Dissociable hippocampal and amygdalar D1-like receptor contribution to discriminated Pavlovian conditioned approach learning.

Pavlovian conditioning is an elementary form of reward-related behavioral adaptation. The mesolimbic dopamine system is widely considered to mediate critical aspects of reward-related learning. For example, initial acquisition of positively-reinforced operant behavior requires dopamine (DA) D1 receptor (D1R) activation in the basolateral amygdala (BLA), central nucleus of the amygdala (CeA), and the ventral subiculum (vSUB). However, the role of D1R activation in these areas on appetitive, non-drug-related, Pavlovian learning is not currently known. In separate experiments, microinfusions of the D1-like receptor antagonist SCH-23390 (3.0 nmol/0.5 µL per side) into the amygdala and subiculum preceded discriminated Pavlovian conditioned approach (dPCA) training sessions. D1-like antagonism in all three structures impaired the acquisition of discriminated approach, but had no effect on performance after conditioning was asymptotic. Moreover, dissociable effects of D1-like antagonism in the three structures on components of discriminated responding were obtained. Lastly, the lack of latent inhibition in drug-treated groups may elucidate the role of D1-like in reward-related Pavlovian conditioning. The present data suggest a role for the D1 receptors in the amygdala and hippocampus in learning the significance of conditional stimuli, but not in the expression of conditional responses.

Structural manipulation on the catecholic fragment of dopamine D(1) receptor agonist 1-phenyl-N-methyl-benzazepines.

A series of new benzazepines with modification on the catecholic fragment were designed. The 8-hydroxyl group, other than the 7-hydroxyl was confirmed crucial to the interaction with the dopamine D1 receptor. Subsequent replacement of the 7-hydroxyl with benzylamino groups was found tolerable. 7-(m-Chlorophenyl)methylamino- and 7-(m- or o-tolyl)methylamino-substituted benzazepines 13b-d displayed Ki values of 270-370 nM at the D1 receptor, which were slightly more potent than that of parent compound 1. In addition, 7-(arylmethyl)amino-benzazepines 13a-c were found possessing high binding affinities less than 10 nM at the 5-HT2A receptor. Among them, the non-substituted 7-benzylamino analogue 13a was the most potent showing a Ki values of 4.5 nM at the 5-HT2A receptor and a 5-HT2A/D1 selectivity of 147.

The nicotinic acetylcholine receptor partial agonist varenicline increases the ataxic and sedative-hypnotic effects of acute ethanol administration in C57BL/6J mice.

BACKGROUND: The costs associated with alcohol abuse are staggering, therefore much effort has been put into developing new pharmacologic strategies to decrease alcohol abuse. Recently, the nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to decrease ethanol consumption in both humans and animal models. METHODS: We examined the effects of varenicline on the ataxic and sedative-hypnotic effects of ethanol. First, varenicline was administered prior to placement in a locomotor activity chamber to determine whether varenicline influenced baseline locomotor activity. To determine the effect of nicotinic modulation on ethanol-induced motor incoordination, varenicline was administered 30 minutes prior to an acute ethanol injection and then mice were tested on the balance beam, dowel test, or fixed-speed rotarod. To examine ethanol's sedative-hypnotic effects, varenicline was administered 30 minutes prior to 4 g/kg ethanol and the duration of loss of righting reflex (LORR) was measured. RESULTS: Varenicline markedly reduced baseline locomotor activity in C57BL/6J mice. Varenicline increased ethanol-induced ataxia when measured on the balance beam and dowel test but had no effect when measured on the fixed-speed rotarod. Pretreatment with varenicline increased the duration of LORR. CONCLUSIONS: These data provide evidence that nAChRs may be involved in the ataxic and sedative effects of ethanol. It is possible that one mechanism that could contribute to the ability of varenicline to decrease ethanol consumption may be through increasing negative behavioral effects of alcohol.

