Evidence in laboratory animals indicates that exposure to stimulants produces sensitization to their rewarding effects, a process that in humans would be expected to increase the risk of substance abuse. However, therapeutic administration of stimulants such as methylphenidate (MPH) in children with attention deficit hyperactivity disorder reportedly reduces the risk of substance abuse. Here we show in rats that exposure to MPH during pre-adolescence causes behavioral and neurobiological adaptations that endure into adulthood, and that are consistent with increased sensitivity to the aversive effects of cocaine.
The mesocorticolimbic dopamine (DA) system is implicated in neurodevelopmental psychiatric disorders including schizophrenia but it is unknown how disruptions in brain development modify this system and increase predisposition to cognitive and behavioural abnormalities in adulthood. Netrins are guidance cues involved in the proper organization of neuronal connectivity during development. We have hypothesized that variations in the function of DCC (deleted in colorectal cancer), a netrin-1 receptor highly expressed by DA neurones, may result in altered development and organization of mesocorticolimbic DA circuitry, and influence DA function in the adult. To test this hypothesis, we assessed the effects of reduced DCC on several indicators of DA function. Using in-vivo microdialysis, we showed that adult mice that develop with reduced DCC display increased basal DA levels in the medial prefrontal cortex and exaggerated DA release in response to the indirect DA agonist amphetamine. In contrast, these mice exhibit normal levels of DA in the nucleus accumbens but significantly blunted amphetamine-induced DA release. Concomitantly, using conditioned place preference, locomotor activity and prepulse inhibition paradigms, we found that reduced DCC diminishes the rewarding and behavioural-activating effects of amphetamine and protects against amphetamine-induced deficits in sensorimotor gating. Furthermore, we found that adult DCC-deficient mice exhibit altered dendritic spine density in layer V medial prefrontal cortex pyramidal neurones but not in nucleus accumbens medium spiny neurones. These findings demonstrate that reduced DCC during development results in a behavioural phenotype opposite to that observed in developmental models of schizophrenia and identify DCC as a critical factor in the development of DA function.
Although the effects of psychostimulants on brain dopamine systems are well recognized, the direct actions of cocaine on serotonin systems also appear to be important to its addictive properties. For example, serotonin actions at 5-HT1B receptors in the ventral tegmental area (VTA) modulate cocaine-induced dopamine release in the nucleus accumbens (NAcc) and alter the rewarding and stimulant properties of cocaine. However, the mechanisms of these effects have been unclear, because several neuron types in VTA express 5-HT1B receptors. One possibility is that 5-HT1B receptors on the terminals of GABAergic projections from NAcc to VTA inhibit local GABA release, thereby disinhibiting VTA neurons. We tested this hypothesis directly by using viral-mediated gene transfer to overexpress 5-HT1B receptors in NAcc projections to VTA. A viral vector containing either epitope hemagglutinin-tagged 5-HT1B and green fluorescent protein (HA1B-GFP) cassettes or green fluorescent protein cassette alone (GFP-only) was injected into the NAcc shell, which sends projections to the VTA. HA1B-GFP injection induced elevated expression of 5-HT1B receptors in neuronal fibers in VTA and increased cocaine-induced locomotor hyperactivity without affecting baseline locomotion. Overexpression of 5-HT1B receptors also shifted the dose-response curve for cocaine-conditioned place preference to the left, indicating alterations in the rewarding effects of cocaine. Thus, increased expression of 5-HT1B receptors in NAcc efferents, probably in the terminals of medium spiny neurons projecting to the VTA, may contribute to psychomotor sensitization and offer an important target for regulating the addictive effects of cocaine.
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