• Energy Research

The effect of the lesion of central serotonergic neurons by 5,7-dihydroxytryptamine (5,7-DHT), on ethanol-induced taste and place aversion conditioning was studied in male Wistar rats. Control biochemical analysis revealed that 5,7-DHT (250 micrograms per rat, free base, i.c.v.) produced marked and selective depletion of serotonin (5-HT) in the hippocampal formation and the limbic forebrain complex. Ethanol-induced (1.5 g/kg, i.p.) conditioned taste aversion (CTA) to saccharin solution was unaffected by the lesion of central serotonergic neurons. The 5,7-DHT-lesioned and sham-lesioned rats showed comparable ethanol-induced CTA even 30 days after the last ethanol injection. Similarly, ethanol-induced (1.5 g/kg, i.p.) conditioned place aversion (CPA) was unaffected by 5,7-DHT administration. These results suggest that central serotonergic pathways are not primarily involved in the aversive effects of high ethanol doses in rats.

The present study examined the effect of ethanol (0.25-1.0 g/kg, I.P.) alone and in combination with drugs affecting different ligand-gated ion channels on a horizontal locomotor activity of male Wistar rats. None of the drugs given alone affected the locomotor activity. Similarly, combining ethanol either with nicotine (0.1 or 0.6 mg/kg, S.C.) or the competitive NMDA receptor antagonist, CGP 40116 (0.5 mg/kg, I.P.) did not result in any significant changes in ambulation. On the other hand, a significant hyperadditive interaction between ethanol (0.5 or 1.0 g/kg) and the uncompetitive NMDA receptor antagonist, dizocilpine (0.1 mg/kg, I.P.) was found. Thus, a combined administration of ethanol and dizocilpine produced a marked stimulation of the locomotor activity. Combining 1.0 g/kg ethanol with the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (5.0 mg/kg, I.P.) tended to produce locomotor stimulation. Our results suggest the existence of interaction between ethanol and the NMDA receptor complex in mediation of locomotor stimulation. Alternatively, a common neurotransmitter system (other than glutamatergic) mediate central stimulatory effects of ethanol and dizocilpine. A possible role of dopamine in this interaction is being discussed.

The drug discrimination test was used to evaluate the role of 5-HT3 receptors in the mediation of the stimulus properties of ethanol in rats trained to discriminate between ethanol (1.0 g/kg, 10% v/v, i.p.) and saline vehicle. Rats trained to discriminate between a lower dose of ethanol (0.5 g/kg i.p.) failed to attain discrimination criteria after 20 weeks (100 sessions) of training. None of the doses of 5-HT3 receptor antagonists (0.001, 0.01, 0.1, 1.0, 10.0 mg/kg of tropisetron or ondansetron) administered i.p. 30 min before ethanol, antagonized the discriminative stimulus properties of ethanol. Furthermore, none of the centrally (1, 10, 35 micrograms per rat) or i.p. (0.1, 1.0, 2.5, 5.0, 10.0 mg/kg) administered doses of 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide, could replace the ethanol discriminative cue. These results suggest that 5-HT3 receptors are not primarily involved in the mediation of the stimulus properties of ethanol.

Several drug discrimination studies reported that both competitive and uncompetitive NMDA receptor antagonists substituted for ethanol stimulus in rats. In the present study we examined if compounds that act as agonists at the NMDA receptor complex, D-cycloserine (a partial agonist at the glycine positive modulatory site) and N-methyl-D-aspartate (an agonist at the glutamate binding site), could antagonize the discriminative stimulus effects of ethanol. Rats were trained to discriminate between IP administered 1.0 g/kg of ethanol (10% v/v) and saline under a sweetened milk-reinforced fixed ratio 10 (FR10) schedule of reinforcement. When the animals met the discriminative criteria, antagonism tests were conducted with D-cycloserine (0.3-10.0 mg/kg, IP) and N-methyl-D-aspartate (15.0-60.0 mg/kg, IP). Neither D-cycloserine nor N-methyl-D-aspartate antagonized the ethanol-mediated discriminative stimulus effects. In addition, D-cycloserine (3.0-300.0 mg/kg, IP) did not substitute for ethanol. These results indicate that at least certain agonists at the NMDA receptor complex do not attenuate the ethanol interoceptive cue in the rat.

Tetrahydrodeoxycorticosterone (5beta-THDOC; 1.3-12.0 mg/kg), a neurosteroid enhancing the GABA(A) receptor-associated chloride conductance, produced predominantly ethanol-appropriate responding (> 80%) in rats trained to discriminate 1.0 g/kg ethanol from saline. However, neither picrotoxin (0.25-1.5 mg/kg), nor dehydroepiandrosterone sulfate (0.01-100.0 mg/kg), a neurosteroid acting as a GABA(A) receptor antagonist, attenuated the stimulus effects of ethanol. These results indicate that: (1) at least certain neurosteroids may produce subjective states similar to these induced by ethanol; (2) blockade of the GABA(A) receptor-associated channel does not eliminate the ethanol interoceptive cue in rats.

