Cocaine and Other Psychomotor Stimulants

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The pharmacological effects of cocaine include blockade of the transporters for 5-HT, norepinephrine, and DA. The action of cocaine to elevate extracellular levels of DA appears to be the primary neurochemical event mediating a number of the behavioral effects of cocaine. Locomotor activity induced by cocaine is attenuated by 6-hydroxydopamine (6-OHDA) lesions of the mesolimbic DA system and treatment with DA receptor antagonists (Kelly and Iversen 1976; Spyraki et al. 1982). Disrupting DA function also blocks the discriminative stimulus properties of cocaine in conventional operant conditioning-based drug-discrimination tasks (Callahan et al. 1991). The effectiveness of cocaine to serve as a positive reinforcer in tests of intravenous cocaine self-administration is also diminished by 6-OHDA lesions of the mesolimbic DA system (Roberts et al. 1980), by DA receptor antagonists (Caine and Koob 1994), and by deletion of the DA transporter gene (Thomsen et al. 2009). The modulation of the functioning of mesolimbic DA function by 5-HT2C receptors provided the impetus for examining the effects of 5-HT2C receptor ligands on behavioral responses to cocaine. Locomotor Activity

A consistent finding regarding the effects of 5-HT2C receptor ligands on the expression of cocaine-induced behavior is that 5-HT2C receptor agonists reduce cocaine-induced locomotor activity. This has been demonstrated for MK212 and Ro60-0175 in several studies (Grottick et al. 2000; Filip et al. 2004). In contrast, cocaine-induced locomotion was increased by the 5-HT2B/2C receptor antagonist SB 206553 (McCreary and Cunningham 1999) and by the more selective 5-HT2C receptor antagonist SB 242084 (Fletcher et al. 2002, 2006). The locomotor stimulant effect of cocaine was also enhanced in 5-HT2C receptor knockout mice, compared with their wild-type controls (Rocha et al. 2002). Thus, the results of experiments using pharmacological and gene-deletion approaches converge to show that impaired transmission through 5-HT2C receptors can enhance the locomotor stimulant effect of cocaine. Collectively, these data show that the unconditioned locomotor stimulant effect of cocaine is altered in a bidirectional fashion by 5-HT2C receptor agonists and antagonists.

Limited evidence suggests that the effects of other psychomotor stimulants are modified by 5-HT2C receptor ligands. The 5-HT2B/2C receptor antagonist SB206553 modestly potentiated the locomotor stimulant effect of the DA releaser amphetamine, the combined DA and 5-HT releaser 3,4-methylenedioxy-N-methylamphet-amine (MDMA) (Bankson and Cunningham 2002), and a cocktail of the DA reuptake blocker mazindol plus the 5-HT reuptake blocker fluvoxamine (McMahon and Cunningham 2001). The more selective 5-HT2C receptor antagonist SB 242084 enhanced the locomotor stimulant effects of MDMA, amphetamine, the DA reuptake blocker methylphenidate (Fletcher et al. 2006) and the N-methyl-d-aspartate (NMDA) antagonists phencyclidine and dizocilpine (Hutson et al. 2000). Thus, enhancement of drug-induced locomotor activity by 5-HT2C receptor blockade is seen across a number of psychomotor stimulants with differing pharmacological actions.

Pairing a specific environment with certain drugs can elicit conditioned responses when animals are subsequently exposed to that environment in a drug-free state. In the case of psychomotor stimulants such as cocaine, this can be seen as a conditioned hyperactivity response. As with the unconditioned locomotor stimulant effects of cocaine, the expression of cocaine-induced conditioned locomotor activity was attenuated by MK212 and enhanced by SB 242084 (Liu and Cunningham 2006). A notable feature of the responses of these two 5-HT2C ligands is that they were obtained in the absence of cocaine, indicating that their effects on activity are not due to pharmacokinetic interactions with cocaine. Drug Discrimination

Drug discrimination assays in which rats learn to produce one response under the influence of a drug, and a different response under the influence of a vehicle injection, measure the interoceptive or stimulus properties of that drug. This assay has been used extensively to model the subjective effects of drugs. Rats readily learn to discriminate cocaine from vehicle, and this discrimination is DA-dependent since it is blocked by DA receptor antagonists, and generalises to other drugs that elevate DA activity (Callahan et al. 1991). The mixed 5-HT1B/2C agonist meta-chlorophe-nylpiperazine (mCPP) and the more selective 5-HT2C receptor agonist MK 212 partially antagonized the discriminative stimulus properties of cocaine (Callahan and Cunningham 1995). mCPP also produced a rightward shift in the cocaine dose-response curve. Given that 5-HT1B agonists induce a leftward shift in the cocaine dose response curve, it seems likely that the effects of mCPP results from 5-HT2C rather than 5-HT1B, receptor stimulation (Callahan and Cunningham 1995). These data show that activation of 5-HT2C receptors diminishes the discriminative state induced by cocaine. Cocaine Self-administration

