Dopamine in the Medial Prefrontal Cortex Controls Genotype-Dependent Effects of Amphetamine on Mesoaccumbens Dopamine Release and Locomotion
ABSTRACT Mice of background DBA/2J are hyporesponsive to the behavioral effects of D-amphetamine in comparison with the widely exploited murine background C57BL/6J. In view of the important role of dopamine (DA) release in the nucleus accumbens (NAc) regarding the behavioral effects of psychostimulants, we tested the hypothesis of an inverse relationship between mesocortical and mesoaccumbens DA functioning in the two backgrounds. Systemic D-amphetamine induces a sustained increase in DA release in the medial prefrontal cortex (mpFC) accompanied by a poor increase in the NAc in mice of the low-responsive DBA/2J background, as shown by intracerebral microdialysis in freely moving animals. The opposite occurs in C57BL/6J mice, which show low prefrontal cortical DA outflow accompanied by high accumbal extracellular DA. Moreover, the DBA/2J background showed lower locomotor activity than C57BL/6J mice following D-amphetamine challenge. Selective DA depletion in the mpFC of DBA/2J mice produced a clear-cut increase in D-amphetamine-induced DA outflow in the NAc as well as locomotor activity that reached levels similar to those observed in C57BL/6J mice. Finally, local infusion of D-amphetamine by reverse microdialysis produced a similar increase in extracellular DA in both the mpFC and the NAc of DBA/2J mice. This finding points to similar transporter-related mechanisms in the two brain areas and supports the hypothesis that low accumbal DA release induced by systemic D-amphetamine in the DBA/2J background is determined by the inhibitory action of prefrontal cortical DA. The present results indicate that genotype-dependent susceptibility to addictive properties of D-amphetamine involves unbalanced DA transmission in the mesocorticolimbic system.
- SourceAvailable from: C.J. Malanga
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- "Compared with C57 mice, DBA mice have more neurons expressing tyrosine hydroxylase (TH) in the VTA and substantia nigra pars compacta, increased dopamine transporter expression in the prefrontal cortex, a more discrete distribution of dopamine transporter and TH immunoreactive fibers in the NAc, higher density of TH-immunoreactive fibers in the prefrontal cortex, lower density of D1 and D2 receptors in the striatum, and greater density of D2 receptors in the midbrain (Ng et al., 1994; Zocchi et al., 1998; D'Este et al., 2007). Amphetamine and cocaine stimulate greater DA release in the NAc and more locomotor activity in C57 than in DBA mice (Cabib et al., 2000; Ventura et al., 2004; Orsini et al., 2005). DBA mice may also have increased D2 autoreceptor activity (Puglisi-Allegra and Cabib, 1997) given their greater sensitivity to apomorphine inhibition of DA metabolism (Cabib and Puglisi-Allegra, 1991) and quinpirole-and haloperidolinduced catalepsy (Kanes et al., 1993; Puglisi-Allegra and Cabib, 1997). "
ABSTRACT: C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation (ICSS) in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose-effects on BSR thresholds and maximum operant response rates (MAX) were determined for the D1 receptor agonist SKF-82958 (0.1 - 0.56 mg/kg) and antagonist SCH 23390 (0.003 - 0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1 - 3.0 mg/kg) and antagonist raclopride (0.01 - 0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6 - 2.4 g/kg p.o.). D1 antagonism dose-dependently elevated while SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, while higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390 but not raclopride prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride but not SCH 23390 prevented potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains.Journal of Pharmacology and Experimental Therapeutics 06/2014; 350(2). DOI:10.1124/jpet.114.216135 · 3.97 Impact Factor
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- "Our previous findings showed that NAc shell dopamine augmentation selectively enhanced HPC-dependent spatial control over appetitive behavior (Ito and Hayen 2011), while our current findings suggest a role of IL DA in inhibiting spatial processing. Together, these findings suggest a possible reciprocity of function between the dopaminergic innervations of IL and the NAc shell in regulating limbic control over appetitive behavior, in accord with previous pharmacological studies showing an inverse relationship between mesoaccumbens and mesocortical dopamine responses, with the latter regulating the former via direct glutamatergic projections or indirectly through the ventral tegmental area (Karreman and Moghaddam 1996; Ventura et al. 2004). Furthermore, our findings support the hypothesis that IL activation generally regulates or inhibits the control of subcortically generated motivational information over behavior (Richard and Berridge 2012). "
