Giulio Baldrighi

Behavioral activation by enkephalins in mice

Intraventricular injection of long lasting enkephalin analogues (D--Ala2Leu and Met enkephalin-amides) produced a sustained elevation of psychomotor activity in mice. The motor syndromes were characterized by continual stereotyped activity and were reversed by naloxone pretreatment. Naloxone administered to a separate group of mice reduced the initial activation seen after exposure to a novel environment. The present findings suggest one or more endogenous opiates normally facilitates behavioral excitation in mice.

A possible interface between autonomic function and pain control: opioid analgesia and the nucleus tractus solitarius

Opioid peptides appear to be important neurochemical mediators in central nervous system mechanisms of analgesia, cardiovascular control, and many endocrinological responses to stress. The nucleus tractus solitarius (NTS), a brain region expressing all 3 opioid peptide families, is also associated with regulation of autonomic and endocrine functions. We now report that electrical stimulation of the NTS causes pronounced analgesia in rats. This analgesia appears to involve opioids and is pharmacologically dissociable from the hemodynamic changes elicited by NTS stimulation. These results suggest the NTS as a neural substrate for inter-relationships between stress, cardiovascular function, alterations in respiration, and pain sensitivity.

A further parametric study of imipramine in an animal model of depression

We have proposed that chronic stress may produce motivational, behavioral, and neuroendocrine symptoms in rats resembling endogenous depression in humans. The chronic stress model has proved responsive to chronic treatment by antidepressant drugs. Two issues concerning this effect remain unresolved, these being; the requirement of drug chronicity, and treatment outcome to different drug doses. The present experiment examined both issues in a factorial design in which vehicle and two doses of the tricyclic antidepressant imipramine were varied across 2 treatment periods; acute (1 hr) and chronic (3 weeks). Both factors were found to significantly interact with treatment outcome, suggesting that chronic treatment is necessary for recovery and that this outcome is dependent upon drug level.

Motivated behavior and the estrous cycle in rats

Abstract (1) The estrous cycle in the rat may be used to study recurrent changes in motor behaviors and motivation which are strongly related to cyclic hormonal and CNS changes. (2) The peak in motivated behaviors occurs during a sharply defined period on the night between proestrus and estrus and is evident in facilitated wheel-running, lordosis, and intracranial self-stimulation. (3) Behaviors without a clearly motivated character do not show an estrous cyclicity. (4) The estrous cyclic variation in intracranial self-stimulation was observed at a specific locus — the pars campacta of the substantia nigra. (5) A neurochemical link between sexually motivated behavior, wheel running and intracranial self-stimulation is suggested. This link is in part dopaminergic but is probably also activated by many other systems.

Appetitive determinants of self-stimulation

Previous reports have pointed to a biologically meaningful relationship between brain-stimulated reward and appetitive motivation such as feeding. The present experiments further examined this relationship in chronically self-stimulating Sprague-Dawley rats. In Expt 1 restriction of ad libitum food produced a subsequent increase in self-stimulation in the substantia nigra. In Expt 2 restriction of ad libitum self-stimulation, from the same sites, produced a subsequent gain in body weight. In Expt 3 restriction of ad libitum self-stimulation produced subsequent increases in responding for stimulation. Soon after the initial discovery of self-stimulation of the brain (ICS; Olds and Milner, 1954) the results of several experiments suggested that the same central nervous system (CNS) circuits subserving electrically elicited reward might also be involved in biological reinforcement. Brady and co-workers (1957) noted increases in self-stimulation rates subsequent to food and water deprivation in rats and cats. This finding was independently confirmed by both Olds (1958) and Hodos and Valenstein (1960). The possible interrelationships between feeding and self-stimulation have since been extensively investigated. Hoebel and Teitelbaum (1962), Margules and Olds (1962), and Wilkinson and Peele (1962) simultaneously reported a behavioral and anatomical identity for hypothalamic feeding and self-stimulation loci: Other CNS sites involved with taste, oral sensation, and ingestive behavior may also support self-stimulation (Micco, 1974; Ritter and Stein, 1973; Van Der Kooy and Phillips, 1977). Finally, the concurrent availability of reinforcing tastes may alter ongoing selfstimulation performance (Hoebel, 1971; Poschel, 1968). These and other related studies have been summarized in a number of recent reviews (Hoebel, 1969, 1974; Mogenson and Phillips, 1976). a The authors gratefully acknowledge support provided by the National Institute of Mental Health (Postdoctoral Grant MH07417 to the first author). The editorial assistance of Esther Washington is also acknowledged with gratitutde. This report is dedicated to the memory of Dr. J. Olds. 5OO

Behavioral responses to linear accelerations in blind goldfish. I - The gravity reference response

Blind goldfish were subjected to linear accelerations on a motor car and on a parallel swing. Moyements of the fish in a tank during the accelerations were recorded with a movie camera. During the horizontal acceleration, the fish aligns his longitudinal axis in a plane perpendicular to the direction of an apparent gravity with the fishs back pointing away from the direction of this apparent gravity vector. This is similar to the manner in which the fish usually aligns himself horizontally in response to the vertically downward terrestrial gravity and can therefore be termed ‘gravity reference response’. It is concluded that blind goldfish cannot distinguish between otolith displacements caused by passive tilts and equivalent otolith displacements caused by moderate inertial forces during rectilinear acceleration. With a horizontal jerk of higher magnitude, two additional responses can occur: horizontal 180° turns following tailward jerks and straight forward darting following noseward jerks.