Assessment of jaw movements by magnetic sensor in relation to topographies of orofacial behaviour in freely moving rats: Studies with the dopamine D(1)-like receptor agonists SKF 83822 vs SKF 83959.

This study applies new magnetic sensor-electromyographic technology for recording jaw movements in freely moving rats to analyse topographies of orofacial movement that occur in association with individual elements of behaviour under challenge with two dopamine D(1)-like receptor agonists, SKF 83822 ([R/S]-6-chloro-7, 8-dihydroxy-3-allyl-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine) and SKF 83959([R/S]-3-methyl-6-chloro-7, 8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine). Grooming of the snout/face involved primarily dominant-mouth opening jaw movements with small activation of digastric muscles; subsequent grooming of the flank/trunk was characterised by repetitive, uniform jaw movements with small activation of digastric and masseter muscles. In contrast, grooming of the fingers and tail typically involved high-frequency jaw movements with variable vertical jaw movements and/or strong activation of masseter muscles. Vacuous chewing involved two distinct patterns of jaw movements: a dominant-closing pattern, with strong activation of masseter muscles, and a dominant-opening pattern, with slight activation of masseter muscles. SKF 83822 stimulates dopamine D(1)-like receptors and activates adenylate cyclase but not phosphoinositide hydrolysis, while SKF 83959 stimulates dopamine D(1)-like receptors and activates phosphoinositide hydrolysis but not adenylate cyclase. These agonists exerted differential effects on jaw movements, as SKF 83959 induced more jaw movements per episode of syntactic grooming than SKF 83822, while SKF 83822 induced more jaw movements during non-syntactic grooming than SKF 83959. Magnetic sensor technology in freely moving animals resolved distinct topographies of orofacial movement and informs on their relationship to other behaviours in the rodent repertoire and to dopamine D(1)-like receptor function.

Dopamine D1B receptor chimeras reveal modulation of partial agonist activity by carboxyl-terminal tail sequences.

NNC 01-0012, a second-generation benzazepine compound, pharmacologically differentiates multiple vertebrate D1 receptor subtypes (D1A, D1B, D1C, and D1D) and displays high selectivity and affinity for dopamine D1C receptors. Functionally, whereas NNC 01-0012 acts as a full or poor antagonist at D1C and D1A receptor-mediated cyclic AMP production, respectively, it exhibits partial agonist activity at the D1B receptor. To define some of the structural motifs that regulate the pharmacological and functional differentiation of vertebrate dopamine D1 receptors by NNC 01-0012, a series of receptor chimeras were constructed in which the divergent carboxyl-terminal (CT) receptor tails were replaced with the corresponding sequences of D1A, D1B, or D1C receptors. Substitution of the vertebrate D1B carboxyl-terminal-tail at position Tyr345 with carboxyl-terminal-tail sequences of the D1A receptor abolished the partial agonist activity of NNC 01-0012 without affecting dopamine-stimulated cyclic AMP accumulation. At vertebrate D1B/D1CcT-tail receptor mutants, however, the intrinsic activity of the partial agonist NNC 01-0012 (10 microM) was markedly enhanced (approximately 60% relative to 10 microM dopamine) with no concomitant alteration in the molecule's ligand binding affinity or constitutive activity of the chimeric receptor. Similar results were obtained with other benzazepines such as SKF-38393 and SCH-23390, which act as partial agonists at vertebrate D1B receptors. Substitution of D1A and D1C receptor carboxyl-terminal tails with sequences encoded by the D1B receptor carboxyl-terminal tail did not, however, produce receptors with functional characteristics significantly different from wild type. Taken together, these data clearly suggest that in addition to well-characterized domains and amino acid residues in the third cytoplasmic loop, partial agonist activity at the D1B receptor is modulated by sequence-specific motifs within the carboxyl-terminal tail, a region that may underlie the possible structural basis for functionally divergent roles of multiple dopamine D1-like receptors.