Franco J. Vaccarino

Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat

A quaternary derivative of naloxone, methyl naloxonium chloride (MN), was administered intracerebrally to rats trained to self-administer heroin intravenously. Increases in intravenous (IV) heroin self-administration rates were found following injections of low doses of MN into the nucleus accumbens (N.Acc), but not following injections of low doses of MN into the ventral tegmental area (VTA). These results were interpreted to suggest that the rewarding properties of IV heroin were decreased following N.Acc opiate receptor blockade. The relative insensitivity of the VTA to MN treatment was taken to suggest that VTA opiate receptors are either not essential or play a secondary role in mediating IV heroin self-administration. The present data support the notion that post-synaptic N.Acc opiate receptors play a crucial role in maintaining IV heroin self-administration.

A Review of Functional Neuroimaging in Mood Disorders: Positron Emission Tomography and Depression

Objective: To examine the progress of positron emission tomography (PET) as a tool for understanding the psychobiology of mood disorders, particularly major depression and bipolar disorder. Method: Review of the literature on functional imaging of mood disorders. Results: Functional imaging techniques have been used in psychiatric research as a noninvasive method to study the behaviour and function of the brain. Techniques used so far have involved the manipulation of emotion in healthy volunteers, the evaluation of depressed (unipolar and bipolar as well as secondary depression), manic, and normal subjects under resting and various activation conditions, such as cognitive activation, acute pharmacological challenge, and chronic thymoleptic treatments. As a result, functional imaging studies tend to support abnormalities in specific frontal and limbic regions. Conclusion: Different PET methods demonstrate consistent abnormalities in the prefrontal, cingulate, and amygdala regions. These findings are in agreement with past animal and clinical anatomical correlates of mood and emotions.

Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans : A comparison of two time points

BACKGROUND Several functional imaging studies have demonstrated increases of brain activity in the temporofrontal, cingulate, and claustrum regions during a pharmacologically induced panic attack when scanning was done at a single point in time. However, no study has evaluated changes in brain activity at two time points during a panic attack. We hypothesized that in response to a single bolus injection of the panicogen cholecystokinin-4 (CCK-4) in healthy volunteers, changes in regional cerebral blood flow (rCBF) might be different if scanning were done at two different time points. METHODS To test this hypothesis, we conducted a single-blind study, using positron emission tomography (PET). To determine the time effect of panic attack on brain activity, we performed either early scan or late scan covering the first or the second minute after CCK-4 bolus injection, respectively. The PET images were analyzed by statistical parametric mapping (SPM) followed by region of interest (ROI) analysis. RESULTS The results showed significant differences between the early and the late scan. The early effects of CCK-4 are accompanied by increases in rCBF in the hypothalamic region, whereas the late scan showed an increase in rCBF in the claustrum-insular region. Reductions in rCBF were observed for both time groups in the medial frontal region. A separate scan for anticipatory anxiety demonstrated rCBF increases in the anterior cingulate region and decreases in the occipital regions. CONCLUSIONS These results may support the hypothesis that changes in rCBF as a function of time during CCK-4-induced panic might correspond to a neurocircuitry involved in panic attacks.

Amphetamine- and morphine-induced feeding: Evidence for involvement of reward mechanisms

The present study examined the possibility that the increased feeding found following central and peripheral administrations of low doses of d-amphetamine (AMP) and morphine (MOR) may involve central reward mechanisms. In order to examine this possibility, the effects of these drugs on food selection and intake of foods that varied in palatability and nutritive content were determined. In addition, the importance of the nucleus accumbens (ACB), a critical structure for AMP and MOR reward, in these effects was determined. Results indicated that MOR increased the intake of preferred food regardless of nutritive content. In contrast, AMP was most effective at increasing the intake of preferred foods which contained carbohydrates. These effects were observed following systematic or intra-ACB administration of low doses of MOR and AMP. Together these findings implicate reward mechanisms in the expression of MOR- and AMP-induced feeding. It is further suggested that the feeding effects of MOR and AMP can be differentiated in paradigms where animals have a choice of several foods which may vary in palatability and/or nutritive content. The relevance of the present findings for our understanding of which elements of food and feeding behavior are coupled with ACB reward signals is also discussed.

Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling.

