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.

Acetylcholine receptor effects on accumbal shell dopamine-mediated turning behaviour in rats.

The nature of acetylcholine receptor effects on dopaminergic functions within the nucleus accumbens shell was studied in rats, using turning behaviour as read-out parameter. Unilateral injections of the acetylcholine receptor agonist, carbachol (1.0-5.0 microg), into the nucleus accumbens shell dose-dependently elicited contraversive circling. Unilateral injections of the combination of a fixed dose of the dopamine D(2) receptor agonist, quinpirole (10.0 microg), with increasing doses of the dopamine D(1) receptor agonist, SKF 38393 (1.0-5.0 microg), into the nucleus accumbens shell dose-dependently elicited contraversive pivoting. The same held for the combination of a fixed dose of SKF 38393 (5.0 microg) with increasing doses of quinpirole (5.0 and 10.0 microg), which was injected into the nucleus accumbens shell. The nicotinic acetylcholine receptor antagonist, mecamylamine (5.0 and 10.0 microg), injected into the nucleus accumbens shell, which alone did not elicit any turning behaviour, significantly suppressed both the contraversive circling induced by carbachol (5.0 microg) and the contraversive pivoting induced by the mixture of SKF 38393 (5.0 microg) and quinpirole (10.0 microg). The muscarinic acetylcholine receptor antagonist, methylscopolamine (1.0 and 2.5 microg), injected into the nucleus accumbens shell, which alone did not elicit any turning behaviour, significantly suppressed the contraversive circling induced by carbachol (5.0 microg), whereas it significantly increased the contraversive pivoting induced by both the mixture of SKF 38393 (1.0 microg) and quinpirole (10.0 microg) and the mixture of SKF 38393 (5.0 microg) and quinpirole (5.0 microg). Neither SKF 38393 (5.0 microg) nor quinpirole (10.0 microg) injected into the nucleus accumbens shell affected the contraversive circling induced by carbachol (5.0 microg). Carbachol (1.0 microg) injected into the nucleus accumbens shell caused a slight initial potentiation followed by an inhibition of the contraversive pivoting induced by the mixture of SKF 38393 (5.0 microg) and quinpirole (10.0 microg). These results confirm that stimulation of both nicotinic and muscarinic acetylcholine receptors in the nucleus accumbens shell is required for the accumbens-dependent, acetylcholine-mediated circling. The study provides the original evidence that stimulation of nicotinic acetylcholine receptors in the nucleus accumbens shell is required for the accumbens-dependent, dopamine-mediated pivoting. Finally, the present study shows that muscarinic acetylcholine receptors in the nucleus accumbens shell play an inhibitory role in the production of the accumbens-dependent, dopamine-mediated pivoting.

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

The ability of GABAA and GABAB receptors in the shell of the nucleus accumbens to modulate distinct types of turning behaviour was investigated in freely moving rats, using the unilateral injection technique. The GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline did not produce turning behaviour; the same holds for the GABAB agonist baclofen and the GABAB antagonist 2-hydroxysaclofen. A mixture of the dopamine D1 receptor agonist SKF 38393 and the dopamine D(2/3) receptor agonist quinpirole has been found to elicit contraversive pivoting, when injected into the shell. This pivoting was dose-dependently inhibited by muscimol, and the inhibitory effect of muscimol was antagonised by bicuculline. Pivoting was also dose-dependently inhibited by baclofen; however, 2-hydroxysaclofen did not antagonise the inhibitory effect. The acetylcholine receptor agonist carbachol has been found to elicit contraversive circling, when injected into the shell. This carbachol-induced circling was inhibited by baclofen, and 2-hydroxysaclofen antagonised the inhibitory effect. Carbachol-induced circling was also partially inhibited by muscimol; however, the inhibitory effect of muscimol was not antagonised by bicuculline. It is concluded that mesolimbic GABAA receptors exert an inhibitory control on dopamine-dependent pivoting that can be elicited from the shell of the nucleus accumbens, and that GABAB receptors exert an inhibitory control on acetylcholine-dependent circling that can be elicited from the shell of the nucleus accumbens. This data extends the earlier reported findings that the neurochemical substrate in the shell of the nucleus accumbens that mediates dopamine-dependent pivoting is fundamentally different from the shell substrate that mediates acetylcholine-dependent circling.

