The effects of lesions of 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN) on ethanol-induced conditioned taste aversion were studied in male Wistar rats. Biochemical analysis revealed that a serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), infused into the DRN produced selective depletion of serotonin (i.e., 5-HT) in the frontal cortex and striatum. Conditioned taste aversion to saccharin solution induced by 2 g/kg of ethanol was not affected by the lesion. In contrast, aversion conditioning produced by a lower dose of ethanol (1 g/kg) was slightly but significantly attenuated by the 5,7-DHT administration. Taken together with our previous observations, the results of the present study may indicate that central serotonergic projections do not have a primary role in the aversive effects of high doses of ethanol (>1 g/kg) in the rat. On the other hand, it seems that serotonergic neurons of the DRN may play some modulatory role in the formation of the aversive-stimulus properties of moderate doses of ethanol.

The present study addressed the relationship between the parameters of saccharin drinking behaviour and locomotor activity in an open field environment and long-term alcohol self-administration. In a 22-day initiation phase, male Wistar rats were presented with increasing concentrations of ethanol (2-8%, v/v) in a choice with water. The rats were then given the choice between water and two ethanol solutions (8 and 16%). Every 28 days, ethanol was withdrawn for 5 days. The ethanol intake and the transient increase in ethanol consumption after each of six deprivation episodes (alcohol deprivation effect) was monitored and correlated with parameters of the subsequent saccharin drinking and open field tests. The total ethanol intake (g/kg/24 h) as well as the consumption of 16% ethanol were stable over time. However, the magnitude of the alcohol deprivation effect increased with the repeated deprivation episodes. None of the parameters measured in the open field or the saccharin drinking tests correlated with either ethanol consumption or the alcohol deprivation effect. These results suggest that (1) repeated episodes of ethanol deprivation may increase the magnitude of the alcohol deprivation effect, (2) neither saccharin drinking nor locomotor activity correlates with long-term ethanol drinking behaviour in rats.

The role of the nicotinic acetylcholine receptor (nAChR) in the discriminative and aversive stimulus effects of ethanol was studied in rats. In the operant drug discrimination procedure the rats were trained to discriminate between 1.0 g/kg ethanol and saline under the FR10 schedule of sweetened milk reinforcement. Neither the nAChR agonist, nicotine (0.1–0.6 mg/kg) nor the nAChR antagonist, mecamylamine (3.0–6.0 mg/kg) substituted for the ethanol stimulus. Moreover, mecamylamine (0.5–6.0 mg/kg) did not antagonise the ethanol stimulus. The cross-familiarisation conditioned taste aversion procedure was used as an alternative method to study stimulus resemblance between ethanol and nicotine. Six daily injections of nicotine (0.6 mg/kg) significantly decreased a subsequent ethanol-induced taste aversion conditioning. The aversive stimulus effects of ethanol were investigated with the conditioned taste aversion (CTA) paradigm. Mecamylamine (1.0–3.0 mg/kg) did not attenuate an ethanol-induced CTA. These results suggest that: (1) nAChRs are not primarily involved in the discriminative stimulus effects of ethanol when studied with the operant drug discrimination test; (2) nAChRs are not critically involved in the ethanol-induced CTA.

Ethanol has been reported to alter NMDA receptor-mediated biochemical and electrophysiological responses in vitro. The aim of the present study was to evaluate the effects of an uncompetitive NMDA receptor antagonist memantine, in animal models of alcoholism. Male Wistar rats were trained to drink 8% ethanol in a free-choice, limited access procedure. A separate group of animals was trained to lever press for 8% ethanol in an operant procedure where ethanol was introduced in the presence of sucrose. The selectivity of memantine's actions was assessed by studying its effects on food or water consumption in separate control experiments. Memantine (4.5-24 mg/kg) significantly, but not dose dependently, affected ethanol drinking in the limited access procedure. However, only 6 mg/kg memantine selectively decreased ethanol drinking. Memantine did not alter ethanol intake in rats trained to lever press for ethanol in the operant procedure. Only 9 mg/kg memantine reduced operant responding in the extinction procedure in the rats trained to lever press for ethanol. The same dose of memantine significantly reduced the operant behaviour of rats trained to respond for water. These results indicate that: (i) single doses of memantine only moderately and not dose dependently reduce alcohol drinking in the limited access procedure; (ii) memantine produces non-selective effects on operant behaviour in rats trained to lever press for ethanol in an oral self-administration procedure.

This study examined the relationship between saccharin drinking, open field behaviour and ethanol drinking in Wistar rats. Correlational analysis revealed that both absolute saccharin drinking and an increase in total fluid intake in the presence of saccharin positively correlated with the initial acceptance of increasing ethanol concentrations in a two-bottle choice situation (2-8% v/v ethanol vs water). This relationship disappeared, however, during further weeks of ethanol drinking when ethanol was available in a three-bottle choice situation (8% ethanol vs 16% ethanol vs water). In contrast, none of the behavioural parameters measured in the open field test (forward locomotion, rearings, central entries, time in central area) correlated with subsequent ethanol consumption. These results indicate that saccharin drinking, rather than open field parameters, may predict subsequent ethanol intake during the initial period of exposure to low ethanol concentrations.

Pretreatment with an uncompetitive NMDA receptor antagonist, dizocilpine [(+)MK-801; six daily injections of 0.1 or 0.2 mg/kg, i.p.] significantly enhanced subsequent 1.5 g/kg ethanol-induced conditioned taste aversion (CTA). In a control experiment, dizocilpine (0.05-.2 mg/kg) produced only a marginal CTA. Thus, pre-exposure to low, non-aversive doses of MK-801 may sensitize rats to the aversive stimulus effects of ethanol.

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.

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 IP) 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.

Using the place conditioning paradigm (biased design), we have shown that five conditioning sessions with ethanol (0.5 or 1.0 g/kg i.p.) did not result in place conditioning response. In contrast, rats that received 20 injections of ethanol (0.5 g/kg) or saline, before the conditioning procedure, showed significant place preference to the compartment paired with 0.5 g/kg ethanol (but not 1.0 g/kg).