Glucagon-like peptide-1 (GLP-1), a potent regulator of glucose homeostasis, is also produced in the central nervous system, where GLP-1 has been implicated in the neuroendocrine control of hypothalamic-pituitary function, food intake, and the response to stress. The finding that intracerebroventricular GLP-1 stimulates LH, TSH, corticosterone, and vasopressin secretion in rats prompted us to assess the neuroendocrine consequences of disrupting GLP-1 signaling in mice in vivo. Male GLP-1 receptor knockout (GLP-1R−/−) mice exhibit reduced gonadal weights, and females exhibit a slight delay in the onset of puberty; however, male and female GLP-1R−/− animals reproduce successfully and respond appropriately to fluid restriction. Although adrenal weights are reduced in GLP-1R−/− mice, hypothalamic CRH gene expression and circulating levels of corticosterone, thyroid hormone, testosterone, estradiol, and progesterone are normal in the absence of GLP-1R−/− signaling. Intriguingly, GLP-1R−/− mice exhibit paradoxic...

Blockade of amphetamine but not opiate-induced locomotion following antagonism of dopamine function in the rat

The effects of pharmacological blockade of dopamine (DA) receptors or 6-OHDA lesions of mesolimbic DA fibers on the locomotor-activating properties of systemic amphetamine (0.35 mg/kg) and heroin (0.5 mg/kg) were examined. Pharmacological blockade of DA receptors or lesions of mesolimbic DA neurons blocked amphetamine but not heroin-induced locomotion. These results show that the opiate receptors essential for opiate-induced locomotor activation are not located on mesolimbic DA neurons. It appears that DA plays a primary role in stimulant-induced locomotion, but may have only a secondary role in opiate locomotion.

Nucleus accumbens dopamine-CCK interactions in psychostimulant reward and related behaviors

The present paper provides an overview of dopamine (DA) and cholecystokinin (CCK) mechanisms that contribute to psychostimulant reward-related behaviors. Three different behavioral paradigms are focused on: intravenous psychostimulant reward, psychostimulant-induced locomotor activity, and psychostimulant-induced feeding. Based on evidence derived from these different behavioral paradigms, this paper reviews data indicating that nucleus accumbens CCK and DA play an important role in mediating reward. Neurobiological mechanisms are proposed to explain the functional relationship between CCK and DA in the nucleus accumbens.

Microinjections of nanogram amounts of sulfated cholecystokinin octapeptide into the rat nucleus accumbens attenuates brain stimulation reward.

Microinjections of nanogram amounts of sulfated cholecystokinin octapeptide (CCK-8S) into the nucleus accumbens were examined for effects on intracranial self-stimulation (ICSS) derived from the ventral tegmental area (VTA). The results showed that CCK-8S dose-dependently antagonized VTA intracranial self-stimulation (ICSS) without affecting maximum response rates. CCK-8S also increased the current threshold required for ICSS. These findings were interpreted to suggest that CCK-8S attenuates brain stimulation reward derived from the VTA.

Intra-nucleus accumbens amphetamine: Dose-dependent effects on food intake

The effects of microinjections into the nucleus accumbens (N.ACC.) of 0.0, 2.0 or 8.0 micrograms of (+)-amphetamine sulphate (AMPH) on food intake and running wheel activity were examined. The 2.0 micrograms dose of AMPH produced increased food intake while 8.0 micrograms significantly decreased food intake. No effect was found on running wheel activity with the 2.0 micrograms dose, though 8.0 micrograms significantly increased the number of wheel revolutions with respect to the saline group. Results were interpreted to suggest that the N.ACC. may be an important site in the mediation of the increased food intake noted with low doses of psychomotor stimulants.

Antagonist treatment in nucleus accumbers or periaqueductal grey affects heroin self-administration

The role of opiate receptors in the periaqueductal grey and nucleus accumbens in maintenance of intravenous heroin self-administration was examined by means of intracranial microinjections of the quaternary opiate antagonist methyl naltrexone. Over a dose range of 0-3.0 micrograms, pre-session infusions of methyl naltrexone in either brain site produced dose-related increases in responding for heroin (0.06 mg/kg/infusion) on a CRF schedule, without causing significant changes in responding on a second activity control lever. Involvement of the periaqueductal grey was also examined in animals administering a lower heroin dose (0.03 mg/kg/infusion) in shorter sessions in order to minimize drug exposure prior to treatment. In this experiment, infusion of methyl naltrexone produced selective increases in responding for heroin, whereas treatment with the identical dose of methyl naltrexone had no effect on cocaine self-administration (1.0 mg/kg/infusion) in the same animals. With respect to the nucleus accumbens, these data confirm its involvement in opiate self-administration. Data for the periaqueductal grey provide the first evidence that opiate receptors in the vicinity of this brain region may play a role in intravenous opiate self-administration.