PHARMACOLOGY OF SENSORY STIMULATION-EVOKED INCREASES IN FRONTAL CORTICAL ACETYLCHOLINE RELEASE E. ACQUAS,† C. WILSON and H. C. FIBIGER* Division of Neurological Sciences, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3 Abstract––Recent research has demonstrated that a variety of sensory stimuli can increase acetylcholine release in the frontal cortex of rats. The aim of the present experiments was to investigate the pharmacological regulation of sensory stimulation-induced increases in the activity of basal forebrain cholinergic neurons. To this end, the effects of agonists and antagonists at a variety of neurotransmitter receptors on basal and tactile stimulation-evoked increases in frontal cortical acetylcholine release were studied using in vivo brain microdialysis. Tactile stimulation, produced by gently stroking the rat’s neck with a nylon brush for 20 min, significantly increased frontal cortical acetylcholine release by more than 100% above baseline. The noradrenergic  2 agonist clonidine (0.1 or 0.2 mg/kg) and  1 antagonist prazosin (1 mg/kg) failed to affect basal cortical acetylcholine release; however, both compounds significantly reduced the increases evoked by sensory stimulation. In contrast, the  2 antagonist yohimbine (3 mg/kg) increased basal cortical acetylcholine release, thereby preventing meaningful investigation of its effects on tactile stimulation-evoked increases. The benzodiazepine agonist diazepam (5 mg/kg) reduced, and the GABA A receptor antagonist picrotoxin (2 mg/kg) increased basal cortical acetylcholine release; in addition, diazepam attenuated the increases in cortical acetylcholine release evoked by tactile stimulation. While dopaminergic D 1 (SCH 23390, 0.15 mg/kg) and D 2 (raclopride, 1 mg/kg) receptor antagonists did not by themselves significantly influence the increases evoked by tactile stimulation, their co-administration produced a significant reduction. The opioid receptor antagonist naltrexone (1.5 mg/kg) failed to a ffect either basal or tactile stimulation-evoked increases in acetylcholine overflow. Finally, the non-competitive N -methyl--aspartate receptor antagonist, dizocilpine maleate (MK-801; 0.025 and 0.05 mg/kg) increased basal cortical acetylcholine release. These results confirm that cortically projecting cholinergic neurons are activated by sensory stimuli, and indicate that the increases in cortical acetylcholine release produced by tactile stimulation are inhibited by stimulation of  2 or blockade of  1 noradrenergic receptors, and by enhanced GABAergic transmission. In addition, simultaneous blockade of dopamine D 1 and D 2 receptors appears necessary to achieve a significant reduction of sensory stimulation-evoked acetylcholine release in the frontal cortex. The results are consistent with the hypothesis that cortical acetylcholine release is a component of the neurochemistry of arousal and/or attention and indicate that this is modulated by GABAergic, noradrenergic and dopaminergic systems. In contrast, endogenous opioid actions do not appear to be involved.  1998 IBRO. Published by Elsevier Science Ltd. Key words: acetylcholine, frontal cortex, dopamine, GABA, microdialysis, noradrenaline. The a fferent connections of cholinergic neurons in the basal forebrain include noradrenergic, 61–63 dopaminergic, 30,35,61,63 GABAergic 61 and peptider- gic 61 elements. At present, relatively little is known about the functional significance of these connec- tions. Microdialysis studies have demonstrated that cholinergic neurotransmission in the frontal cortex is regulated by dopamine (DA) D 1 receptors. 1,18 Although the anatomical locus of the relevant D 1 receptors remains to be elucidated, there is evidence that a trans-synaptic mechanism which includes GABAergic neurons in the nucleus accumbens may be involved. 9 In accordance with this model, bidirec- tional regulation of frontal cortical acetylcholine (ACh) release has been demonstrated for GABA- benzodiazepine ligands. 38,39,53 Cortical ACh release also appears to be modulated by noradrenaline (NA) as it can be reduced by the  2 receptor agonist clonidine 6,40 and enhanced by  2 receptor antagonists. 14,40,58 Finally, studies using sodium- dependent high-a ffinity choline uptake (NaHACU) to estimate the activity of cholinergic neurons have implicated opioid receptors in the regulation of these neurons. 31,33 *To whom correspondence should be addressed. †Present address: Department of Toxicology and CNR Centre for Neuropharmacology, University of Cagliari, V.le A. Diaz, 182-09126 Cagliari, Italy A bbreviations: ACh, acetylcholine; DA, dopamine; HPLC, high performance liquid chromatography; MK-801, dizo- cilpine maleate; NA, noradrenaline; NaHACU, Na-dependent high-a ffinity choline uptake; nBM, nucleus basalis magnocellularis; NMDA, N -methyl--aspartate; TS, tactile stimulation; VTA, ventral tegmental area. Pergamon N euroscience Vol. 85, No. 1, pp. 73–83, 1998 Copyright  1998 IBRO. Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306–4522/98 $19.00+ 0.00 PII: S0306-4522(97)00546-0 73