Table 3.

Dopamine depletion hypothesis and similar studies suggesting endorphin deficiency.

Reference	Topic	Comment
[55]	A rationale for opiate withdrawal symptomatology	Withdrawal of opiates removes this “tonic” inhibition of the locus coeruleus (LC) and could readily result in a piperoxane-like release from inhibition.
[56]	Endorphin locus coeruleus connection mediates opiate action and withdrawal	This hypothesis suggests that chronic opiate administration inhibits LC activity and that opiate abstinence after addiction results in a release from inhibition with resultant LC hyperactivity.
[57]	Endorphins, lithium, and Naloxone: their relationship to pathological and drug-induced manic-euphoric states	Opioid peptides play a role in drug-induced manic –euphoric stares
[58]	Decreased serum prolactin in opiate withdrawal and dopaminergic hyperactivity is investigated	Dopaminergic hyperactivity is present in opiate withdrawal but may not be related to the signs and symptoms of withdrawal; the culprit is norepinephrine; however, dopamine reduces symptoms.
[59]	New concepts in cocaine addiction: the dopamine depletion hypothesis due to hypodopaminergia	Cocaine addiction was a dopamine derangement depletion disease. DA depletion is hypothesized to result from the overstimulation of these neurons and excessive synaptic metabolism of the neurotransmitter. Cocaine was addicting on this basis, and cocaine withdrawal looks like retarded-psychomotor depression.
[60]	Bromocriptine treatment for cocaine abuse: the dopamine (DA) depletion hypothesis	Bromocriptine, a DA/antagonist, appears to have efficacy with acute and maintenance trials and may represent a test of the cocaine-dopamine hypothesis and new adjunctive treatment for cocaine abuse.
[61]	Anti-endorphin effects of methadone.	Depression is common and may be induced by methadone. Post-detoxification depression and other affective symptoms may be due to hypodopaminergia and contribute to relapse.
[62]	A possible opioid receptor dysfunction in some depressive disorders	In some depressive symptoms, the etiology may reside in the dysfunction of the opioid peptide system
[63]	Clonidine used in detoxification from opiates	Clonidine hydrochloride in detoxification from opiates has demonstrated that a non-opioid medication can rapidly suppress the symptoms associated with opiate withdrawal. The alpha-2 adrenergic and endorphinergic systems are parallel inhibitors of the nucleus locus coeruleus.
[64]	Identification of a subregion within rat neostriatum for the dopaminergic modulation of lateral hypothalamic self-stimulation	Dopaminergic transmission in Ventral Anterior Striatum (VAS), alone among the striatal sites tested, is facilitatory on hypothalamic self-stimulation.
[65]	Platelet serotonin transporter in cocaine patients	Chronic cocaine inhibits serotonin transporter increasing synaptic serotonin. This increase has been documented through optogenetics to inhibit GABAergic firing increasing DA signaling
[66]	Naltrexone augments the effects of nicotine replacement therapy (NRT) in female smokers	Naltrexone, causes extinction blocks D2 receptors, and combined with NRT and psychosocial therapy, appears to have a positive cessation effect for women and is a potential new treatment for recidivist female nicotine smokers.
[67]	Diagnosis of alcohol dependence and family history prevalence in cocaine dependence	The study finds a high prevalence of alcohol (68% and 89%) and cannabis dependence (53% and 46%) in patients with cocaine dependence. These various dependencies support the RDS concept.
[68]	Dopaminergic activation in the reward circuitry regulates food and drug craving behavior	The dopaminergic, enkephalinergic, and fos gene expressions are important regulatory genetic pathways for both food and drug craving behaviors as proposed in RDS
[69]	Dysfunctional connectivity patterns in chronic heroin users: an fMRI study	This dysfunctional brain connectivity may contribute to decreasing self-control, impaired inhibitory function as well as deficits in stress regulation in chronic heroin users.
[70]	Gray matter deficits and resting-state abnormalities in abstinent heroin-dependent individuals was studied	Chronic heroin dependence impairs the right Dorsolateral Prefrontal Cortex (DLPFC) in heroin-dependent individuals, including structural deficits and resting-state functional impairments.
[71]	Buprenorphine effect on fentanyl withdrawal in rats	Buprenorphine prevents affective and somatic fentanyl withdrawal signs. Moreover, buprenorphine is rewarding in rats previously exposed to fentanyl, but not in opioid-naïve rats.
