Striatal met-enkephalin concentration increases following nigrostriatal denervation.

Following specific lesion of the nigrostriatal dopaminergic pathways in rat brain, striatal met-enkephalin on the lesioned side increased to 245% of that on the non-lesioned side. This increase was evident only after a lag period of 7 days and the increase was maintained for at least 2 months after lesion. By contrast, there was no change in striatal somatostatin or vasoactive intestinal polypeptide concentration, indicating that the effect was not a generalised one. Levels of all three of these neuropeptides were unchanged in frontal cortex. These findings support the concept of a dopaminergic-enkephalinergic functional interrelationship in the striatum. In addition, the findings provide evidence that, following destruction of nigrostriatal dopaminergic neurons, not only is there a gradually developing postsynaptic dopamine receptor supersensitivity but also a compensatory alteration in the enkephalinergic system.

Pentazocine, cyclazocine, and nalorphine as discriminative stimuli.

Pentazocine, cyclazocine, and nalorphine are narcotic antagonists that also have analgesic activity of their own. The present investigation compared the stimulus properties of these three drugs in rats. Each drug was used as a discriminative stimulus for a separate group of rats. Depression of one lever resulted in food reinforcement following the administration of drug, and the opposite lever was reinforced after saline. Each drug readily acquired control of discriminated responding. The specific narcotic antagonist, naloxone, which antagonizes many of the effects of pentazocine, cyclazocine, and nalorphine, also antagonized the discrimination of these drugs. Stimulus generalization tests to each other narcotic antagonist, d-amphetamine, morphine, and LSD, showed that each narcotic antagonist has highly specific stimulus properties. Clear generalization occurred only to pentazocine and cyclazocine in the nalorphine-saline group, but neither cyclazocine nor pentazocine generalized to nalorphine.

Generalization of morphine and lysergic acid diethylamide (LSD) stimulus properties to narcotic analgesics.

The present investigation sought to determine whether the stimulus properties of morphine and lysergic acid diethylamide (LSD) would generalize to several narcotic analgesics which vary in their subjective effects. Morphine and saline served as discriminative stimuli for one group of rats in a 2-lever discrimination task. LSD and saline were discriminative stimuli for a second group. Depression of one lever in an operant chamber resulted in reinforcement following the administration of morphine or LSD and the opposite lever was reinforced after saline. After discriminated responding was stable, stimulus generalization tests with narcotic analgesics and antagonists showed that the stimulus properties of morphine generalized to methadone and meperidine, and partially to pentazocine, all of which produce morphine-like subjective effects in humans. Morphine stimulus properties did not generalize to nalorphine or cyclazocine, which produce dissimilar subjective effects. The stimulus properties of LSD generalized partially to cyclazocine, but not to nalorphine. In humans cyclazocine and nalorphine produce a high incidence of psychotomimetic effects, but the subjective effects of cyclazocine are differentiable from those of LSD.

Dopamine receptor sensitivity following nigrostriatal lesion in the aged rat.

This investigation sought to determine whether the ability to regulate dopamine receptor sensitivity following removal of dopaminergic innervation is altered during aging. Aged (24-26 months old) Fisher 344 rats compared with young (6 months old) rats had lower levels of dopamine and dopamine receptor binding ([3H]ADTN), but no change of dopamine-stimulated adenylate cyclase activity. Unilateral lesion of the nigrostriatal pathway produced equivalent dopaminergic denervation in rats of both age groups. The denervated striata of young rats had greatly enhanced dopaminergic sensitivity as evidenced by apomorphine induced rotational behavior and increased dopamine stimulated adenylate cyclase activity and [3H]ADTN binding. Old rats responded similarly with a very high degree of increased dopaminergic sensitivity in both the behavioral and biochemical parameters, demonstrating that the ability to regulate dopamine receptors remains basically intact. However, deficits of supersensitivity occurred in apomorphine induced rotational behavior and [3H]ADTN binding and there was a large deficit in the guanine nucleotide sensitive subcomponent of [3H]-ADTN binding. Supersensitivity of dopamine stimulated adenylate cyclase was not altered. The diminished ability to develop supersensitivity to [3H]ADTN binding could contribute to decreased [3H]ADTN binding in unlesioned rats.

Evidence for a role of endogenous opioids in the nigrostriatal system: influence of naloxone and morphine on nigrostriatal dopaminergic supersensitivity.

The effects of morphine and naloxone on nigrostriatal function were evaluated by their influence on rotational behavior in rats with unilateral lesions of the substantial nigra. Two different rotational syndromes which result from different lesion placements, were examined. Rats with the contraversive syndrome, when given apomorphine, rotate away from the lesioned side, while rats with the ipsiversive syndrome rotate toward the lesioned side. In both syndromes, rats rotate toward the lesioned side when given amphetamine. Morphine or naloxone, alone, was without effect in either syndrome. Morphine antagonized rotation by either apomorphine or amphetamine in both syndromes. Naloxone stimulated apomorphine-induced rotation in contraversive rats and antagonized amphetamine-induced rotation in ipsiversive rats. These findings support a functional role of endogenous opioids in this dopaminergic system. The effects of morphine and naloxone on apomorphine-induced rotation indicate that opiates act at a postsynaptic site in this system. Finally, the different responses to naloxone and morphine in the two rotational syndromes suggest that an enkephalinergic asymmetry may underlie the differences in behavioral responses between these two syndromes.

Altered characteristics of striatal [3H]ADTN binding following substantia nigra lesions.

The present experiments examined some characteristics of the enhanced striatal [3H]ADTN binding which occurs following substantia nigra lesion. The amount of binding of a fixed concentration of [3H]ADTN was greatly increased. The amount of guanine nucleotide sensitivity increased to an even greater extent than total [3H]ADTN binding. Saturation experiments showed one component of [3H]ADTN binding (KD 7 nM) in intact striata whereas there were two components of binding (KD 9 nM and KD 1 nM) in substantia nigra-lesioned striata. Most of the enhanced binding in substantia nigra-lesioned striata was the higher affinity component. Kainic acid lesion of substantia nigra-lesioned striata caused loss of the enhanced [3H]ADTN binding and the high affinity component of [3H]ADTN binding. These results indicate that following dopaminergic denervation, either the binding characteristics of a single type of dopamine receptor are altered or there is a specific increase in a distinct subtype of dopamine receptor with high agonist affinity and sensitivity to guanine nucleotides.

Differences in the stimulus properties of barbital and hallucinogens.

The present investigation sought to determine whether drugs which produce markedly different perceptual effects in man, barbital and mescaline or LSD produce different stimuli in rats. In a standard 2 lever operant test chamber, rats received sweetened milk for correct responses according to a variable interval schedule. All sessions were preceded by 1 of 2 treatments; following Treatment A, only responses on Lever A were reinforced and, in a similar fashion, Lever B was correct following Treatment B. No responses were reinforced during the first 5 min of a daily 30 min session. It was found that barbital can serve as a discriminative stimulus when this drug is paired with saline. Previously, we had demonstrated that mescaline or LSD can serve as discriminative stimuli. When barbital was administered to animals trained to discriminate mescaline or LSD and saline, they made either random responses or responses appropriate to saline treatment. This observation suggests that the stimulus properties of barbital are difference from those of the hallucinogens. A subsequent demonstration of discriminated responding when barbital and mescaline or LSD were paired as discriminative stimuli supports this conclusion. The present results extend previous findings which suggest that the degree of similarity or difference of drug stimuli in rats is congruent with the degree of similarity or difference of perceptual drug effects in man.