (mirfentanil) under similar conditions, results of the current study suggest this chemical class might be especially fertile for the development of novel analgesics that might have reduced toxicity and abuse liability as compared to fentanyl and related compounds that are currently used in medicine.

Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys.

l-Deprenyl and its stereoisomer d-deprenyl did not maintain intravenous self-administration behavior in rhesus monkeys. In contrast, l-methamphetamine, the major metabolite of l-deprenyl, as well as the baseline drug, cocaine, maintained high rates of intravenous self-administration behavior. Treatment with l-deprenyl doses up to 1.0 mg/kg before self-administration sessions failed to alter self-administration of either cocaine or l-methamphetamine. Thus l-deprenyl did not appear to have cocaine- or methamphetamine-like reinforcing properties in monkeys and was ineffective in altering established patterns of psychomotor-stimulant self-administration behavior. These results support clinical findings that despite long-term use of l-deprenyl for the treatment of Parkinson's disease by large numbers of patients, no instances of abuse have been documented. l-Deprenyl has recently been suggested as a potential medication for the treatment of various types of drug abuse, including cocaine abuse, but its failure to produce selective effects in decreasing cocaine or methamphetamine self-administration behavior in the present experiments makes such an application seem unlikely.

Analgesic, anesthetic, and respiratory effects of the competitive N-methyl-D-aspartate (NMDA) antagonist CGS 19755 in rhesus monkeys.

The competitive excitatory amino acid antagonist cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755) increased the latency for monkeys to remove their tails from warm water (analgesia); larger doses produced ataxia, loss of righting, salivation, and eliminated reactivity to stimulation (anesthesia). CGS 19755 decreased tidal volume and had little effect on frequency of respiration. Although longer lasting, the effects of CGS 19755 were similar to the effects of ketamine, suggesting these effects result from actions at the NMDA receptor complex.

MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys.

The behavioral effects of MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e], a proposed noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were compared to those of phencyclidine (PCP). In pigeons, MK-801 produced PCP-like catalepsy (i.e., loss of righting without eye closure and without muscle relaxation) and PCP-like discriminative stimulus effects. In rats, MK-801 produced PCP-like behavior (i.e., locomotion, sniffing, swaying and falling). In rhesus monkeys, like PCP, MK-801 produced 1) ketamine-like discriminative stimulus effects, 2) positive reinforcing effects and 3) ketamine-like anesthetic effects (i.e., anesthesia without eye closure and without respiratory depression, but with profuse salivation and with some muscle relaxation). Thus, MK-801 produced PCP-like behavioral effects in each species and with each procedure. MK-801 was 2 to 10 times more potent than PCP, depending on the effect measured and the species tested. Because MK-801 has been shown to have NMDA-antagonist properties, the findings of this study offer further support for the hypothesis that certain behavioral effects of PCP-like drugs may result from a reduction of neurotransmission at excitatory synapses utilizing NMDA-preferring receptors. The behavioral similarities between MK-801 and PCP make it relevant to evaluate PCP-like activity in clinical trials of MK-801.

Compounds of novel structure having kappa-agonist behavioral effects in rhesus monkeys.

The kappa-agonist behavioral effects of several compounds were studied in rhesus monkeys and mice. Rhesus monkeys trained to discriminate ethylketazocine from saline responded as if ethylketazocine had been administered when given bridged oripavines with either N-allyl or N-cyclopropylmethyl, but not N-methyl, substituents. These compounds had C7 substitutions of either 2-hydroxy-2-pentyl or 2-hydroxy-5-methyl-2-hexyl. Monkeys also showed ethylketazocine-like responding when given U-50,488 (trans-3,4-dichloro-N-methyl-N-[2- (1-pyrrolidinyl) cyclohexyl]-benzeneacetamide), a compound with an atypical structure not resembling any known narcotic. Additionally, ethylketazocine-like responding was produced by two 5,9-alpha dimethyl 6-7-benzomorphans with either an N-2-methoxyisobutyl or an N-2-methoxy-propyl substituent. The latter compound was the only compound active in producing ethylketazocine-like discriminative effects that also reversed morphine-withdrawal signs. The N-methyl bridged oripavines that were inactive in producing ethylketazocine-like discriminative effects reversed morphine withdrawal signs.