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This study examined the effects of hypotensive stress on classical conditioning of the rabbit's nictitating membrane response. Hypotension, consisting of an approximately 45% decrease in blood pressure, was maintained for 30 min by the i.v. infusion of sodium nitroprusside. Twenty minutes later animals were exposed to a conditioning session consisting of 60 pairings of a 200 ms tone conditioned stimulus with a 100 ms airpuff unconditioned stimulus directed at the cornea. This procedure was repeated for four consecutive days. Animals exposed to the hypotensive stress demonstrated a significantly retarded acquisition of conditioned responses as measured by their frequency and onset latency as well as by an increase in the number of trials required to reach acquisition criteria of five and 10 consecutive conditioned responses as compared with controls. A separate group of animals received a nitroprusside infusion one day after the acquisition of conditioned responses to the tone conditioned stimulus. These animals demonstrated a normal retention of conditioned responses and a normal response to varying intensities of the conditioned stimulus. Hypotensive stress also had no effect on the frequency and topography of the unconditioned response. It was concluded that a decrease in blood pressure can serve as a physiological stressor. One of the reactions to this stress consists of a retardation in the formation of associations during a learning task, without any decrease in the ability to retrieve previously learned material.

Pavlovian conditioning of the rabbit's nictitating membrane response was used to determine whether the retardation of learning produced by enkephalin derivatives was mediated through an action on mu- or delta-opioid receptors. Intraventricular injection of the highly selective mu-agonist, [D-Ala2, MePhe4, Gly-ol5] enkephalin (DAMGO) significantly retarded (2 nmol) or completely blocked (20 nmol) the acquisition of conditioned responses. The retarded or blocked acquisition of conditioned responses produced by DAMGO could still be detected when the rabbits were tested two days after cessation of drug injections, suggesting that DAMGO had affected learning and not simply performance of conditioned responses. Intraventricular injection of a comparable dose (20 nmol) of the highly selective delta-agonist, [D-Pen2,5] enkephalin (DPDPE) did not retard learning. A higher dose of DPDPE (200 nmol), which would be expected to act at both mu- and delta-receptors, did produce a retardation of acquisition that was comparable to the effects of a 2-nmol dose of DAMGO. However, unlike DAMGO, the retardation of learning produced by this dose of DPDPE appeared to be due, at least in part, to a reduction in the aversive properties of the unconditioned stimulus. The retardation of learning produced by 2 nmol of DAMGO and 200 nmol of DPDPE was due to an action on an opioid receptor because this effect was blocked by a subcutaneous injection of naloxone (2.5 mumol/kg), a specific opioid antagonist. The stereoselective effects of the mu-opioid agonist levorphanol further confirmed that the retarded learning was mediated through actions at the mu-opioid receptor. Autoradiographic studies indicated that a 2-nmol, intraventricular dose of DAMGO achieved contents greater than 1 pmol/mg in tissue lying within 2 mm of the lateral ventricle, third ventricle and cerebral aqueduct. These data suggest that enkephalins produce a retardation of learning through an effect on the mu-type of opioid receptor and that at least one locus of their actions is produced at periventricular sites lying within 2 mm of the ventricles.(ABSTRACT TRUNCATED AT 250 WORDS)