Effects of Nomifensine (HOE 984) Upon Psychomotor Activity and Intracranial Self-Stimulation in the Rat

The effects of nomifensine maleate (HOE 984) were evaluated using two behavioral tasks. The drug produced dose related increases in both psychomotor activity and operant responding for brain stimulation reward. These results may point to possible psychostimulant properties for the drug.

Effects of meprobamate, chlordiazepoxide, diazepam, and sodium pentobarbital on visually evoked responses in the tectotegmental area of the rat.

The effects of meprobamate, chlordiazepoxide, diazepam and sodium pentobarbital on sensory input to the boundary area between the dorsal midbrain tegmentum and ventral tectum of the rat have been investigated in order to find out whether effects obtained with these compounds in the hypothalamus can also be observed at the mesencephalic level. The following results have been obtained. (1) At a dose of 2·5 mg/kg i.p., chlordiazepoxide had no effect; at 5, 10, 15, and 20 mg/kg, this compound decreased the amplitude of the initial components of the visually evoked responses in the rat. There was an increased effect at higher doses. (2) Diazepam had effects similar to those produced by administration of chlordiazepoxide. The evoked responses were of smaller amplitude after injection of 5, 10, and 20 mg/kg i.p. At the highest dose, diazepam caused larger reductions in amplitude than chlordiazepoxide at 20 mg/kg. (3) Meprobamate at 40, 80 and 100 mg/kg i.p. increased the amplitude of the evoked responses. There was more individual variation with this compound than with chlordiazepoxide, and more waxing and waning of the effects, but little difference in the magnitude of facilitation at the various doses. At a dose of 120 mg/kg, the size of the evoked responses decreased. (4) At doses of 5, 10, and 20 mg/kg i.p., sodium pentobarbital caused increases in the amplitude of the evoked responses. Only at a dose of 20 mg/kg was there a slight decrease in amplitude, lasting only 25 min after drug administration. Thereafter, responses to this dose were larger than control responses, but not as large as responses to the two smaller doses. The significance of these results is discussed in the context of earlier data on the effects of these compounds and the barbiturates on sensory input to the midbrain reticular formation. A difference in mode of action, at low doses, is shown by the data. A relationship between the effects of meprobamate and the barbiturates on sensory input in the rat finds support in these results.

[D-Ala2,(F5)Phe4]-dynorphin1-13-NH2 (DAFPHEDYN): A potent analog of dynorphin 1-13

Intracerebroventricular administration of the dynorphin analog, [D-Ala2,(F5)Phe4]-dynorphin 1-13-NH2 (DAFPHEDYN) in rats produced diuresis and profound analgesia. Both effects were antagonized by central administration of naltrexone or naloxone. Intravenous administration of 10, 25, and 50 mg/kg of DAFPHEDYN failed to induce diuresis. The increased potency of DAFPHEDYN was apparent from the failure of an equal dose of the parent compound (dynorphin 1-13) to produce diuresis and the failure of [D-Ala2]-dynorphin 1-13-NH2 to produce analgesia. Radioligand binding studies indicated the DAFPHEDYN retains the same degree of kappa selectivity as the parent compound (dynorphin 1-13) though a drop in affinity occurred. DAFPHEDYN may be of significant interest because it retains the essential pharmacology of the parent compound and exhibits marked in vivo potency.

Serotonergic Mediation of Reward Within the Medial Raphe Nucleus: Some Persistent Problems in Interpretation

Adult male Sprague Dawley rats were implanted with unipolar stimulating electrodes aimed at the medial forebrain bundle (MFB) or the medial raphe nucleus (MR). All MFB implanted subjects self-stimulated at high stable rates for at least three weeks. Only a minority (1/3) of MR rats self-stimulated at all. Rates for the MR group were considerably more variable, and could not be maintained for more than two weeks. Treatment with methysergide increased MFB self-stimulation but decreased MR self-stimulation. While this result suggests serotonergic mediation of self-stimulation this conclusion must be interpreted cautiously since parachlorophenylalanine (PCPA) reinstated self-stimulation in raphe animals which had spontaneously ceased responding.