Differential Reinforcement of Low Rate

As was previously mentioned, the establishment of stimulus-response associations requires the striatal processing of stimulus-response contingencies, as demonstrated by McDonald and White, among others, in their studies of the dissociation of three memory systems (for a complete review see McDonald and White 1993; White and McDonald 2002). In the differential reinforcement of a low rate 72-s operant task (DRL-72), the rat is trained in an operant chamber and must learn to wait a minimum of 72 s between lever presses in order to obtain food reinforcement. Any early response resets the clock and is not reinforced (Andrews et al. 1994). Thus, this task implies stimulus-response association as well as temporal discrimination. Early work demonstrated that the neurotoxic lesions produced by either kainic acid or 6-hydroxydopamine (6-OHDA) injection into the ventrolateral striatum impair DRL-20 performance (Dunnett and Iversen 1982). Likewise, the dopaminergic modulation of differential reinforcement of low rate (DRL) schedules through action on the ventral striatum was evaluated by Neill and Herndon (Neill and Herndon 1978). They observed that the direct application of dopamine, d-amphetamine, and scopolamine into the ventral anterior region of the neostriatum of the rat decreased the efficiency of the animals in a DRL-10 schedule of reinforcement.

Serotoninergic modulation of conditioned reward responses has been addressed leading to the paradigm that an increase in serotoninergic activity attenuates conditioned reward responses, whereas selective reduction of cerebral serotoninergic activity enhances conditioned responses. Fletcher et al. (1993) reported that intrar-aphe injection 8-OHDPAT (where it acts on autoreceptors and inhibits serotonin release) is sufficient to induce conditioned place preference, serving as an unconditioned stimulus. In a later work, Fletcher et al. (1999) observed that the destruction of serotoninergic raphe bodies with 5,7-DHT increases response in conditioned rewarded tasks. However, drugs that inhibit serotonin uptake (such as fluoxetine), improve the performance of rats in a DRL-72 schedule, presumably through indirect stimulation of 5-HT1 receptors (Marek et al. 1989a), whereas the nonselective serotonin antagonist methysergide, blocks the increase in reinforcement seen under DRL schedules (Marek and Seiden 1988). Accordingly, McGuire and Seiden (1980) demonstrated that tricyclic antidepressant drugs may reduce the response rate and increase the reinforcement rate of rats under a DRL-18 operant task, depending on the doses. In this operant schedule responses are reinforced only when they occurred with a delay of at least 18 s, after a previous response, resulting in interresponse intervals (IRTs) longer than 18 s. Interresponse-interval frequency histogram typically showed an inverted U-shaped distribution that changes by shifting to the right as a consequence of lengthening of IRT induced by imipramine or desipramine. However, the effect of increased serotonin could be mediated through diverse 5-HT receptors.

Marek et al. (1989b) did not observe a consistent effect of mCPP, or other 5-HT2 agonists, on DRL-72. However, when the more specific 5-HT2C agonists Ro 60-0175 and Ro 60-0332 where tested, the rate of lever pressing (10 mg/kg IP) significantly decreased (without observable sedation), although only Ro 60-0175 significantly increased the number of reinforcements obtained, whereas a nonsignificant increase (1.7-fold vehicle baseline) in this parameter was induced by Ro 60-0332 (Martin et al. 1998). Thus, 5-HT2C activation apparently modulates the accuracy, evaluated by the increase in the number of reinforcements obtained, in this task.

Striatal 5-HT2C receptor activation or inactivation under DRL schedules has not been evaluated; hence, the assumption that the effect observed in these previous experiments occurs through the action of agonists on striatal 5-HT2C receptors could be speculative.

It can be stated that the effect of an increase of serotonin on the reinforcement rate may be exerted through 5-HT2C receptors. However, specific experimental designs aimed to elucidate a principal role of 5-HT2C receptors must be done since several results show an inhibitory influence of these receptors on reward or reinforcement responses (Di Giovanni et al. 2000; Di Matteo et al. 2000a). The relevant role of dopamine in reward and reinforcement regulation (Bardo 1998; Wise 2002) through projections from the ventral tegmental area to the nucleus accumbens (Wise 2002) is widely accepted. Moreover, 5-HT2C receptors are located in the mesocorticolimbic system affecting the activity of dopamine-dependent neurons, through an inhibitory effect on dopamine release (Di Giovanni et al. 2000; Di Matteo et al. 2000a; De Deurwaerdere et al. 2004), whereas the systemic application of 5-HT2C agonists has been reported to decrease the dopamine efflux into the striatum

(Gobert et al. 2000; De Deurwaerdere et al. 2004; Alex et al. 2005). The effect of the reduction of dopamine after 5-HT2C receptor stimulation and the increase in rewarded responses in the DRL task seems difficult to interpret in view of evidence indicating a relevant participation of dopamine in sustaining the task. It has been reported that the application of the D1 antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine (SCH-23390) or the D2 receptor antagonist raclopride caused a severe deficit on DRL-10 schedule behavior in rats, evident in a flattening of the IRT curve after the administration of these antagonists (Cheng and Liao 2007). In agreement with these above data, dopamine depletion in the prefrontal cortex by local injection of 6-OHDP, produced an impairment in DRL-30 schedules evidenced by an increase in the number of responses at shorter IRTs and a fewer number of the obtained reinforcers; in absence of an increase in spontaneous locomotor activity, suggesting a deficit in inhibitory control of these responses (Sokolowski and Salamone 1994). The possibility that the observed effect after the application of a 5-HT2C receptor agonist was due to influences on temporal discrimination seems improbable, since the effects 5-HT2 receptor stimulation on this ability are mediated through action on 5-HT2A receptors, whose activation causes impairment in temporal discrimination in rats (Asgari et al. 2006; Body 2003).

Thus, an indirect involvement of the 5-HT2C receptors on DRL tasks may be inferred from these results.

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