Nicotine

The pharmacological actions and physiological effects of nicotine are complex. It is widely accepted that the reinforcing effects of nicotine are mediated in part by interactions between nicotinic acetylcholine receptors (nAChRs), GABA, glutamate, and DA in the VTA (for reviews, see Markou 2008; Di Matteo et al. 2007). A major neurochemical event that is involved in the behavioral effects of nicotine, including locomotor activity and reinforcement, is indirect activation of mesolimbic DA neurons (Clarke et al. 1988; Di Chiara 2000; Corrigall et al. 1994).

15.3.2.1 Locomotor Activity

The critical importance of the VTA as a substrate for the acute reinforcing effect of nicotine (as well as other drugs of abuse) provided us with a rationale to examine the effects of Ro60-0175 on the motor stimulant and reinforcing effects of nicotine and cocaine (Grottick et al. 2000, 2001; Higgins and Fletcher 2003b). In rats previously exposed to nicotine, Ro60-0175 blocked the hyperactivity induced by an acute challenge injection of nicotine (Fig. 15.2a); this effect was reversed by SB 242084 (Grottick et al. 2001). Further experiments revealed that Ro60-0175 given concomitantly with nicotine blocked the development of sensitization to the locomotor stimulant effect of nicotine. Two recent studies found that WAY 161503 (Hayes et al. 2009) and WAY 163909 (Zaniewska et al. 2009) also blocked the effects of nicotine to stimulate locomotion in rats with prior nicotine exposure and that these effect were reversed by SB 242084.

15.3.2.2 Drug Discrimination

As with cocaine, rats readily discriminate nicotine from saline. Again this nicotine-induced discriminative state is partially DA dependent since it is blocked by DA receptor antagonists. Recently it has been shown that the 5-HT2C receptor agonists Ro60-0175 and WAY 163909 attenuated the discriminative stimulus properties of nicotine (Zaniewska et al. 2007; Quarta et al. 2007). For both drugs the reduction in the expression of the nicotine cue was shown to be dependent on 5-HT2C receptor stimulation since the effects of the agonist were blocked by the 5-HT2C receptor antagonist SB 242084 (Zaniewska et al. 2007). By itself, SB 242084 di2dC not alter the nicotine cue, although it engendered some nicotine appropriate responding (~30%). Taken together, the results show that while tonic activation of 5-HT2C receptors does not play a major role in the subjective effects of nicotine, pharmacological activation of 5-HT2C receptors diminishes the discriminative stimulus properties of nicotine.

Fig. 15.2 5-HT2C receptor agonists alter behavioral, electrophysiological, and neurochemical effects of nicotine. (a) Effect of Ro 60-0175 on hyperactivity induced by nicotine (0.4 mg/kg) in rats previously exposed to nicotine (ten daily injections of nicotine 0.4 mg/kg). * indicates significantly different from vehicle/vehicle; #, indicates significantly different from vehicle/nicotine (Redrawn from Fig. 1a and b in Grottick et al. 2001). (b) Ro 60-0175 reduced self-administration of nicotine (0.03 mg/infusion) on an FR5TO1min schedule of reinforcement (Redrawn from Fig. 2b in (Grottick et al. 2001). (c) Nicotine (1 mg/kg i.p) increased extracellular dopamine levels in the nucleus accumbens. This effect was reduced by 1 mg/kg Ro60-0175 (arrow) (Adapted from Fig. 4 in Di Matteo et al. 2004). (d) Effect of nicotine (IV) and Ro 60-0175 (0.1 mg/kg IV) on the firing pattern of VTA dopamine neurons. The data represent the mean ± SEM difference between the percentage of spikes occurring in bursts during baseline versus postdrug periods. The data show that nicotine increases burst firing of VTA dopamine neurons and that this effect is blocked by Ro 60-0175 (Data adapted from Table 2 in Pierucci et al. 2004)

