David N. Velázquez-Martínez

Discriminative stimulus properties of indorenate in a conditioned taste aversion paradigm.

Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors. It possesses anxiolytic and antihypertensive actions mediated by 5-HT(1A) receptors and anorectic activity mediated by 5-HT(2C/1B) receptors. This study examined whether INDO may exert discriminative control using a conditioned taste aversion (CTA) paradigm, and whether differential participation of 5-HT receptor subtypes may be involved in its cue. Male Wistar rats trained to drink their daily water in a 30-min period were trained to discriminate INDO from saline. One group received the intraperitoneal administration of INDO (10.0 mg/kg) before saccharin-LiCl pairings; on alternate days, rats received saline before the saccharin-saline pairings (Group D(+)S(-)). The other group had the contingencies reversed (i.e., the administration of INDO preceded saccharin-saline pairings: Group D(-)S(+)). In two-bottle generalization tests (one bottle containing saccharin, the other plain water), the preference for saccharin was evaluated after different doses of INDO, [3H]-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) (5-HT(1A)), buspirone (5-HT(1A)), RU24969 (5-HT(1A/1B)), TFMPP (5-HT(1B/2C)), MK212 (5-HT(2C)), alpha-Me-5-HT (5-HT(2C/2A)), 2-Me-5-HT (5-HT(3)) and cisapride (5-HT(4)). The results showed that INDO, RU24969, TFMPP, alpha-Me-5-HT and MK 212 produced a dose-dependent generalization; 8-OH-DPAT and buspirone produced only partial generalization, while 2-Me-5-HT and cisapride did not produce generalization. The results indicate that INDO administration may exert discriminative control over saccharin preference mediated mainly by 5-HT(1B/2C) receptors, but with an important contribution of 5-HT(1A) receptors.

The GABA-B antagonist 2-hydroxysaclofen reverses the effects of baclofen on the discriminative stimulus effects of D-amphetamine in the conditioned taste aversion procedure

Some of the behavioral effects of d-amphetamine (d-AMPH) are mediated by an increase in dopamine neurotransmission in the nucleus accumbens. However, there is evidence that gamma-amino-butyric-acid-B (GABA-B) receptors are involved in some behavioral effects of D-AMPH and cocaine. Here, we examined the effects of baclofen on the discriminative stimulus properties of D-AMPH, using conditioned taste aversion (CTA) as the drug discrimination procedure. Male Wistar rats were deprived of water and trained in the CTA procedure. They received D-AMPH (1 mg/kg, i.p.) before gaining access to saccharin, which was followed by an injection of LiCl. On alternate days, the subjects received saline before and after the access to saccharin. After the rats learned the D-AMPH-saline discrimination, the standard dose of D-AMPH was replaced by different doses of D-AMPH, baclofen (a GABA-B receptor agonist), 2-hydroxysaclofen (a GABA-B receptor antagonist), a combination of baclofen+D-AMPH, or a combination of 2-hydroxysaclofen+baclofen+D-AMPH. Baclofen did not substitute for D-AMPH, but, when combined with D-AMPH, it produced a small but significant decrease in the discriminative stimulus effects of D-AMPH. This effect was reversed by administration of 2-hydroxysaclofen. These data suggest that GABA-B receptors play a regulatory role in the discriminative stimulus effects of D-AMPH.

Participation of the dorsal hippocampus in stimulus discrimination with scopolamine.

Stimulus discrimination is the capacity of an organism to differentiate between stimuli and emit associated responses. The administration of the muscarinic antagonist scopolamine can be used as a stimulus by mammals in a discrimination task. The present study analyzes the contribution of the hippocampus in scopolamine discrimination and generalization. Male Wistar rats, weighing 250-300 g at the beginning of the experiment, were trained to discriminate between scopolamine (1.0 mg/kg, i.p.) and saline administration using a two-lever operant task; rats had to respond differentially to each lever depending on the preceding drug or saline administration. Once stimulus control was attained, rats were tested with different scopolamine doses (0.0, 0.056, 0.091, 0.16, 0.31 and 1.0 mg/kg, i.p.) in order to obtain generalization curves. After generalization the rats were randomly assigned to hippocampal CA1 lesion or control groups. Hippocampus impairment produced a transient decrease in the capacity to discriminate between scopolamine and saline conditions; nonetheless, scopolamine correct responses were rapidly recovered after a few sessions and even maintained after 90 days. Correct responses for saline condition were never recovered. The generalization curve obtained after hippocampus lesion showed a response gradient severely flattened. Results suggest that the hippocampus participates as a neural system supporting the sensitivity to detect discrete changes in stimulus properties and relational memory, more than on the capacity to recall for simple associative responses.

