Role of orexin receptors in the nucleus accumbens in dopamine-dependent turning behaviour of rats.

The role of orexin receptors in the nucleus accumbens shell in rat turning behaviour of rats was studied. Unilateral injection of neither the orexin 1 and 2 receptor agonist orexin A (2 microg) nor the orexin 1 receptor antagonist SB 334867 (20 ng) into the nucleus accumbens shell elicited turning behaviour. Unilateral injection of a mixture of dopamine D(1) (SKF 38393) and D2 (quinpirole) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting. Orexin A (1 and 2 microg) dose-dependently potentiated the contraversive pivoting induced by a mixture of SKF 38393 (1 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell whereas SB 334867 (10 and 20 ng) did not significantly affect the pivoting. The potentiating effect of orexin A (2 microg) on the dopaminergic pivoting was not significantly inhibited by SB 334867 (10 and 20 ng) injected into the nucleus accumbens shell. The contraversive pivoting induced by a mixture of SKF 38393 (1 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell was also potentiated by the orexin 2 receptor agonist orexin B (0.5, 1 and 2 microg), which alone did not elicit turning behaviour. These results suggest that orexin 2 receptors in the nucleus accumbens shell play a modulatory role in rat turning behaviour.

A vehicle injection into the right core of the nucleus accumbens both reverses the region-specificity and alters the type of contralateral turning elicited by unilateral stimulation of dopamine D2/D3 and D1 receptors in the left core of the nucleus accumbens.

The goal of the present study was to analyse to what extent variables such as (1) injected volume, (2) nature of the solvent of drugs (saline versus distilled water) and (3) placement of an additional cannula to inject the solvent of the drugs at the opposite side of the brain, influenced the behavioural effects of the combined administration of the dopamine D(1) receptor agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine-7,8-diol (SKF 38393, 5.0 microg) and the dopamine D(2)/D(3) receptor agonist quinpirole (10.0 microg) into the shell or core of the nucleus accumbens of freely moving rats. First, we found that increasing the injected volume from 0.2 microl to 0.5 microl significantly increased the amount of contralateral turning after injection of the drugs into the shell and, especially, the core of rats equipped with one cannula. More importantly, the type of turning behaviour changed: instead of a predominance of pivoting, both pivoting and circling appeared. Second, replacing the solvent saline by distilled water resulted in a minor, but significant, decrease of the amount of contralateral turning elicited from either the shell or the core of the nucleus accumbens of rats equipped with one cannula. The type of turning was not changed by this new solvent. Third, and most importantly, this study showed that the vehicle injection into the right core exerted a potentiating effect on the number of contralateral rotations elicited by injections of SKF 38393+quinpirole into the left core, whereas such a vehicle injection into the right shell did not affect the number of contralateral rotations elicited by injections of SKF 38393+quinpirole into the left shell. The type of turning in these rats was not changed when compared to rats equipped with one cannula. It is hypothesized that the fluid injected into the core, directly or indirectly, enhanced the dopaminergic asymmetry between the left and the right brain, implying that this manipulation anyhow reduced the dopaminergic activity in the region under discussion. In conclusion, subtle changes in the methodology used to study both the behaviour-specificity and the region-specificity of drug injections into the brain significantly directs the outcome of such studies.

Adrenergic receptors in the nucleus accumbens shell differentially modulate dopamine and acetylcholine receptor-mediated turning behaviour.

The role of alpha- and beta-adrenoceptors in the nucleus accumbens shell in turning behaviour of rats was investigated. Unilateral injections of the alpha-adrenoceptor agonist (phenylephrine; 10 microg) and antagonist (phentolamine; 10 microg) as well as the beta-adrenoceptor agonist (isoprenaline; 1 microg) and antagonist (propranolol; 5 microg) into the nucleus accumbens shell did not produce turning behaviour more than that of control vehicle injection. Unilateral injection of a mixture of dopamine D(1) ((+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol, SKF 38393; 5 microg) and D(2) (quinpirole; 10 microg) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting. Such pivoting was dose-dependently inhibited by phenylephrine (5, 10 microg), injected into the nucleus accumbens shell, and the inhibitory effect of phenylephrine (10 microg) was antagonised by phentolamine (10 microg) that per se had no effect on this pivoting. Isoprenaline (0.5, 1 microg) dose-dependently increased the contraversive pivoting induced by the mixture of SKF 38393 (1 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell. The effect of isoprenaline (1 microg) was antagonised by propranolol (5 microg) that per se had no effect on this pivoting. It is concluded that stimulation of accumbal alpha-adrenoceptors inhibits the dopamine-dependent pivoting in contrast to stimulation of accumbal beta-adrenoceptors that facilitates this dopamine-dependent pivoting. Unilateral injection of the acetylcholine receptor agonist carbachol (5 microg) into the nucleus accumbens shell has been found to elicit contraversive circling. Such circling was significantly reduced by accumbal administration of either phenylephrine (10, 20 microg) or phentolamine (5, 10 microg) in a dose-independent manner; moreover, both drugs potentiated, but did not counteract, each other's effects. Carbachol-induced circling was also reduced by propranolol (2.5, 5 microg), but again in an aspecific manner. It is concluded that alpha- and beta-adrenergic agents have an effect on accumbal acetylcholine receptor-mediated circling through a non-adrenergic mechanism. The impact of the present study for putative new treatments of various neuropsychiatric and neurological disorders is discussed.