Fig. 15.2 5-HT2C receptor agonists alter behavioral, electrophysiological, and neurochemical effects of nicotine. (a) Effect of Ro 60-0175 on hyperactivity induced by nicotine (0.4 mg/kg) in rats previously exposed to nicotine (ten daily injections of nicotine 0.4 mg/kg). * indicates significantly different from vehicle/vehicle; #, indicates significantly different from vehicle/nicotine (Redrawn from Fig. 1a and b in Grottick et al. 2001). (b) Ro 60-0175 reduced self-administration of nicotine (0.03 mg/infusion) on an FR5TO1min schedule of reinforcement (Redrawn from Fig. 2b in (Grottick et al. 2001). (c) Nicotine (1 mg/kg i.p) increased extracellular dopamine levels in the nucleus accumbens. This effect was reduced by 1 mg/kg Ro60-0175 (arrow) (Adapted from Fig. 4 in Di Matteo et al. 2004). (d) Effect of nicotine (IV) and Ro 60-0175 (0.1 mg/kg IV) on the firing pattern of VTA dopamine neurons. The data represent the mean ± SEM difference between the percentage of spikes occurring in bursts during baseline versus postdrug periods. The data show that nicotine increases burst firing of VTA dopamine neurons and that this effect is blocked by Ro 60-0175 (Data adapted from Table 2 in Pierucci et al. 2004)

15.3.2.3 Self-administration and Conditioned Place Preference

In the only published report of the effects of a 5-HT2C receptor agonist on nicotine self-administration, Ro60-0175 reduced rates of responding for nicotine on a FR5TO60s schedule (Grottick et al. 2001) (see Fig. 15.2b). This occurred over a similar dose range for reductions in cocaine self-administration (Grottick et al. 2000). To the best of our knowledge, no further studies of 5-HT2C receptor ligands on nicotine self-administration or reinstatement of nicotine seeking behavior have been conducted.

Another technique that has been used to study the rewarding effects of drugs is the conditioned place preference technique. In this procedure noncontingent drug injections are paired with a distinct environmental context, whereas noncontingent injections of vehicle are paired with a different context. Many drugs of abuse elicit a preference for the drug-paired context when the animal is allowed a choice between the drug and vehicle-associated contexts. The effects of 5-HT2C receptor agonists on the acquisition of a nicotine-induced conditioned place preference have been examined with mixed results. In rats, doses of WAY 161503 that blocked nicotine-induced locomotion failed to alter nicotine-induced place preference (Hayes et al. 2009). In contrast, Ro60-0175 blocked the ability of nicotine to induce a place preference in mice (Ji et al. 2006). In this latter study Ro60-0175 also prevented place conditioning with tetrahydrocannabinol (THC). Whether these discrepancies relate to the use of different species or result from the use of different 5-HT2C receptor agonists is not known.

15.3.2.4 Interaction Between 5-HT2C Receptor Ligands and Nicotine's Electrophysiological and Neurochemical Effects

Electrophysiological work showed that in animals previously exposed to nicotine, the basal level of activity of midbrain DA cells in the VTA and the SNR was not altered. However, a challenge injection of nicotine increased the burst firing activity of these neurons, and this effect was attenuated by Ro60-0175 (Pierucci et al. 2004). In animals previously exposed to nicotine, an acute challenge with nicotine increased DA efflux in the nucleus accumbens and the dorsal striatum. Consistent with the electrophysiological findings these effects were blocked with Ro60-0175 (Di Matteo et al. 2004). At the present time, it seems that the effect of 5-HT2C receptor agonists to reduce nicotine-induced or nicotine-maintained behaviors most likely involves an alteration of the ability of nicotine to alter mesolimbic DA function (Di Matteo et al. 2004; Pierucci et al. 2004; Fletcher et al. 2008b) (see Fig. 15.2c and d).

Drug Free Life

Drug Free Life

How To Beat Drugs And Be On Your Way To Full Recovery. In this book, you will learn all about: Background Info On Drugs, Psychological Treatments Statistics, Rehab, Hypnosis and Much MORE.

Get My Free Ebook


Post a comment