Role of mu- and delta-opioid receptors in the nucleus accumbens in turning behaviour of rats.

The role of mu-, delta1- and delta2-opioid receptors in the nucleus accumbens in pivoting was investigated in freely moving rats. Unilateral injections of the mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO, 1 and 2 microg) and the delta2-opioid receptor agonist, deltorphin II (1 and 2 microg), but not the delta1-opioid receptor agonist, [D-Pen(2,5)]-enkephalin (DPDPE, 1-4 microg), into the shell or the core of the nucleus accumbens significantly induced contraversive pivoting. The pivoting induced by DAMGO (2 microg) and deltorphin II (2 microg) was inhibited significantly by the mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP, 0.1 and 1 microg), and the delta2-opioid receptor antagonist, naltriben (NTB, 0.1 and 1 mg/kg, i.p.), respectively. The DAMGO (2 microg)- or deltorphin II (2 microg)-induced pivoting was also inhibited significantly by co-administration of the dopamine D1/D2 receptor antagonist, cis(Z)-flupentixol (1 and 10 microg). The pivoting induced by unilateral injections of a mixture of dopamine D1 (SKF 38393, 5 microg) and D2 (quinpirole, 10 microg) receptor agonists into the shell was significantly inhibited by cis(Z)-flupentixol (1 and 10 microg) or NTB (1 and 3 mg/kg, i.p.), but not CTOP (1 microg) or delta1-opioid receptor antagonist, (E)-7-benzylidenenaltrexone (1 mg/kg, i.p.). The contraversive pivoting elicited by the cholinergic agonist, carbachol (5 microg), into the core was inhibited by co-administration of the muscarinic M1 antagonist, pirenzepine (1 microg), but not cis(Z)-flupentixol (1 microg). The results suggest that unilateral activation of mu- or delta2-opioid, but not delta1-opioid, receptors in the core and/or shell of the nucleus accumbens elicits contraversive pivoting that requires intact dopamine D1/D2 receptors in the shell, but not intact muscarinic M1 mechanism in the core. The study also shows that delta2-opioid, but not mu- and delta1-opioid, receptors in the core and/or shell modulate the shell-specific, dopamine D1/D2 receptor mechanisms involved in the production of pivoting.

GABA(A) receptors in the nucleus accumbens core modulate turning behavior induced by dopamine receptor stimulation.

The role of GABA(A) and GABA(B) receptors in the core of the nucleus accumbens in turning behavior of rats was investigated. Unilateral injections into the core of the nucleus accumbens of the GABA(A) receptor agonist (muscimol, 50 ng) and antagonist (bicuculline, 200 ng), and the GABA(B) receptor agonist (baclofen, 100 ng) and antagonist (2-hydroxysaclofen, 2 microg) did not produce turning behavior. In rats pretreated with unilateral injections of the dopamine D1-like/D2-like receptor antagonist, cis(Z)-flupentixol (10 microg), into the ventrolateral striatum and saline into the nucleus accumbens core of contralateral side, systemic injection of a mixture of dopamine D1-like (SKF 38393, 3 mg/kg) and D2-like (quinpirole, 1 mg/kg) receptor agonists has been found to elicit contraversive pivoting, namely pivoting away from the side of the core injection. This dopamine D1-like/D2-like receptor-mediated pivoting was significantly inhibited by injections into the core of the nucleus accumbens of muscimol (50 ng), but not bicuculline (200 ng). In contrast, the dopamine D1-like/D2-like receptor-mediated pivoting was suppressed by either baclofen (100 ng) or 2-hydroxysaclofen (2 microg) injected into the nucleus accumbens core. It is therefore concluded that neither GABA(A) nor GABA(B) receptor stimulation in the core of the nucleus accumbens produces turning behavior, and that GABA(A), but not GABA(B), receptors in the nucleus accumbens core may modulate dopamine D1-like/D2-like receptor-mediated pivoting.