ABSTRACT: Increasing evidence points to the prelimbic (PL) and infralimbic (IL) cortices of the medial prefrontal cortex (mPFC) and their dopaminergic innervations subserving opposing roles in the regulation of instrumental behavior. However, it is at present unclear if they hold similar roles in the regulation of Pavlovian learning. The present study investigated the role of the dopaminergic innervations of the PL and IL in the modulation of Pavlovian appetitive cue and place conditioning, previously shown to be dependent on the basolateral amygdala and hippocampus, respectively. Rats received preconditioning microinfusions of D-amphetamine, cis-flupenthixol, or vehicle solution directly into the PL or IL and were trained to simultaneously acquire conditioned cue and place preference in a radial maze. Preconditioning blockade of dopamine neurotransmission in the PL and amphetamine microinfusions in the IL had the same effect of attenuating place conditioning. In contrast, place conditioning remained intact following preconditioning amphetamine microinfusions in the PL and dopamine receptor blockade in the IL. Instead, conditioned cue preference was attenuated following IL dopamine receptor blockade. These data indicate that PL dopaminergic mechanisms are critical for the acquisition of appetitive place learning, while IL dopamine may oppose the influence of PL dopamine upon hippocampal-dependent learning. Furthermore, they implicate a functional reciprocity between mPFC and associated subregions of the nucleus accumbens in the regulation of limbic information processing.Psychopharmacology 01/2014; 231(12). DOI:10.1007/s00213-013-3414-0 · 3.88 Impact Factor
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- "Decreased or increased mPFC DA activity as a consequence of social stress during adolescence or adulthood, respectively , could have similar outcomes on some behavioral measures. For example, sensitization to psychostimulants and salience of psychostimulant-associated cues can be enhanced by either decreased or excessive PFC DA activity (Beyer and Steketee 1999; Everitt and Wolf 2002; Ventura et al. 2004; Kalivas et al. 2005; Burke et al. 2011, 2013), and both adolescent and adult social defeat increase behavioral sensitivity to psychostimulants (Nikulina et al. 2004; Covington and Miczek 2005; Miczek et al. 2008, 2011; Burke et al. 2011, 2013). However, mPFC DA hypofunction due to social stress experienced in adolescence may also result in additional negative behavioral outcomes that would not occur as a result of adult social stress exposure. "
ABSTRACT: Adverse social experience in adolescence causes reduced medial prefrontal cortex (mPFC) dopamine (DA) and associated behavioral deficits in early adulthood. This study aims to determine whether mPFC DA hypofunction following social stress is specific to adolescent experience and if this results from stress-induced DA D2 receptor activation. Male rats exposed to repeated social defeat during adolescence or adulthood had mPFC DA activity sampled 17 days later. Separate experiments used freely moving microdialysis to measure mPFC DA release in response to adolescent defeat exposure. At P40, 49 and 56 mPFC DA turnover was assessed to identify when DA activity decreased in relation to the adolescent defeat experience. Finally, nondefeated adolescent rats received repeated intra-mPFC infusions of the D2 receptor agonist quinpirole, while another adolescent group received intra-mPFC infusions of the D2 antagonist amisulpride before defeat exposure. Long-term decreases or increases in mPFC DA turnover were observed following adolescent or adult defeat, respectively. Adolescent defeat exposure elicits sustained increases in mPFC DA release, and DA turnover remains elevated beyond the stress experience before declining to levels below normal at P56. Activation of mPFC D2 receptors in nondefeated adolescents decreases DA activity in a similar manner to that caused by adolescent defeat, while defeat-induced reductions in mPFC DA activity are prevented by D2 receptor blockade. Both the developing and mature PFC DA systems are vulnerable to social stress, but only adolescent defeat causes DA hypofunction. This appears to result in part from stress-induced activation of mPFC D2 autoreceptors.Psychopharmacology 11/2013; 231(8). DOI:10.1007/s00213-013-3353-9 · 3.88 Impact Factor