[72]	The Salted Food Addiction Hypothesis may explain the overeating and obesity epidemic	Salt may increase reinforcement produced by fat-rich and other foods. This combination may be an addictive substance that can stimulate opiate and dopamine receptors in the brain's reward and pleasure center. This effect may explain the salted food preference, urge, craving, and hunger manifestations of opiate withdrawal.
[73]	Distinct resting-state brain activities in heroin-dependent individuals	BOLD activation pattern differences of heroin-dependent and healthy subjects included the orbitofrontal cortex (OFC), cingulate gyrus, frontal and paralimbic regions, anterior cingulate cortex (ACC), hippocampal/parahippocampal region, amygdala, caudate, putamen, & posterior insula and thalamus
[74]	Body mass index and alcohol use	Obese patients have lower alcohol use rates than found in the general population of women. As BMI increases, rates of alcohol consumption are lower. Overeating may compete with alcohol for brain reward sites, making alcohol ingestion less reinforcing.
[75]	Mice with a deficiency of the G protein Go have multiple neurological abnormalities	The G protein Go is highly expressed in neurons and mediates effects of a group of rhodopsin-like receptors that includes the opioid, alpha2-adrenergic, M2 muscarinic, and somatostatin receptors. Go plays a central role in motor control, motor behavior, pain perception and is involved in Ca2+ channel regulation
[76]	Neuro-chemical activation of brain reward mesolimbic circuitry is associated with relapse prevention and drug hunger: a hypothesis	Proposing a paradigm shift in residential, non-residential, and aftercare involving the incorporation of genetic testing to identify risk alleles coupled with D2 receptor stimulation using neuroadaptogen amino acid precursor enkephalinase–catecholamine-methyltransferase (COMT) inhibition therapy. A natural but therapeutic nutraceutical formulation potentially induces DA release and cause the induction of D2-directed mRNA and proliferation of D2 receptors in the human.
[77]	The relationship between obesity and drug use	Obesity may inhibit drug reinforcement. Neurotransmitter release in the nucleus accumbens is linked to self-administration and learning following drug use. Food intake or sex activates this endogenous reward system. Therefore, hyperphagia following abstinence may be a rebound mechanism to replenish neurotransmitter release in this reward system, which leads to weight gain and a rise in body BMI during recovery from substance abuse.
[78]	Na(+) channel blockers for the treatment of pain: context is everything, almost	Voltage-gated Na + channels (VGSCs) remain viable targets for the development of novel analgesics
[79]	Addiction conceptualized from an Osteopathic Perspective: Dopamine Homeostasis	The basis of much of osteopathic philosophy is the idea of total body allostasis and homeostasis. The achievement of dopamine homeostasis as part of a comprehensive biopsychosocial treatment strategy in the effective management of addiction is discussed in this article.
[80]	The Food and Drug Addiction Epidemic: Targeting Dopamine Homeostasis.	Strategies indicated by this understanding of nutriepigenomics and neurogenetics in the treatment and prevention of metabolic syndrome and obesity include the moderation of mRNA expression by DNA methylation and inhibition of histone deacetylation.
[81]	Microglial activation in the brains of human users of Methamphetamine was investigated.	Midbrain, striatum, thalamus, orbitofrontal and insular cortices binding levels correlated inversely with the methamphetamine abstinence duration (p < 0.05). These results suggest that reactive microgliosis can result from chronic self-administration of methamphetamine, but the level of activation appears to subside over longer periods of abstinence.
[82]	Methamphetamine (METH)- and trauma-induced brain injuries (TBI): comparative cellular and molecular neurobiological substrates	Functional changes in the brain from METH use disorder (MUD) result in changes similar to those in TBI. A greater benefit to those with MUD might result from rehabilitation and treatment with neuroprotective pharmacological agents such as calpain and caspase inhibitors, used to treat TBI.
[83]	Depression in Opiate Addicts	The authors note that methadone programs have a high prevalence of depression and concurrent treatment for depression. They gave the dexamethasone suppression test (DST) to 42 opiate addicts two weeks after detoxification. The DST provided a sensitivity of 80%, and a specificity of 93% for Major Depression diagnosed according to the Research Diagnostic Criteria.
[84]	Methadone-induced endorphin dysfunction in MUD.	Similar to alcohol as reported by Blum et al. methadone induces an apparent endorphin dysfunction in polydrug abusers