(D-Ala2)deltorphin II: D1-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens.

In order to investigate the relative role of central delta- and mu-opioid receptors in behavior, the effects of (D-Ala2)deltorphin II, a natural delta-opioid peptide, and PL017, a beta-casomorphin derivative specific for mu receptors, were compared after local intracerebral and intraventricular administration. Intracerebral infusion of the two peptides was done bilaterally in the limbic nucleus accumbens and in the ventral and dorsal caudate putamen of freely moving rats through chronic intracerebral cannulas. After intra-accumbens infusion, the two peptides elicited marked but opposite behavioral effects: while (D-Ala2)deltorphin II evoked dose-dependent motor stimulation characterized by locomotion, sniffing, and oral stereotypies, PL017 elicited motor inhibition with rigidity and catalepsy. These effects were site specific because they could not be evoked from the ventral or from the dorsal caudate. Low doses of naloxone (0.1 mg/kg, s.c.) blocked the effects of PL017 but not those of (D-Ala2)deltorphin II, which instead were reduced by high doses of naloxone (1.0 mg/kg) and by the putative delta-antagonist naltrindole; this drug failed to affect the catalepsy induced by PL017. Therefore, while (D-Ala2)deltorphin II effects were delta-mediated, PL017 effects were mu-mediated. Blockade of dopamine D1 receptors by SCH 23390 abolished (D-Ala2)deltorphin II effects, while blockade of dopamine D2 receptors by raclopride or by haloperidol was without effect. Local application by reverse dialysis of (D-Ala2)deltorphin II (5 microM) to the accumbens resulted in a naloxone-sensitive increase of extracellular dopamine concentrations; these effects could not be evoked from the caudate, nor by PL017 in the accumbens. Intracerebroventricular administration of (D-Ala2)deltorphin II or of PL017 elicited behavioral effects qualitatively similar to those obtained from the accumbens.

Blockade of acquisition of drug-conditioned place aversion by 5HT3 antagonists.

The effect of two 5HT3 antagonists, ICS 205-930 and MDL 72222, on drug-induced place aversion was studied in a two-compartment apparatus with a procedure including a pre-test for spontaneous preference. Naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) and picrotoxin (2.0 mg/kg IP) paired with the preferred compartment elicited a significant place aversion. ICS 205-930 and MDL 72222 failed to modify spontaneous place preference when paired with both compartments. ICS 205-930 (30 micrograms/kg SC) paired with the preferred and, in other experiments, with the non-preferred compartment, also failed to modify spontaneous preference. ICS 205-930 (7.5, 15 and 30 micrograms/kg SC), paired with both compartments, dose-dependently reduced the place aversion induced by naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) and picrotoxin (2.0 mg/kg IP). MDL 72222 (30 micrograms/kg SC) paired with both compartments had a similar effect. The result indicate that 5HT, via 5HT3 receptors, plays a role in the aversive properties of drug stimuli.

Familial rates of affective illness in Sardinia with special reference to schizoaffective disorder.

Familial rates of psychiatric disorders were studied in southern Sardinia and showed an increase in relatives of probands with the following research diagnostic criteria (RDC) diagnoses: normal, unipolar depression, schizoaffective depressive, schizoaffective bipolar, bipolar with mania and bipolar with hypomania. A significantly higher risk for bipolar schizoaffective disorder was observed in relatives of bipolar schizoaffectives compared with relatives of normal probands.

Time and dose dependence of the 'priming' of the expression of dopamine receptor supersensitivity.

The D-1 receptor agonist, SKF 38393 (2 mg/kg s.c.), failed to elicit contralateral turning when administered to drug-naive rats 17 days after unilateral 6-hydroxydopamine (6-OHDA) lesioning of the medial forebrain bundle, while it elicited intense contralateral turning 90 days post-lesioning. On the other hand the D-1/D-2 receptor agonist, apomorphine (0.1 mg/kg s.c.), induced contralateral turning in drug-naive rats lesioned 14 days earlier and made the administration of SKF 38393 (2 mg/kg s.c.) 3 days later effective to evoke contralateral turning ('priming'). The effectiveness of apomorphine as a primer of SKF 38393-induced turning depended critically on the interval between the administration of the two agonists. Effectiveness was minimal after 3 h and increased after 6-12 h, peaked at 72 h and was reduced after 10 days. The D-2 receptor agonist, LY 171555 (0.2 mg/kg s.c.), was also effective as a primer of SKF 38393-induced contralateral turning and this effect also was dependent upon the interval between priming and SKF 38393 administration. Moreover, priming was dependent on the dose of drug used as primer and on the dose of SKF 38393 used as a challenge. In contrast to SKF 38393, priming was unable to make effective a dose of LY 171555 that was ineffective in drug-naive rats, suggesting that LY 171555 affects D-1-dependent turning to a greater extent than D-2-dependent turning. The results indicate that the priming phenomenon is rather strictly time- and dose-dependent.

Properties of benzodiazepine binding sites in peripheral blood lymphocytes.

Benzodiazepine (BDZ) binding sites were studied by using 3H-diazepam and 3H-Ro 5-4864 in intact lymphocytes from peripheral blood (PBL), in comparison to kidney and cerebellum. Experiments with 3H-diazepam performed at equilibrium and measuring kinetics revealed that BDZ binding sites are indeed present in rat PBL. The binding is saturable (Bmax 557 fmoles/10(6) cells), with high affinity (KD = 9.3 nM) and reversible. Specific binding sites are also observed by saturation experiments with 3H-Ro 5-4864 (Bmax 175 fmoles/10(6) cells, KD 2.2 nM). In addition, analysis of saturation isotherms obtained with 3H-diazepam indicates that BDZ binding sites are also present in human PBL. Scatchard plot of binding isotherms revealed an apparent single population of sites in all cases. The pharmacological characterization of BDZ binding sites in PBL, as compared with those of kidney and cerebellum, showed that these sites belong to the so-called "peripheral type."