Larry Stein

Self-administration of the D1 agonist SKF 82958 is mediated by D1, not D2, receptors

We have previously reported that two D1 dopamine agonists, SKF 82958 and SKF 77434, are readily self-administered by rats. However, due to the limited selectivities of these agents, it was not possible to attribute their reinforcing effects exclusively to their D1 actions. To assess the relative involvement of D1 and D2 receptors in SKF 82958 reinforcement, rats were pretreated 30 min before self-administration sessions with either the D1-selective antagonist (+)SCH 23390 or the D2-selective antagonist raclopride. The D1 antagonist (+)SCH 23390 (5–20 µg/kg, SC) produced significant, dose-related (compensatory) increases in SKF 82958; in contrast, the D2 antagonist raclopride (25–400 µg/kg, SC) did not significantly increase SKF 82958 self-administration, although raclopride did increase cocaine self-administration. Compensatory increases in self-administration rates are thought to reflect antagonist-induced reductions in drug reinforcement. Hence, we conclude that SKF 82958 self-administration depends on activation of a D1-regulated reinforcement substrate.

Substantia nigra self-stimulation: Dependence on noradrenergic reward pathways

Electrodes in the dopamine cell groups of the substantia nigra lose their ability to support self-stimulation after mechanical or chemical damage to ipsilateral noradrenergic pathways, or after pharmacological inhibition of norepinephrine synthesis. Replenishment of depleted stores of norepinephrine by central administration of exogenous transmitter selectively reinstates the suppressed behavior. These findings, which demonstrate an essential role for norepinephrine in the mediation of substantia nigra self-stimulation, lend no support to the hypothesis that self-stimulation can result from the activation of dopamine neurons alone.

Potent analgesic activity of the enkephalin-like tetrapeptide H-Tyr-D-Ala-Gly-Phe-NH2.

Abstract The N-terminal tetrapeptide amide analog of enkephalin (H-Tyr-D-Ala-Gly-Phe-NH 2 ) is approximately equipotent with highly active pentapeptide analogs of enkephalin (and with morphine) in producing analgesia after either intracerebroventricular or intravenous administration. Smaller fragments exhibited diminished potency, but even the dipeptide (H-Tyr-D-Ala-NH 2 ) retained naloxone-reversible analgesic activity at high intraventricular doses. These findings suggest that while the dipeptide has full intrinsic activity, the tetrapeptide sequence may be a minimum structural requirement for potent analgesia.

Neuropharmacology of Reward and Punishment

A hungry pigeon is easily trained to peck at a target to obtain food. A frightened rat, periodically subjected to electrical foot shock, learns equally well to avoid the painful stimulation by pressing a pedal. These demonstration experiments illustrate a high form of behavioral adaptation which Skinner (1938) has termed operant reinforcement. The term operant emphasizes the fact that the behavior operates on the environment to generate consequences. The term reinforcement refers to the fact that the behavior is strengthened when its consequences are favorable or rewarding.

Brain endorphins: possible mediators of pleasurable states

Present conceptions (Kosterlitz and Hughes, 1975; Akil and Liebeskind, 1975; Snyder, 1975) of endorphins as natural analgesic substances for regulation of the response to pain are probably correct (Belluzzi et al. 1976), but these formulations are too narrow to accommodate the role postulated for these peptides in mental disease (Bloom et al. 1976; Terenius et al. 1976). We propose here a broadening of the functions attributed to endorphins—along lines previously suggested (Goldstein, 1976; Byck, 1976; Belluzzi and Stein, 1977a)—to include the regulation of affective states and appetitive drives. More precisely, we suggest that endorphins may serve as transmitters or modulators in neuronal systems for the mediation of pleasure and reward. The possibility that reward dysfunction is an etiological factor in affective disorders and schizophrenia has been considered elsewhere (Stein, 1962; Stein and Wise, 1971).

Enhanced analgesic activity of D-Ala2 enkephalinamides following D-isomer substitutions at position five

Abstract The analgesic potency of D-Ala 2 , Met 5 - and D-Ala 2 , Leu 5 -enkephalinamide was increased following substitution of the D-isomers at position five. The substituted analogs were 2.5 times as potent as morphine in producing analgesia in rats when administered intraventricularly and 0.2 as potent as morphine when administered intravenously. D-Ala 2 , D-Leu 5 -enkephalinamide produced naloxone-reversible analgesia by the intravenous route in monkeys. The enhanced systemic activity following D-isomer substitutions at position five appeared to be due to some factor other than increased stability to peptidase degradation at the C-terminus.

Brain endorphin levels increase after long-term chlorpromazine treatment

Observations in animals (Bloom et al., 1976; Jacquet and Marks, 1976) and man (Terenius et al., 1976; Gunne et al., 1977; Kline et al., in press) suggest the possible involvement of brain endorphins in mental illness. Terenius et al. (1976) reported that four chronic schizophrenics exhibited elevated levels of endorphins in their cerebrospinal fluid during ‘a symptom-rich’ phase of their disease. In two of these patients, whose condition improved during neuroleptic therapy, there was a return to low endorphin level (Gunne et al., 1977). These findings are consistent with the idea that some psychotic symptoms might be caused by excessive endorphin activity. We report here raised endorphin levels in brains of rats after long-term administration of the antipsychotic agent chlorpromazine (CPZ), but not after the structurally-related antidepressant imipramine. This raises the possibility that the therapeutic action of antipsychotics may be associated with changes in endorphin activity.

BAM-18: Analgesia, hyperalgesia and locomotor effects

BAM-18, a proenkephalin A-derived opioid peptide, is widely distributed throughout rat CNS and displays high affinity for both mu and kappa opioid receptors. In the present study, BAM-18 was tested in two analgesia paradigms, tail-flick and hot-plate. Injections were centrally administered through a chronically implanted unilateral cannula in the lateral ventricle. In the tail-flick, low doses of BAM-18 (5 micrograms) produced a hyperalgesia while high doses of BAM-18 (50 micrograms) produced an analgesic response. Naloxone (10 mg/kg, s.c.) reversed the BAM-18-induced analgesia and unmasked a persistent hyperalgesia. Morphine-induced (1 microgram) analgesia was completely reversed by 5 micrograms BAM-18. In the hot-plate test, high doses of BAM-18 produced analgesia, with no hyperalgesia observed at any dose. Naloxone reversed the BAM-18-induced analgesia. The locomotor effects of BAM-18 did not differ from those of morphine except in effective dose (50 micrograms vs. 5 micrograms, respectively). Opioid and non-opioid effects of BAM-18 are discussed and compared with other endogenous peptides.