Further evidence that the discriminative stimulus properties of indorenate are mediated by 5-HT1A/1B/2C receptors

Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors. Unlike other anxiolytics such as 5-HT receptor agonists, INDO may not share tolerance or dependency with the benzodiazepine anxiolytics. It has been reported that the discriminative stimulus properties of 5-HT(1A/1B/2C) agonists, but not those of 5-HT(3/4) agonists, generalize to INDO. Therefore, the aim of the present study was to obtain further evidence on the differential involvement of 5-HT(1A/1B/2C) receptors in the discriminative stimulus properties of INDO by evaluating its interactions with antagonists of the 5-HT(1A), 5-HT(1B), 5-HT(2C), and 5-HT(3/4) receptor subtypes. Rats were trained to discriminate INDO from saline in a conditioned taste aversion paradigm. For Group D(+)S(-), administration of INDO signalled that saccharin flavour was followed by LiCl, while injection of vehicle signalled safe consumption of saccharin solution. Group D(-)S(+) had the contingencies reversed. After this training, rats had generalization tests where INDO administration was preceded by different doses of the following antagonists: WAY100635 (5-HT(1A)), NAN190 (5-HT(1A)), methiothepin (5-HT(1A/1B/2C)), GR127935 (5-HT(1B/1D)), ketanserin (5-HT(2A/2C)), ritanserin (5-HT(2C/2A)), mesulergine (5-HT(2C/2A)), metergoline (5-HT(2C/2A)), SB206553 (5-HT(2B/2C)), and tropisetron (5-HT(3/4)). In Group D(+)S(-), the order of potency to block the discriminative stimulus properties of INDO was WAY100635>ketanserin>ritanserin>GR127935>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190, while in Group D(-)S(+), the order was WAY100635>GR127935>ketanserin>ritanserin>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190. Tropisetron did not produce any alteration of the discriminative control by INDO. These results suggest that the discriminative signal of INDO is mediated by 5-HT(1A/2C/1B) receptors and that blockade of any of its components produces a degradation of its discriminative effects.

Dorsolateral frontal cortex and peripheral muscarinic receptors participation in the discriminative stimulus properties of scopolamine in rats.

Organisms are capable of making decisions based on their ability to discriminate between different stimuli. This principle is fundamental for the adaptation of organisms to their environment, by emitting appropriate behaviors based on a previously acquired discriminative process. The present study analyzed the participation of the peripheral nervous system, the M₁ muscarinic receptor subtype, as well as the contribution of the dorsolateral frontal cortex to discrimination process using scopolamine as discriminative stimulus. Male Wistar rats were trained to discriminate between scopolamine (1.0 mg/kg) and saline injections (i.p.) using a two-lever operant procedure. Once discrimination was acquired, generalization curves for scopolamine, methylscopolamine, pirenzepine, dorsolateral frontal cortex lesion and control conditions were obtained. Results showed that rats were able to discriminate and generalize its responses to different doses of scopolamine but not for methylscopolamine or pirenzepine, thus the data suggest that discriminative properties of scopolamine are processed in CNS and that the M₁ receptor does not participate in this process. Dorsolateral frontal cortex lesion did not produce any statistically significant difference in the generalization curve, which suggests that a system different from the dorsolateral prefrontal cortex may be responsible for the control of stimulus produced by scopolamine.

Attentional Mechanisms during the Performance of a Subsecond Timing Task.

There is evidence that timing processes in the suprasecond scale are modulated by attentional mechanisms; in addition, some studies have shown that attentional mechanisms also affect timing in the subsecond scale. Our aim was to study eye movements and pupil diameter during a temporal bisection task in the subsecond range. Subjects were trained to discriminate anchor intervals of 200 or 800 msec, and were then confronted with intermediate durations. Eye movements revealed that subjects used different cognitive strategies during the bisection timing task. When the stimulus to be timed appeared randomly at a central or 4 peripheral positions on a screen, some subjects choose to maintain their gaze toward the central area while other followed the peripheral placement of the stimulus; some others subjects used both strategies. The time of subjective equality did not differ between subjects who employed different attentional mechanisms. However, differences emerged in the timing variance and attentional indexes (time taken to initial fixation, latency to respond, pupil dilatation and duration and number of fixations to stimulus areas). Timing in the subsecond range seems invariant despite the use of different attentional strategies. Future research should determine whether the selection of attentional mechanisms is related to particular timing tasks or instructions or whether it represents idiosyncratic cognitive “styles”.

Super-reactivity to amphetamine toxicity induced by schedule of reinforcement.

The chronic exposure of rats to a schedule of operant water reinforcement coupled with chronically restricted access to water sensitized the animals to intermittentd-amphetamine injections (0.31–2.5 mg/kg with intervals of 12–23 days between any two injections) in such a way that this drug came to produce catastrophic losses of body weight (32.4% of control levels). In the sessions whend-amphetamine was administered, the rats were also given a total of 12 brief electric shocks. Loss of body weight was unaccompanied by parallel changes in operant behavior performance, or in food or water intake. Remarkably, in other studies with the same interventions (sham schedule sessions, water deprivation, and foot shocks), with the exception that reinforcers were never delivered,d-amphetamine did not produce catastrophic falls in body weight. This super-reactivity tod-amphetamine toxicity may be mediated by a possible stressor action of the schedule of reinforcement. Its mechanism might be analogous to the known sensitization produced by classical experimental stressor stimuli to the repeated administration ofd-amphetamine.