Blunted response to cocaine in the Flinders hypercholinergic animal model of depression
Section snippets
Animals
For experiment 1, adult male FSL (n=11) and FRL (n=9) rats, approximately 9 weeks old and weighing 230–370 g, were used from a colony maintained at the department of Pharmacology, Karolinska Institute. For experiment 2, 24 male FSL and FRL rats, approximately 7 weeks old, were transferred from the breeding colony maintained at the department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA to the department of Pharmacology, Karolinska Institute (Stockholm, Sweden). The
Experiment 1
The first 10 days of cocaine self-administration are shown in Fig. 2A. ANOVA analysis revealed a main effect of day (F9,117=29.56, P<0.0001) and a line×day interaction (F9,117=3.27, P<0.001), but no main effect of line. The number of responses increased as training continued over days. There was no significant difference between the Flinders lines at any day studied. Furthermore the total cocaine intake over 10 days was similar between the FSL and FRL rats (114±14 and 128±12 injections,
Discussion
The present study provides experimental support that a depression genotype affects the response to psychostimulants. The FSL hypercholinergic rats showed marked blunting of cocaine-evoked responses in locomotor activity and prodynorphin mRNA regulation but only a subtle effect on self-administration behavior. The differences were, however, not correlated to extracellular dopamine overflow monitored in the Acc-Sh.
The underlying hypercholinergic depression genotype of the FSL rat did not
Acknowledgments
We thank Marjan Pontén and Åse Elfving for technical assistance and Prof. Alexander Mathé for providing animals from the Karolinska Flinders colony. This work was supported by grants from the Swedish Medical Research Council (11252), and the Karolinska Institute.
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The impact of GABA<inf>B</inf> receptors and their pharmacological stimulation on cocaine reinforcement and drug-seeking behaviors in a rat model of depression
2020, European Journal of PharmacologyCitation Excerpt :Consequently, is seems that OBX rats are not more reactive to cocaine reinforcing effects than SHAM animals. These findings are in line with previous studies, which demonstrated that rats with depressive-like behavior and controls exhibited the same response to cocaine self-administration in the present or other paradigm (Fagergren et al., 2005; Jastrzębska et al., 2016, 2017). However, experiments involving other psychostimulant drugs (amphetamine, methamphetamine) proved that OBX rats exhibit increased drug taking (Holmes et al., 2002; Kucerova et al., 2012).
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2017, Brain ResearchCitation Excerpt :Previous studies have shown that OBX rats exhibit increased low-dose amphetamine or methamphetamine intake (Holmes et al., 2002; Kucerova et al., 2012) and more potent cocaine- or cue-induced reinstatement of cocaine-seeking behavior (Frankowska et al., 2012) in the self-administration paradigm. On the other hand, other authors (Roth-Deri et al., 2009) have recently reported that rats with a genetic model of depression, Flinders Sensitive Line (FSL) rats, exhibit a considerable decrease in intravenously administered low-dose cocaine intake, although Fagergren et al. (2005) found that FSL rats did not differ from controls in terms of their response to cocaine self-administration. At the same time, subsensitivity to self-administered cocaine or amphetamine has been found in rats selectively bred for a depression-like phenotype (Lin et al., 2012).
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2017, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Vulnerability to psychostimulant drugs in FSL rats has only been tested in paradigms of acquisition and maintenance of cocaine self-administration (Table 4). FSL rats exhibited a reduction in cocaine self-administration under a FR-1 schedule of reinforcement compared to FRL rats (Fagergren et al., 2005) and control Sprague-Dawley rats (Roth-Deri et al., 2009) although only with available low doses of cocaine (0.09 or 1 mg/kg/injection), not slightly higher doses (1.5 mg/kg/injection). These studies suggest that depressive-like behavior in FSL rats is associated with decreased sensitivity to psychostimulant reinforcing effects.
The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited
2015, European Journal of PharmacologyCitation Excerpt :Furthermore, this line exhibits depression-like behaviors including lower startle thresholds (Markou et al., 1994), fulfilling some criteria of face, construct, and predictive validities [see Overstreet (1993) for review]. More recently, the Flinders Sensitive Line model of depression was demonstrated to exhibit a blunted response to the behavioral effects of cocaine (Fagergren et al., 2005). Hence, this Flinders Sensitive Line with its hypersensitivity to cholinergic manipulations together with another animal model for cholinergic supersensitivity (Orpen and Steiner, 1995) supports a cholinergic imbalance contributing to depression-related behaviors.
Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: An autoradiographic study
2012, Brain Research BulletinCitation Excerpt :Moreover, there is a strong correlation between depression and substance abuse [21,59]. FSL rats showed reduced cocaine intake and less locomotor activation following prolonged (10 days) cocaine administration (30 mg/kg) while microdialysis dopamine sampling from the AN showed no difference between the FSL and control rats [21]. Similarly, it was shown that the mGluR5 knockout mice do not self-administer cocaine, nor do they increase their locomotor activity after repeated cocaine administration despite an increase of dopamine (DA) levels in the nucleus accumbens (AN) [12].
CART mRNA expression in rat monkey and human brain: Relevance to cocaine abuse
2007, Physiology and Behavior