Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens

Abstract

Chronic exposure to cocaine causes long-lasting behavioral changes associated with cocaine reinforcement and addiction. An important neural substrate for cocaine addiction is the nucleus accumbens (NAc), which receives dopaminergic input from the ventral tegmental area. Although the neural circuit of the NAc is controlled by several other neurotransmitters, their involvement in cocaine addiction remains elusive. In this investigation, we ablated cholinergic interneurons from the adult NAc with immunotoxinmediated cell targeting and examined the role of acetylcholine transmitter in adaptive behavioral changes associated with cocaine reinforcement and addiction. Acute exposure to cocaine induced abnormal rotation in unilaterally cholinergic cell-eliminated mice. This abnormal turning was enhanced by repeated exposure of cocaine. In bilaterally cholinergic cell-eliminated mice, chronic cocaine administration induced a prominent and progressive increase in locomotor activity. Moreover, these mice showed robust conditioned place preference with a lower dose of cocaine, compared with wild-type littermates. This investigation demonstrates that acetylcholine in the NAc plays a key role in both acute and chronic actions of cocaine.

Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions

“…Differences in the psychostimulant used or the area of the striatum targeted is unlikely to account for such a discrepancy, suggesting that our phenotype might not be the direct consequence of striatonigral damage. Interestingly, an increased sensitivity to acute cocaine has been reported after elimination of cholinergic cells in the dorsal striatum or the nucleus accumbens (Hikida et al, 2001;Sano et al, 2003), suggesting that the loss of striatal cholinergic interneurons rather than ablation of striatonigral MSNs might be responsible for the potentiation of cocaineinduced locomotor response.…”

The Role of Acetylcholine in Cocaine Addiction

“…Although ablation of cholinergic striatal neurons did not impair either contextual or cued fear conditioning in rats , infusions of scopolamine into the dorsal striatum impaired the conditioned learning of a radial arm task when administered soon after training (Legault et al, 2006). With respect to cocaine, ablation of NAc cholinergic interneurons by an immunotoxin-mediated cell targeting technique induced CPP for cocaine at much lower doses of cocaine than that in wild-type littermates (Hikida et al, 2001). The administration of AChE inhibitors (which increase ACh synaptic concentrations) also suppressed cocaine-induced CPP, and this effect was blocked by the ablation of ACh cells within the NAc .…”

“…It would, therefore, be expected that an increase in striatal ACh would be associated with not only the increased salience of cocaine's effect (as described in a previous section), but also the salience of associated stimuli. The absence of this effect (in fact, the reverse is observed: increased striatal ACh attenuated and decreased striatal ACh augmented (Hikida et al, 2001) cocaine-induced CPP) may, in part, be due to the NAc target of these studies, as conditioned learning is primarily a function of the dorsal striatum. In particular, the association of TANs with associative learning has been confined to the dorsal striatum (Apicella, 2007).…”

“…Striatal ACh increase associated with cocaine acquisition Crespo et al, 2006;Mark et al, 1999) Striatal ACh alters cocaine-induced locomotor sensitization Hikida et al, 2001Hikida et al, , 2003 mACh receptors decrease after chronic cocaine (Lipton et al, 1995;Macedo et al, 2004;Wilson et al, 1994;Zeigler et al, 1991) Amygdala mAChR may facilitate acquisition of associative learning underlying context-dependent sensitization Itzhak and Martin, 2000) Explicit memory Hippocampus ACh involved in the encoding of new information (Hasselmo and Fehlau, 2001;Hasselmo et al, 2002) Hippocampal ACh increases following cocaine use (Imperato et al, 1993a(Imperato et al, , b, 1996Smith et al, 2004a, b) Conditioned learning VTA VTA ACh involved in conditioned learning (Bechara and van der Kooy, 1989;Museo and Wise, 1994;Olmstead and Franklin, 1993) M 5 -deficient rats decrease cocaine-induced CPP (Fink-Jensen et al, 2003) Striatum Striatal ACh involved in conditioned learning (Legault et al, 2006) NAc ACh inhibits cocaine-induced CPP (Hikida et al, 2001 ACh antagonist blocks induction of locomotor sensitization to cocaine-induced CPP (Itzhak and Martin, 2000) Amygdala Amygdalar ACh facilitates conditioned learning (McIntyre et al, 1998;Power et al, 2003) Amygdalar ACh alters cocaine-induced conditioned learning (See et al, 2003;Zeigler et al, 1991) Attention PFC Elevated ACh may focus attentional resources toward salient stimuli (Baxter and Chiba, 1999;Robbins, 2002;Sarter et al, 2003) Cocaine-addicted subjects show impaired attention (Horner et al, 1996;Jovanovski et al, 2005) Set shifting PFC ACh involved in set shifting (Ragozzino and Choi...…”

“…Although Itzhak and Martin (2000) found no effect of scopolamine (1.0 mg/kg s.c.) on cocaine (20 mg/kg i.p. )-induced 'place-independent' sensitization, Hikida et al (2001) examined the role of accumbens ACh in cocaine-induced sensitization by ablating these interneurons with an immunotoxin-mediated cell targeting technique. Transgenic mice with bilateral ACh interneuron ablation displayed a prominent and progressive increase in locomotor activity at baseline and following daily cocaine administration (5, 10, and 20 mg/kg) relative to their wild-type littermates.…”