Evalena Ericson

Suppression of conditioned avoidance behavior by the local application of (-)sulpiride into the ventral, but not the dorsal, striatum of the rat.

The local application of (-)sulpiride, 200 ng side-1, into the nucleus accumbens produced a suppression of conditioned avoidance behavior in male rats, 10 and 90 min after injection. The decrease in avoidance behavior was accompanied by a decrease in motor activity, as evidenced by changes in the number of intertrial crosses. When injected into the dorsolateral neostriatum, or the amygdala, (-)sulpiride produced a suppression of conditioned avoidance behavior at the 90-min time interval only. Considering diffusion from the injection site, as indicated by an increase in local dopamine turnover [(DO-PAC + HVA) DA-1], the effects obtained in the dorsolateral neostriatum, and possibly also the amygdala, 90 min after injection could be due to diffusion to the nucleus accumbens. The local application of (-)sulpiride into the posterior neostriatum, or into the prefrontal cortex, produced no statistically significant effect on conditioned avoidance behavior 10 or 90 min after injection. It is concluded that the performance of conditioned avoidance behavior in the rat is critically dependent on an intact dopaminergic neurotransmission in the nucleus accumbens or adjacent areas of the ventral striatum.

Suggestive evidence for inhibitory effects of galanin on mesolimbic dopaminergic neurotransmission.

The objective was to examine effects of galaninrat on forebrain monoamine synthesis and on spontaneous locomotor activity in the rat. The rate of monoamine synthesis was estimated by measuring the accumulation of l-DOPA and 5-HTP, following inhibition of cerebral aromatic l-amino acid decarboxylase by means of NSD-1015 (100 mg kg-1 i.p.), after i.c.v. or intracerebral administration of galanin in adult male Wistar rats. Spontaneous locomotor activity was observed in an automated open-field arena ( approximately 0.5 m2). The i.c.v. administration of galanin (0.5-5.0 nmol bilaterally) produced a dose-dependent, statistically significant, increase in DOPA accumulation throughout the neostriatum, and in the olfactory bulb, indicating an increase in the rate of DA synthesis. No increase was observed in brain areas where noradrenaline is the predominant catecholamine, such as the neocortex or the ventral hippocampus. In addition, there was a tendency for an increase in 5-HTP accumulation in the dorso-lateral neostriatum and in the accumbens. The same i.c.v. administration of galanin produced a dose-dependent, and statistically significant, decrease in spontaneous locomotor activity. The effect on forebrain DA synthesis could also be produced by local bilateral application of galanin (2x1 nmol) into the ventral tegmental area, but not the nucleus accumbens (2x2 nmol). There were no effects on forebrain DOPA or 5-HTP accumulation by the local application of galanin into the locus coeruleus, or into the dorsal raphe nucleus. It is concluded that the neuropeptide galanin modulates forebrain dopaminergic neurotransmission. The effect appears to be mediated at the somato-dendritic level of the meso-neostriatal pathway, and could perhaps be utilized to normalize perturbations ascribed to dysfunction in this neuronal pathway, such as schizophrenia.

Loss of discriminative avoidance behavior by local application of kynurenic acid into the nucleus accumbens of the rat

Male Sprague-Dawley rats, trained to perform a visual discrimination, were administered kynurenic acid, an antagonist of excitatory amino acid receptors, 4.7 micrograms bilaterally into the nucleus accumbens. The performance of the visual discrimination was impaired 15, but not 360, min after administration. In addition, motor activity in the test apparatus was markedly increased by the treatment, whereas no effects were noted when the animals were observed in an open field. The abnormal behavior produced by kynurenic acid has previously been observed after administration of high doses of compounds like d-amphetamine and L-DOPA, and generally discriminative behavior has been shown to be highly dependent on normal impulse mediated release of dopamine in brain. The present results show that this behavior also is dependent on an intact excitatory amino acid neurotransmission.

Phencyclidine-induced disruption of an aversely motivated two-choice successive discrimination in the rat

Rats were trained to performed an aversely motivated discriminative task in a shuttle-box. The administration of phencyclidine (PCP), 2 mg kg−1 SC at −20 min, produced disruption of discriminative performance and an increase in intertrial crosses. There were no changes in avoidance performance or in avoidance latency. Pretreatment with haloperidol, 0.1 or 0.2 mg kg−1 SC at −40 min, or remoxipride 8 mg kg−1 IP at −30 min, did not antagonize the PCP-induced disruption of discriminative performance, nor was the PCP-induced increase in number of intertrial crosses antagonized. In fact, there appeared to be a further increase in intertrial crosses, above PCP levels, by haloperidol treatment and this effect was statistically significant after remoxipride treatment. The present results, together with previous observations that alsod-amphetamine disrupts discriminative conditioned avoidance behavior, suggest the possibility that this model could be used in the search for new, non-dopaminergic, antipsychotic drugs.

