Short- and long-lasting behavioral and neurochemical adaptations: relationship with patterns of cocaine administration and expectation of drug effects in rats

Abstract

Cocaine dependence is a significant public health problem, characterized by periods of abstinence. Chronic exposure to drugs of abuse induces important modifications on neuronal systems, including the dopaminergic system. The pattern of administration is an important factor that should be taken into consideration to study the neuroadaptations. We compared the effects of intermittent (once daily) and binge (three times a day) cocaine treatments for 1 (WD1) and 14 (WD14) days after the last cocaine injection on spontaneous locomotor activity and dopamine (DA) levels in the nucleus accumbens (Nac). The intermittent treatment led to a spontaneous increase in DA (WD1/WD14), and in locomotor activity (WD1) at the exact hour which rats were habituated to receive a cocaine injection. These results underline that taking into consideration the hours of the day at which the experiments are performed is crucial. We also investigated these behavioral and neurochemical adaptations in response to an acute cocaine challenge on WD1 and WD14. We observed that only the binge treatment led to sensitization of locomotor effects of cocaine, associated to a DA release sensitization in the Nac, whereas the intermittent treatment did not. We demonstrate that two different patterns of administration induced distinct behavioral and neurochemical consequences. We unambiguously demonstrated that the intermittent treatment induced drug expectation associated with higher basal DA level in the Nac when measured at the time of chronic cocaine injection and that the binge treatment led to behavioral and sensitization effects of cocaine.

The inhibition of cocaine-induced locomotor activity by CART 55-102 is lost after repeated cocaine administration

“…Our study confirms the effect of intra-NAc CART peptide on acute cocaine administration [13], and shows for the first time that the inhibitory effect of CART peptide is lost after repeated, non-contingent cocaine administration. There are significant differences between the design of our study and a previous study that shows that intra-NAc CART peptide suppresses locomotor sensitization 3 weeks after withdrawal from a repeated cocaine (15 mg/kg ip × 7 days) regimen [26] and there is evidence that experimental designs for the effects of repeated cocaine regimen is critical [22]. Our data implies that chronic cocaine persistently altered the CART peptide system in the NAc.…”

“…For instance, chronic intermittent administration of cocaine leads to a lowering of basal dopamine levels in the NAc [22]. Also, repeated daily injections of cocaine (10 mg/kg, i.p.)…”

Exercise as a novel treatment for drug addiction: A neurobiological and stage-dependent hypothesis

“…Evidence from studies primarily with cocaine show that chronic exposure produces neuroadaptations in the dopamine system, such as an upregulation of D1 receptors and a downregulation of D2 receptors, with evidence to suggest that dopamine signaling in the reward pathway may become sensitized over extended periods of abstinence (Casanova et al, 2013; Henry et al, 1988; Puig et al, 2012; Unterwald et al, 1994). Thus, it is also possible that exercise beginning later during abstinence may lead to further increases in dopaminergic signaling and enhance rather than attenuate drug-seeking.…”

15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse

“…In some reports, the locomotor response to cocaine was reduced in mu KO mice (Chefer et al, 2004; Yoo et al, 2006; Yoo et al, 2003) as well as in βend KO mice (Marquez et al, 2008), while in many other mu KO studies, this cocaine effect was unchanged (Becker et al, 2002; Chefer et al, 2004; Contarino et al, 2002; Hall et al, 2004; Lesscher et al, 2005). Furthermore, sensitization to locomotor effects of cocaine was reduced (Yoo et al, 2006; Yoo et al, 2003), maintained (Lesscher et al, 2005), or enhanced (Hummel et al, 2004), depending on the mouse genetic background (Hummel et al, 2004) and the pattern of drug exposure (administration regimen and timing of injections) (Allouche et al, 2013; Puig et al, 2012). In mu KO mice also, methamphetamine-induced locomotion, was decreased at one dose, maintained in lower and higher doses, and no behavioral sensitization was found (Shen et al, 2010), therefore altogether, evidence exist that mu receptor activity contributes to locomotor effects of cocaine, and the adaptive response to repeated exposure to the drug.…”