Intravenous drug self-administration procedures are the most widely used method to study the direct reinforcing effects of drugs of abuse. Our group was the first to examine the impact of selective 5-HT2C receptor ligands on cocaine self-administration. In our first study we trained rats to self-administer cocaine under a fixed ratio of 5, 60-s timeout schedule (FR5TO60s) of reinforcement (Grottick et al. 2000). The effect of Ro60-0175 on cocaine self-administration was measured and compared with the effect seen in a different group of rats responding for food under the identical FR5TO60s schedule. The results demonstrated a dose-related reduction in the rate of cocaine self-administration over a similar dose range to that which reduced food maintained responding, even though response rates varied markedly between the two reinforcers (Grottick et al. 2000). This effect to reduce the rate of cocaine self-administration was subsequently replicated in a later study, which also showed that the effects of Ro60-0175 were stable over eight daily injections (Fletcher et al. 2008a).

In a progressive ratio schedule of reinforcement the number of responses required to earn successive infusions of the drug escalate, usually according to an exponential function. The number of ratios completed (or infusions earned) increases in a linear fashion with increasing dose of the self-administered drug. The ratio at which responding ceases is termed the breaking point and provides a good measure of the direct reinforcing effects of the drug. Consistent with results from the FR5 schedule, Ro60-0175 also reduced breaking points for cocaine (Grottick et al. 2000; Fletcher et al. 2008a) (see Fig. 15.1a).

While these observations might suggest a generalized suppression of motivated behavior, control experiments demonstrated little or no motor or neurological impairments, at least over the dose range of Ro60-0175 (Grottick et al. 2000, 2001; Fletcher et al. 2008a) that reduced responding for cocaine. In the cocaine self-administration studies, initial rates of responding and mean interinfusion intervals were similar under drug and control conditions, suggesting an earlier termination of responding following Ro60-0175 treatment. Finally, the number of responses emitted on the progressive ratio schedule by rats treated with the highest dose of Ro60-0175 were considerably higher than response rates emitted under vehicle treatment on the FR5TO60s schedule (Grottick et al. 2000). Consequently, these data suggest that 5-HT2C receptor stimulation has a generalized effect to reduce motivation for cocaine and food that is not the product of some indiscriminate neurological or motor disturbance.

Fig. 15.1 Effects of 5-HT2C receptor agonists on several behavioral effects of cocaine. (a) Systemic injection of Ro60-0175 subcutaneous (SC) reduced the number of cocaine infusions earned on a progressive ratio schedule. * and ** indicate significant differences from Veh (Redrawn from Grottick et al. 2000). (b) Microinjection of Ro60-0175 into the ventral tegmental area reduced the number of cocaine infusions earned on a progressive ratio schedule. ** indicates significant difference from Veh (Redrawn from Fletcher et al. 2004). (c) MK212 reduced the ability of a priming injection of cocaine (10 mg/kg) to reinstate bar pressing in rats that had undergone extinction of cocaine self-administration. At each dose of MK 212 response rates are shown for a baseline test, without cocaine (BL), a test with vehicle and cocaine (V), and a test with MK212 and cocaine (MK). Graph element * indicates significantly different from BL; +, significantly different from V (Redrawn from (b) in Neisewander and Acosta 2007) (d) Ro60-0175 reduced the reinstatement of bar pressing induced by reexposure to the context in which drug self-administration occurred (Reinstatement). In a control group, responding remained low in a context that differed from the self-administration context and was not altered by Ro60-0175 (Responses on an inactive lever were uniformly low and not altered by Ro60-0175; data not shown) (Data are redrawn from Fletcher et al. 2008a)

In contrast to the effects of Ro60-0175, SB 242084 enhanced responding for cocaine on a PR schedule of reinforcement (Fletcher et al. 2002). This effect did appear to be dependent upon the infusion dose of cocaine. Thus, responding was enhanced only at low to moderate doses of cocaine. Consistent with this finding, and with effects on cocaine-stimulated locomotor activity, the 5-HT2C receptor knockout mouse also displayed an enhanced motivation to seek cocaine on the PR schedule (Rocha et al. 2002). Reinstatement of Cocaine Seeking

Three classes of stimuli elicit drug craving and relapse in humans. These stimuli can also trigger reinstatement of drug-seeking behavior in animals, and this has prompted the development of preclinical models to study factors relating to relapse to drug-seeking behavior (Epstein et al. 2006; Shaham et al. 2003). The typical experimental design involves a period of drug self-administration followed by a period in which the drug-seeking response is extinguished by ensuring that responses are no longer reinforced by drug delivery. Reinstatement tests can then be conducted using a noncon-tingent injection of the previously self-administered drug, exposure to a stressor, or reexposure to the drug associated cues. Reinstatement is then measured as an increased emission of the previously reinforced response relative to a baseline control. The mechanisms involved in reinstatement of drug-seeking behavior elicited by these three types of stimuli are separable but overlap to some degree in terms of circuitry and neurochemical substrates. The mesocorticolimbic DA pathways including projections to the mPFC and amygdala are especially important for mediating reinstatement induced by priming and drug-paired cues (Epstein et al. 2006; Shaham et al. 2003; Crombag et al. 2008; Schmidt et al. 2005; See 2005).

