Research reportHippocampal θ activity after systemic administration of a non-peptide δ-opioid agonist in freely-moving rats: relationship to D1 dopamine receptors
Introduction
Slow electrical activity recorded in the hippocampus represents a rhythmic pattern observed in mammals during oriented and motivated responding [35], and is related to learning [24], arousal and paradoxical sleep [3]. This electroencephalographic (EEG) pattern has been described as θ activity, and is one of the largest electrophysiological signals generated in the brain 3, 13, 29.
Several studies have shown that there are at least two generators of θ in the hippocampus, one located in the stratum oriens of the CA1 pyramidal cell region and the other, approximately 180° out of phase, in the stratum moleculare of the dentate gyrus 3, 29. According to hippocampal EEG recorded in several species, the frequency of θ activity varies from 3 to 12 Hz. Pharmacological and behavioral criteria have established that while cats show only one type of θ activity of low frequency, other species, including rats, rabbits, and guinea pigs, show two types of θ activity 3, 29, 30. Type 1 θ, ranging from 7.5 to 12 Hz, occurs during voluntary motor and appetitive behavior, but is generally absent during more repetitive and stereotyped activities such as, for example, consummatory behavior, licking, defecating and digging 29, 30, 35. Type 2 θ ranges from 3.5 to 7 Hz, and is thought to be mediated by cholinergic system, since it is abolished by atropine 3, 10. Hippocampal θ appears to be modulated by several neurochemical systems such as the serotonergic inputs from the mesencephalic raphe nuclei 1, 2, 9, 20, 21, 28, 34, and the noradrenergic influences arising from the locus coeruleus 29, 25.
Recently, it has been shown in rabbits that the systemic administration of deltorphin, a naturally occurring heptapeptide that selectively binds to δ-opioid receptors, produces increased alertness and a shift toward the slow components of EEG, but such changes were not specifically referred to hippocampal electrical activity or to θ rhythm [8]. Since deltorphin does not penetrate the blood–brain barrier, it is unclear to which extent these effects are of central origin.
Recently, a series of centrally active non-peptide agonists of δ-opioid receptors has been synthesized. The first of these substances, BW 373U86 [6], induces, after systemic administration, a syndrome of behavioral stimulation characterized by increased oriented motor activity suppressed by naltrindole 6, 7, 23. As it has been described that increased alertness and exploratory motor activities are strongly correlated to Type 2 hippocampal θ[35], in order to investigate the role of δ-opioid receptors in hippocampal θ we studied the effects of systemic BW 373U86 in rats on hippocampal EEG.
Moreover, since previous studies from this laboratory have demonstrated the suppression of several δ opioid-induced behaviors following intra-accumbens injections of a selective dopamine (DA) D1 antagonist [17], we studied the effects of the DA D1 agonist SKF 82958 by itself and the DA D1 antagonists SCH 23390 upon the BW 373U86-induced θ pattern, in order to analyze the relationships between δ-opioid receptors and dopamine upon hippocampal θ rhythm.
Section snippets
Animals
Sprague-Dawley rats (Charles River, Como, Italy) weighing 250 g at the beginning of the experiments were used in this study. Animals were housed individually in a temperature- and light-controlled room and had free access to food and water.
Surgical procedures
Rats were anesthetized with ketamine and placed in a stereotaxic instrument. A bipolar electrode was stereotaxically implanted in the dorsal hippocampus for recording θ activity. The electrode consisted of two insulated nichrome wires (0.042-inch diameter)
Effect of BW 373U86 on Type 2 θ
Results were obtained from 32 rats that displayed distinct hippocampal θ activity during quiet waking. During baseline recordings Type 2 θ activity (3.5 to 7 Hz) accounted for 35.3±2.7% of the total power spectrum (0.25–30 Hz).
θ-Activity was recorded in response to s.c. administration of the non-opioid δ agonist BW 373U86 (0.5–2.5 mg/kg) (Fig. 1).
A polygraphic recording showing a typical hippocampal EEG response to s.c. injection of BW 373U86 (1.0 mg/kg) is shown in Fig. 2.
While 0.5 mg/kg of BW
Discussion
Our study shows that the administration of the selective non-peptidic δ-opioid receptor agonist BW 373U86 significantly increases the relative hippocampal Type 2 θ power. This activation ranges between 4.5 and 7 Hz, lasts about 60 min and correlates with an increased alertness. On the contrary, Type 1 θ activity in the range of 7.5–12 Hz failed to show any significant change in relation to BW 373U86 administration. The observation that the administration of the selective δ antagonist
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