The NMDA antagonist MK-801 affects nonspatial learning in preweanling rats.

The N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptor has been implicated in several kinds of learning and memory, as well as in long-term potentiation (LTP), a putative cellular mechanism for learning and memory. This experiment examined the role of the NMDA receptor in patterned single-alternation (PSA) learning in preweanling rats following intraperitoneal injections of 0.05 mg/kg MK-801, a selective NMDA antagonist. MK-801 significantly inhibited PSA at both 60-s and 30-s intertrial intervals (ITIs), and attenuated, but did not block, learning at 8-s ITI. These results are compared with effects on PSA, a form of nonspatial, memory-based learning, observed after early postnatal exposure to alcohol, infant hippocampal lesions, and infant exposure to X-irradiation, and they add strongly to these earlier demonstrations of the role of the hippocampus in learning and memory that is clearly nonspatial and non-cognitive-map-related.

Extracellular characteristics of putative cholinergic neurons in the rat laterodorsal tegmental nucleus.

The extracellular electrophysiological properties of neurons in the laterodorsal tegmental nucleus (LDT), a major source of cholinergic afferents to the thalamus, were studied in chloral hydrate-anesthetized rats. A combination of antidromic activation from the thalamus and histological verification of recording sites was used to correlate the identity of extracellular recordings in the rat LDT with cholinergic neurons in that region. All neurons antidromically activated by stimulation of the anteroventral thalamus were histologically verified to be within clusters of cholinergic (NADPH-d-positive) cells in the LDT or in the adjacent nucleus locus coeruleus (LC). The thalamically projecting LDT neurons had a homogeneous neurophysiological profile consisting of long duration action potentials (mean = 2.5 ms), slow conduction velocities (mean = 0.78 m/s), and lengthy chronaxie values (mean = 0.725 ms). The appearance and axonal characteristics of these neurons resembled those of noradrenergic LC neurons, but the two populations exhibited substantially different spontaneous activity patterns and sensory responsiveness. These characteristics may be useful in the preliminary identification of putative cholinergic neurons in vivo, and thereby provide a foundation for exploring the neuropharmacology, afferent modulation, sensory responsiveness and behavioral correlates of the brainstem cholinergic system.

Ng-nitro-L-arginine, an NOS inhibitor, reduces tolerance to morphine in the rat locus coeruleus.

Ng-nitro-L-arginine (L-NArg), a potent nitric oxide synthase inhibitor, has been implicated as a potential mechanism for attenuating the development of tolerance to opioid drugs and for suppressing opioid withdrawal. Neurons in the locus coeruleus (LC) express opioid receptors and these neurons exhibit both tolerance to chronic administration of opioids and antagonist-precipitated withdrawal hyperactivity. This study tested the hypothesis that L-NArg would attenuate the development of opioid tolerance in LC neurons. Challenge doses of morphine were administered while recording single-cell extracellular activity in brain slices from rats who had been concurrently treated for 5 days with morphine (75 mg morphine sulfate base pellets) and L-NArg (10 mg/kg, i.p., bid). The average ED50 for morphine of cells from rats who received L-NArg injections and morphine pellets was similar to that in cells from rats who had been implanted with sham pellets (14.5-18 nM). In contrast, the average ED50 of cells from morphine pelleted animals who received saline injections was substantially higher (34.5 nM). These results demonstrate that L-NArg attenuates the development of tolerance to morphine in LC neurons.

Alleviation of x-irradiation-based deficit in memory-based learning by D-amphetamine: suggestions for attention deficit-hyperactivity disorder.

Selective exposure to x-irradiation during infancy, from postnatal days (PND) 2-11 in the rat, results in severe hippocampal granule cell hypoplasia. Preweanling (PND 17-18) rats, which suffer such hippocampal granule-cell agenesis, show deficits in patterned single alternation (PSA), a form of memory-based learning. Deficits in short-term memory along with increased arousal have been suggested as characteristic of children diagnosed with attention deficit-hyperactivity disorder (ADHD). We report here on the ameliorating effects of D-amphetamine, a drug commonly used in the treatment of ADHD, before Ritalin, on PSA, after infantile (PND 2-15) exposure to x-irradiation. After i.p. injections of 0.3 mg/kg D-amphetamine, the onset and magnitude of the PSA memory-based discrimination in the x-irradiated preweanling rats was restored to about the level of controls. These results, showing alleviation of x-irradiation-related deficits in short-term memory by D-amphetamine injections, along with our earlier and present results, showing substantial deficits after x-irradiation alone, encourage the hypothesis that hippocampal granule-cell hypoplasia, which would occur in humans prenatally and is Altman's model of "minimal brain dysfunction" [Altman, J. (1986) in Learning Disabilities and Prenatal Risk, ed. Lewis, M. (Univ. of Illinois Press, Urbana), pp. 241-304], may be a factor in at least some forms of ADHD and may provide a basis for an animal model of the disease.

Effects of early postnatal alcohol exposure on learning in the developing rat: replication with intubation method of delivery.

Early postnatal exposure to alcohol during early development produces deficits in learned persistence, as reflected in the partial reinforcement extinction effect (PREE) in weanling rats, and deficits memory-based learning, as shown by patterned single alternation (PSA) discrimination learning in preweanling rats. We report a partial replication of these effects using the intubation method instead of artificial rearing. Rat pups were intubated once per day with 4.5 g/kg/day alcohol in a milk-based diet or control diet on postnatal days (PNDs) 4 to 9, and then assessed for the PREE on PNDs 20 and 21 or PSA learning on PNDs 17 and 18. Compared with previous artificial rearing reports, the intubation method produced healthier and heavier pups, and yielded a consistently lower and less variable blood alcohol levels. Even with the lower alcohol levels, intubation with alcohol eliminated the PREE. Intubation with alcohol had a weaker but still detrimental effect on PSA learning. These results suggest that alcohol exposure during development can produce behavioral deficits in the absence of the more severe effects on brain and body growth typically associated with fetal alcohol syndrome.

Reversal of a postnatal alcohol-induced deficit in learned persistence in the rat by d-amphetamine.

Periodic (high peak) exposure to alcohol during early infancy in the rat has been shown to disrupt the partial reinforcement extinction effect (PREE), a measure of persistence learning, when rats were tested at weaning age. The current study examined the effects of d-amphetamine (0.3 mg/kg, i.p.) on the PREE after early postnatal exposure to alcohol (4.5 mg/kg) delivered in a milk-based diet or an isocaloric control diet via oral intubation once a day on postnatal days 4 to 9. On postnatal days 20 and 21, rats were trained on either a continuously reinforced or partially reinforced schedule of food reward, followed by extinction. Rats were randomly assigned to eight conditions, depending on diet, drug, and reward schedule. The results were (1) a replication of the finding that periodic (high peak) exposure to alcohol diminishes the PREE, and (2) that amphetamine restores the PREE to normal levels in alcohol-treated animals, and may reduce the PREE in control subjects. The possible role of noradrenergic and dopaminergic systems in situations of extinction and nonreward are discussed.