A generally consistent picture is emerging regarding the effects of 5-HT2C receptor agonists in reinstatement models. In rats previously trained to self-administer cocaine, Ro60-0175 reduced responding reinstated by priming injections of cocaine (Grottick et al. 2000). In contrast the 5-HT2C receptor antagonist SB 242084 enhanced the ability of cocaine to reinstate responding (Fletcher et al. 2002). A more recent study found that MK212 also attenuated the priming effect of cocaine (see Fig. 15.1c) and that this action was prevented by SB 242084 (Neisewander and Acosta 2007). However, in comparison with results from the earlier study (Fletcher et al. 2002), SB 242084 did not enhance the effects of cocaine to reinstate responding. Although the reason for the discrepancy between these studies is not known, there is quite a marked difference in doses of SB 242084 used between the two experiments: 0.5 mg/kg (Fletcher et al. 2002) versus 3 mg/kg (Neisewander and Acosta 2007), and possible loss of receptor selectivity could have occurred in the latter study.

One commonly used behavioral procedure for measuring cue-induced reinstatement involves training rats to self-administer cocaine, extinguishing the operant response in the absence of cue presentations, and then delivering cues in a response contingent manner during reinstatement tests. In this procedure the 5-HT releaser d-fenfluramine reduced cue reinstatement. The effect of d-fenfluramine was blocked by SB 242084 indicating a major role for 5-HT2C receptors in the expression of fenfluramine's action (Burmeister et al. 2004). Using a pharmacologically more selective approach, it was then shown that MK212 reduced cue-induced reinstatement and that this effect was prevented by SB 242084 (Neisewander and Acosta 2007). Finally, using a slightly modified procedure, Ro60-1075 dose-dependently attenuated cue-induced reinstatement over the dose range 0.1 to 1 mg/kg (Burbassi and Cervo 2008). Again, this was a 5-HT2C receptor-mediated effect since it was blocked by SB 242084. The results of these studies converge to show that 5-HT2C receptor stimulation attenuates cue induced responding based on cocaine self-administration.

Cue-induced reinstatement can also be elicited by contextual cues, as well as discrete cues; Shaham and colleagues have devised a procedure in which the entire context, including discrete drug-paired cues, in which the drug is experienced serves as the stimulus complex for reinstatement (Crombag et al. 2002). This procedure has good face validity in that a common trigger for relapse in addicts may be a return to the home environment (Childress et al. 1993). Basically this test involves letting rats self-administer drug in one environment, extinguishing responding in another environment, reinstatement is elicited by then reexposing animals to the original context. In keeping with the results of previous studies outlined above, this contextual reinstatement was attenuated by Ro60-1075 (Fletcher et al. 2008a) (see Fig. 15.1d). Again, this effect of Ro60-0175 was blocked by SB 242084, which did not alter reinstatement in its own right.

Stress induced reinstatement has typically been studied using footshock stress. However, a number of reports have shown that extinguished responding for a variety of drugs can be reinstated by the pharmacological stressor yohimbine (Shepard et al. 2004; Lee et al. 2004a). In keeping with results from reinstatement procedures using cocaine priming and cue reexposure yohimbine induced reinstatement was attenuated by Ro60-0175 (Fletcher et al. 2008a). This effect was reversed by SB 242084. By itself, SB 242084 did not alter yohimbine-induced reinstatement. Interaction Between 5-HT2C Receptor Ligands and Cocaine's Neurochemical Effects

As described above, 5-HT2C receptor agonists reduce the basal activity of VTA neurons, and extracellular levels of DA in terminal areas whereas 5-HT2C receptor antagonists exert the opposite effects (Di Matteo et al. 2008; Di Giovanni et al. 2008). Behaviorally, 5-HT2C receptor agonists and antagonists inhibit and enhance respectively some behavioral effects of cocaine, and a logical prediction is that cocaine's impact on DA neurotransmission would be altered by 5-HT2C receptor ligands. This prediction is true in the case of a 5-HT2C antagonist; SB 242084 enhanced the ability of cocaine to elevate levels of DA in the nucleus accumbens (Navailles et al. 2004). However, Ro60-0175 failed to alter cocaine-induced DA overflow in nucleus accumbens or dorsal striatum (Navailles et al. 2004). This finding is difficult to reconcile with the reports that systemically injected 5-HT2C agonists reduced several cocaine-induced behaviors, that Ro60-0175 injected into the VTA attenuated the effects of cocaine on DA efflux (Navailles et al. 2008) and behavior (Fletcher et al. 2008a), and that systemically injected Ro60-0175 attenuated the ability of nicotine to elevate accumbens levels of DA (Di Matteo et al. 2004). A potential limitation of the study by Navailles et al. (Navailles et al. 2004) is that it was conducted in anesthetised and therefore nonbehaving rats challenged with acute injections of cocaine and Ro60-0175. It will be important to extend this work into drug-experienced, behaving animals to more closely resemble conditions under which behavioral interactions between 5-HT2C agonists and cocaine have been found.

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