Florencio Miranda

Effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric modulator of the GABAB receptor, CGP7930, on the development and expression of amphetamineinduced locomotor sensitization in rats

BACKGROUND Several of the behavioral effects of amphetamine (AMPH) are mediated by an increase in dopamine neurotransmission in the nucleus accumbens. However, evidence shows that γ-aminobutyric acid B (GABAB) receptors are involved in the behavioral effects of psychostimulants, including AMPH. Here, we examined the effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric modulator of the GABAB receptor, CGP7930, on AMPH-induced locomotor sensitization. METHODS In a series of experiments, we examined whether baclofen (2.0, 3.0 and 4.0 mg/kg), CGP7930 (5.0, 10.0 and 20.0 mg/kg), or co-administration of CGP7930 (5.0, 10.0 and 20.0 mg/kg) with a lower dose of baclofen (2.0 mg/kg) could prevent the development and expression of locomotor sensitization produced by AMPH (1.0 mg/kg). RESULTS The results showed that baclofen treatment prevented both the development and expression of AMPH-induced locomotor sensitization in a dose-dependent manner. Furthermore, the positive allosteric modulator of the GABAB receptor, CGP7930, increased the effects of a lower dose of baclofen on AMPH-induced locomotor sensitization under both conditions. CONCLUSION These data provide further evidence that GABAB receptor ligands may modulate psychostimulant-induced behaviors.

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.

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.