Stimulation of brain dopamine autoreceptors by remoxipride administration in reserpine‐treated male rats

Abstract— Male Sprague‐Dawley rats were treated subcutaneously with reserpine (5 mg kg−1, — 18 h) and with the aromatic amino acid decarboxylase inhibitor, NSD‐1015 (3‐hydroxybenzylhydrazine) (100 mg kg−1 ‐30 min). Remoxipride 0 ‐8, 3 ‐2 or 12 ‐8 mg kg−1 was administered subcutaneously at ‐50 min. Immediately following decapitation (0 h), the ventral striatum and the anterior neocortex were dissected. Dopa and 5‐hydroxytryptophan accumulation in these brain areas were analysed by HPLC with electrochemical detection. Reserpine produced a marked increase in striatal and neocortical dopa accumulation, in comparison with glucose vehicle + NSD‐1015‐treated controls, and this increase was dose‐dependently antagonized by remoxipride treatment. Thus, together with demonstrated dopamine receptor antagonist actions in intact animals, remoxipride behaves as a mixed dopamine receptor agonist‐antagonist. Such properties could contribute to the favourable endocrine and extrapyramidal side effect profile of remoxipride as an antipsychotic agent.

In vivo characterization of novel full and partial 2-(4-aminophenyl)-N, N-dipropylethylamine dopamine D2 receptor agonists

Behavioral and biochemical techniques were used to compare the in vivo intrinsic efficacy of two new 2-(4-aminophenyl)-N, N-dipropylethylamine dopamine D(2) receptor agonists, 2-(4-amino-3-trifluoromethylphenyl)-N-N-dipropyl-ethylamine (NBF-203) and 2-(4-amino-3-bromo-5-trifluoromethylphenyl)-N-N-dipropylethylamine (NBF-234). Adult male Sprague-Dawley rats were used as experimental animals. NBF-203 was characterized as a full dopamine D(2) receptor agonist, whereas NBF-234 displayed properties of a partial agonist, or antagonist, at dopamine D(2) receptors. Thus, NBF-203 produced effects similar to those of apomorphine in models for dopamine synthesis, release and turnover. As a strong indication of markedly less intrinsic efficacy, the administration of NBF-234 did not result in antagonism of reserpine-induced suppression of locomotor activity in the presence of (+/-)-1-phenyl-2,3,4,5, -tetrahydro-(1H)-3-benzazepine-7,8-diol HCl (SKF-38393)-induced dopamine D(1) receptor activation. The present series of compounds offer the possibility of adjusting intrinsic efficacy at dopamine D(2) receptors, and such fine-tuning could be an important strategy in the search for optimal antipsychotic or antiparkinson drugs within the partial dopamine D(2) receptor agonist concept.

Specific effects by the psychotomimetic drugsd-amphetamine and phencyclidine on the performance of an aversely motivated successive visual discrimination in the rat.

SummaryRats were trained to perform a conditioned avoidance response to white noise in a conventional two-compartment “shuttle-box”. The partition between the compartments had two openings, however, and the correct passage (leftor right) was signalled by changes in background illumination. In this situation the psychotomimetic compoundsd-amphetamine (4 mg kg−1 IP) and phencyclidine (PCP) (2 mg kg−1 SC) were found to selectively disrupt the visual discrimination. Thed-amphetamine-induced abnormal behavior in this situation has previously been linked to excessive dopamine (DA) receptor stimulation, not controlled by nerve impulse flow and its regulation by important local feed-back mechanisms. Thus, the psychotomimetic effects produced by this compound should not only by due to increased DA receptor activationper se, but also to a disruption of normal patterns of firing and release in dopaminergic neurons. There is evidence to suggest that PCP via an excitatory amino acid (EAA) receptor produces a similar net effect on brain meso-limbic dopaminergic neurotransmission via an increased rate of firing, accompanied by regularization of firing (loss of burst activity). In support for a mediation of PCP-induced effects via EAA receptors, the local application of kynurenic acid into the ventral forebrain (4.7µg, bilaterally) was found also to produce a selective disruption of discriminative performance. It should be noted, however, thatd-amphetamine-induced loss of discriminative behavior, but not that induced by PCP, was antagonized by haloperidol (0.1–0.2 mg kg−1 IP) administration. It is thus possible that at least some effects of PCP in this situation are mediated on the efferent side of the dopaminergic neuron. It is suggested that the abnormal behavior, as evidenced by a loss of discriminative (but not avoidance) behavior, is due to disruption of normal, feed-back regulated, nerve impulse flow.