Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats - PubMed (original) (raw)

Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats

Gregory P Mark et al. Brain Res. 2006.

Abstract

Mesencephalic dopamine neurons form synapses with acetylcholine (ACh)-containing interneurons in the nucleus accumbens (NAcc). Although their involvement in drug reward has not been systematically investigated, these large aspiny interneurons may serve an important integrative function. We previously found that repeated activation of nicotinic cholinergic receptors enhanced cocaine intake in rats but the role of muscarinic receptors in drug reward is less clear. Here we examined the impact of local changes in muscarinic receptor activation within the NAcc on cocaine and food self-administration in rats trained on a progressive ratio (PR) schedule of reinforcement. Animals were given a minimum of 9 continuous days of drug access before testing in order to establish a stable breaking point (BP) for intravenous cocaine infusions (0.75 mg/kg/infusion). Rats in the food group acquired stable responding on the PR schedule within 7 days. On the test day, rats were bilaterally infused in the NAcc with the muscarinic receptor agonist oxotremorine methiodide (OXO: 0.1, 0.3 or 1 nmol/side), OXO plus the M(1) selective antagonist pirenzepine (PIRENZ; 0.3 nmol/side) or aCSF 15 min before cocaine or food access. OXO dose dependently reduced BP values for cocaine reinforcement (-17%, -44% [p<0.05] and -91% [p<0.0001] for 0.1, 0.3 and 1.0 nmol, respectively) and these reductions dissipated by the following session. Pretreatment with PIRENZ blocked the BP-reducing effect of 0.3 nmol OXO. Notably, OXO (0.1, 0.3 and 1.0 nmol/side) injection in the NAcc did not affect BP for food reward. The results suggest that muscarinic ACh receptors in the caudomedial NAcc may play a role in mediating the behavior reinforcing effects of cocaine.

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Figures

Figure 1

A. Schematic drawing of the extent of bilateral injections within the NAcc shell. The diagram is taken from the atlas of Paxinos and Watson (1998) at the level of bregma +1.7 mm. All injector tips in rats used for analysis in these studies were located within the shaded area. B. Photomicrograph showing the track of an injector (arrow) in a representative section. Vertical bar indicates 1 mm. Abbreviations: AcbC, nucleus accumbens core; ac, anterior commissure; cc, corpus callosum, CgCtx, cingulate cortex; CPu, caudate-putamen.

Figure 2

A. Cocaine infusions per session for the last two days before test injections (Baseline: BL1 and BL2), the test day (Test: aCSF [N=8] or 0.1 [N=5], 0.3 [N=6], 1.0 nmol/side OXO [N=4]) and the two sessions following a test injection (Post 1 and Post 2) for rats responding on a progressive ratio reinforcement schedule. Values are mean (±SEM). Right Y-axis depicts the corresponding break point ratio for the number of cocaine infusions received. Asterisks indicate significant difference from aCSF: *P < 0.05; **P < 0.001. B. Number of bar presses on the inactive lever for the average of the two days before test injections (Baseline: BL), the test day (Test: aCSF or 0.1, 0.3, 1.0 nmol/side OXO) and the average of the two days following a test injection (Post). Values are mean (±SEM).

Figure 3

A. Cocaine infusions per session on a progressive ratio schedule across two baseline days and post-injection days bracketing a test day where rats were given bilateral NAcc injections of 0.3 nmol/side PIRENZ [N=9] or a co-injection of 0.3 nmol/side OXO plus 0.3 nmol/side PIRENZ [N=4] prior to cocaine access. Results of aCSF [N=8] and 0.3 nmol/side OXO [N=6] injections are re-plotted from Figure 2A for comparison. Right Y-axis depicts the corresponding break point ratio for the number of cocaine infusions received. *P < 0.05 versus all other groups. B. Inactive lever presses per session across the average of two baseline days (BL) and the average of two post-injection days (Post) bracketing a test day where rats were given bilateral NAcc injections of 0.3 nmol/side OXO, 0.3 nmol/side PIRENZ or a co-injection of 0.3 nmol/side OXO plus 0.3 nmol/side PIRENZ prior to cocaine access. Values are mean (±SEM).

Figure 4

A. Number of pellets received per session for the last two days (Baseline: BL1 and BL2) before test injections, the test day (Test: aCSF [N-12] or 0.1 [N=8], 0.3 nmol/side OXO [N=8]; 1.0 nmol/side OXO [N=5]) and the two sessions following a test injection (Post: P1 and P2) for rats responding on a PR reinforcement schedule. Values are mean (±SEM). Right Y-axis depicts the corresponding break point ratio for the number of food pellets received. B. Number of bar presses on the inactive lever for the average of the two days before test injections (Baseline: BL), the test day (Test: aCSF or 0.1, 0.3, 1.0 nmol/side OXO) and the average of the two days following a test injection (Post). Values are mean (±SEM).

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Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats - PubMed (original) (raw)