There is a large body of experimental evidence that both stress and N-methyl-D-aspartate (NMDA) receptor antagonists may alter acute behavioural effects of ethanol. Notably, an uncompetitive, low-affinity NMDA receptor antagonist, memantine, has been recently claimed to possess anti-craving properties in rats with a long-term history of ethanol consumption. The aim of the present study was to assess the effects of restraint stress and memantine on the dose-response curve of ethanol discrimination. Rats were trained to discriminate 1 g/kg ethanol from saline in the two-lever drug discrimination procedure. When ethanol discrimination was acquired, the subjects were exposed to 30-min sessions of acute restraint stress, and different doses of ethanol (0.25, 0.5 or 1 g/kg) or saline were administered. In subsequent experiments the effects of memantine (2.25 or 4.5 mg/kg) on the cueing effects of ethanol were tested. Neither the stress sessions nor memantine influenced the ethanol discrimination dose-response curve. Moreover, the stress did not alter the rate of responding. However, both doses of memantine tended to increase the rate of responding when given in combination with lower doses of ethanol (0.25-0.5 g/kg). In contrast, 4.5 mg/kg memantine decreased the response rate when combined with 1 g/kg ethanol. These results suggest that: (1) pre-exposure to acute restraint stress or memantine does not affect the dose-response curve of ethanol discrimination; (2) memantine given in combination with low doses of ethanol may stimulate operant behaviour in the food-reinforced drug discrimination procedure.

Numerous works have demonstrated an interaction between 5-HT3 receptor antagonists and some of the effects of ethanol (EtOH) using biochemical, electrophysiological, and behavioral techniques. Thus 5-HT3 antagonists are capable of reducing EtOH-induced release of dopamine in the nucleus accumbens, EtOH-induced hyperlocomotion, and voluntary EtOH consumption in laboratory animals. In addition to its rewarding effect, EtOH possesses aversive properties as demonstrated in the conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms. The role of 5-HT3 receptors in aversive effects of EtOH remains, however, unknown. We decided to study the effect of 5-HT3 antagonist, tropisetron, on aversive properties of EtOH (1.5 g/kg i.p.) in rats using the CTA and CPA models. In addition, effect of tropisetron on morphine (Mf)-induced CTA (10.0 mg/kg SC) was investigated. Tropisetron (0.001-0.5 mg/kg) did not influence CTA produced by EtOH and Mf. When given alone, it failed to produce any taste conditioning. Furthermore, tropisetron did not modify CPA induced by EtOH. Our results suggest that 5-HT3 receptors are not involved in aversive effects of acute doses of EtOH.

The aim of the present study was to determine if nicotinic acetylcholine receptors (nAChRs) might be involved in the regulation of alcohol intake by Wistar rats. A non-selective nAChR agonist, nicotine, and a non-competitive nAChR antagonist, mecamylamine, were tested in alcohol-preferring Wistar rats maintained on a limited access (4 h/24 h) to ethanol (10%, v/v). In addition, the effects of nicotine and mecamylamine on intake of standard laboratory chow were studied in a separate control experiment. Nicotine (0.1-0.6 mg/kg, s.c.) decreased ethanol consumption, but had no effect on food intake. In contrast, mecamylamine (1-3 mg/kg, s.c.) did not alter ethanol drinking even at the dose (3 mg/kg) which significantly decreased food intake. These results suggest that activation of nAChRs may selectively reduce ethanol consumption in outbred Wistar rats.

It has been shown that ethanol produces a complex interoceptive cue in rodents with distinct GABAergic, glutamatergic, and serotonergic (5-hydroxytryptamine, 5-HT) components. The present study aimed to examine the contribution of the 5-HT system originating in the dorsal raphe nucleus (DRN) to the discriminative stimulus effects of ethanol in male Wistar rats. Therefore, selective lesions of 5-HT neurons in the DRN were induced by microinfusions of 5,7-dihydroxytryptamine. The DRN- and sham-lesioned rats were trained to discriminate ethanol (1.0 g/kg) from saline in a standard two-lever drug discrimination procedure. Acquisition of ethanol discrimination and discrimination performance after consumption of lower doses of ethanol did not differ between the groups. In substitution tests, diazepam (0.5-2.5 mg/kg), a nonselective benzodiazepine receptor agonist, partially generalized from the ethanol cue in both groups. In contrast, m-chlorophenylpiperazine (0.1-0.9 mg/kg), a mixed 5-HT(1B/2C) receptor agonist, did not mimic the ethanol cue. The drug decreased response rates in both groups, but this effect was more evident in the sham-lesioned group. A 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyloamino)-tetraline (0.05-0.4 mg/kg), did not produce significant increase in ethanol-appropriate responding in either group. These results may indicate that 5-HT neurons of the DRN are not critically involved in ethanol discrimination in the rat.